
    inclusion rythm too slow.
  
['colorectal neoplasms']
['5 fluorouracyl', 'acide folinique', 'irinotecan', 'oxaliplatin', 'capécitabine', 'bevacizumab']

        Inclusion Criteria:

          -  Metastatic colorectal cancer, histologically proven (on primary tumour and/or
             metastases)

          -  Unresectable and non-pretreated metastases

          -  BRAF wild-type

          -  Patient considered able to receive 3 lines of chemotherapy

          -  At least one measurable target lesion > 1 cm according to RECIST 1.1 (Appendix 4)

          -  Tumour assessment according to RECIST, performed 4 weeks or less prior to
             randomization

          -  Age ≥ 18 years

          -  WHO performance status ≤ 2 (Appendix 5)

          -  No major surgery within 4 weeks prior to randomisation. Wound healing must be complete

          -  Life expectancy greater than 3 months

          -  Laboratory tests: Neutrophils ≥ 1500/mm3, platelets ≥ 100,000/mm3, haemoglobin > 9
             g/dL

          -  Creatinine clearance > 30 mL /min (capecitabine dose modification if the creatinine
             clearance < 30-50 mL/min), serum creatinine < 1.25 x ULN

          -  Liver function tests: bilirubin < 1.25 x ULN, AST/ALT < 5 x ULN

          -  Women of childbearing age and men (who have sexual relations with women of
             childbearing age) must agree to use effective contraception without interruption
             throughout the duration of treatment and for 6 months after the last administration

          -  Signed informed consent

        Exclusion Criteria:

          -  Patient with a potentially resectable colorectal cancer; i.e. for whom the goal of
             chemotherapy would be to make all metastases resectable

          -  Patients with symptomatic metastases

          -  Patient with aggressive disease and a large tumour volume

          -  Active gastroduodenal ulcer, wound or bone fracture

          -  At least one of the following laboratory values: Neutrophils <1500/mm3, platelets <
             100,000/mm3, haemoglobin < 9 g/dL, total bilirubin > 1.5 N, alkaline phosphatase > 2.5
             N (or > 5 N in case of hepatic involvement), serum creatinine > 1.5 N, 24 hr
             proteinuria > 1 g

          -  Chronic inflammatory bowel disease, extensive resection of the small bowel

          -  Clinically significant coronary artery disease or a history of myocardial infraction
             within the last 6 months. Uncontrolled hypertension while receiving chronic medication

          -  Abdominal or major extra-abdominal surgical procedure (except diagnostic biopsy) or
             radiation within 4 weeks before starting treatment

          -  Previous treatment with an anti-angiogenic or irinotecan

          -  Known or suspected central nervous system metastasis CNS metastases, or suspected CNS
             metastases

          -  Other previous malignancies within 5 years, except for basal cell carcinoma of the
             skin or pre-invasive carcinoma of the cervix - Peritoneal macro-nodular carcinomatosis

          -  History of haemoptysis ≥ grade 2 (defined as ≥ 2.5 mL of bright red blood per episode)
             in the month prior to inclusion

          -  Known hypersensitivity to any component of bevacizumab or to one of the study
             treatments

          -  Active infection requiring intravenous antibiotics at start of treatment

          -  History of abdominal fistula, gastrointestinal perforation, intra-abdominal abscess or
             active gastrointestinal bleeding within 6 months prior to treatment start

          -  Pregnant or breastfeeding women

          -  Concomitant participation in another clinical study involving a drug during the
             treatment phase and 30 days before starting the study treatment

          -  Patient unable to undergo medical treatment for geographical, social, psychological or
             legal reasons.
      