First-line FOLFOXIRI In Combination With Bevacizumab For Metastatic Colorectal Cancer

Inclusion Criteria:

* Histologically confirmed colorectal adenocarcinoma
* Unresectable and measurable metastatic disease (RECIST criteria)
* Male or female, aged \> 18 years and ≤ 75 years
* ECOG Performance Status (PS) \< 2 if aged \< 71 years
* ECOG PS = 0 if aged 71-75 years
* Life expectancy of more than 3 months
* Adequate haematological function: ANC ≥ 1.5 x 109/L; platelets ≥ 100 x 109/L, Hb ≥ 9 g/dL
* INR ≤ 1.5 and aPTT ≤ 1.5 x ULN within 7 days prior to starting study treatment
* Adequate liver function: serum bilirubin ≤ 1.5 x ULN; alkaline phosphatase and transaminases ≤ 2.5 x ULN (in case of liver metastases \< 5 x ULN)
* Serum Creatinine ≤ 1.5 x ULN
* Urine dipstick for proteinuria \< 2+. If urine dipstick is ≥ 2+, 24- hour urine must demonstrate ≤ 1 g of protein in 24 hours
* Previous adjuvant chemotherapy is allowed if more than 12 months have elapsed between the end of adjuvant therapy and first relapse
* At least 6 weeks from prior radiotherapy and 4 weeks from surgery

Exclusion Criteria:

* Prior palliative chemotherapy
* Prior treatment with bevacizumab
* Bowel obstruction (or subobstruction)
* History of inflammatory enteropathy or extensive intestinal resection (\> hemicolectomy or extensive small intestine resection with chronic diarrhea)
* Symptomatic peripheral neuropathy \> 2 grade NCIC-CTG criteria
* Presence or history of CNS metastasis
* Active uncontrolled infections
* Active disseminated intravascular coagulation
* Major surgical procedure, open biopsy or significant traumatic injury within 28 days prior to treatment, or anticipation of the need for major surgery during the course of the study
* Central Venous Access Device (CVAD) for chemotherapy administration inserted within 2 days prior to study treatment start
* Past or current history of malignancies other than colorectal carcinoma, except for curatively treated basal and squamous cell carcinoma of the skin cancer or in situ carcinoma of the cervix
* Clinically significant cardiovascular disease, for example cerebrovascular accidents (CVA) (≤ 6 months before treatment start), myocardial infarction (≤ 6 months before treatment start), unstable angina, NYHA ≥ grade 2 chronic heart failure (CHF), uncontrolled arrhythmia
* Uncontrolled hypertension
* 24-hour urine protein \> 1 g if dipstick \> 2+
* History of thromboembolic or hemorrhagic events within 6 months prior to treatment
* Evidence of bleeding diathesis or coagulopathy
* Serious, non healing wound/ulcer or serious bone fracture
* No therapeutic anticoagulation or antiplatelet agents or NSAID with anti-platelet activity (aspirin ≤ 325 mg/day allowed)
* Pregnancy or lactation
* Fertile women (\< 2 years after last menstruation) and men of childbearing potential not willing to use effective means of contraception