Sequential Treatment Strategy for Metastatic Colorectal Cancer

Inclusion Criteria: 1. Histologically or cytologically confirmed untreated metastatic or locally advanced, non resectable CRC; previous adjuvant chemotherapy for CRC or neoadjuvant/adjuvant chemoradiotherapy for rectal cancer is permitted but must have been completed at least 6 months prior to enrolment; 2. Resected CRC patients who have developed metastases do not require separate histological or cytological confirmation unless \> 5 yrs have elapsed between primary surgery or primary tumor stage I; 3. Evaluation of Kras status from the primary tumor or metastases 4. Measurable disease according to Response Evaluation Criteria in Solid Tumors (RECIST criteria) 5. Age ≥ 18 years and \< 70 years with Performance Status (ECOG) ≤ 2 or age \> 70 years with ECOG ≤ 1; 6. Estimated life expectancy of at least 12 weeks; 7. Adequate hematological, hepatic and renal function, as follows: hemoglobin ≥ 9 g/dl,absolute neutrophil count ≥1,500/μL, platelets ≥100,000/μL, total bilirubin ≤1.5 x upper limit of normal (ULN),alkaline phosphatase, aspartate aminotransferase (AST(SGOT)) and alanine aminotransferase (ALT(SGPT)) ≤ 2.5 x ULN (≤ 5 x ULN if liver metastases present), serum creatinine ≤ 1.5 x ULN or calculated creatinine clearance \>50 mL/min (calculated on the basis of Standard Cockcroft and Gault Formula, urinary excretion (if protein \> 30 mg/dL or +1, patients must have ≤ 1 g of protein/24 hours) 8. Either international normalized ratio (INR) or activated partial thromboplastin time (APTT) \< 1.5 x ULN and D-dimer within normal range (if abnormal, thromboembolic events must be excluded); 9. Negative pregnancy test no more than 7 days before randomization; test pregnancy can be omitted only in women without any reproductive potential (e.g.: postmenopausal women, i.e. amenorrhoea ≥2 years or with previous hysterectomy or bilateral ovariectomy). Women of child-bearing potential and men must agree to use adequate contraception at the time of randomization and for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while participating in this study, she must inform her treating physician and coordinating centre (CC) immediately; women in lactation period must be excluded; 10. Ability to understand and the willingness to sign a written informed consent document. Exclusion Criteria: 1. Prior treatment with cetuximab, bevacizumab or other anti Epidermal Growth Factor Receptor (antiEGFR) or anti-angiogenesis agents; 2. Prior chemotherapy or immunotherapy for metastatic or advanced disease; 3. Participation in another clinical trial with any investigational agents ≤ 30 days prior to study randomization; 4. Contraindications or hypersensitivity to study drugs; 5. Treatment with other concomitant antineoplastic drugs; 6. Other known malignant neoplastic diseases in the patient's medical history with a disease-free interval of less than 5 years (except for previously treated basal cell carcinoma and in situ carcinoma of the uterine cervix); 7. Symptomatic brain or central nervous system metastases or clinically relevant central nervous diseases (for example: primary brain tumor, uncontrolled convulsions with medical therapy, carcinomatous meningitis); 8. Grade \> 1 peripheral neuropathy (as defined by the National Cancer Institute - Common Toxicity Criteria for Adverse Effects (NCI CTCAE) v3.0); 9. Clinically significant (i.e. active) cardiovascular disease e.g. cerebrovascular accidents ≤ 6 months prior to randomization), myocardial infarction (≤ 1 year prior to randomization), uncontrolled hypertension whilst receiving chronic medication, unstable angina, New York Heart Association (NYHA) grade II or more congestive heart failure,or serious cardiac arrhythmia requiring medication; 10. Malabsorption syndrome or lack of physical integrity of the gastrointestinal tract. Diverticulitis. Patients with colostomy or ileostomy may enter at the investigator's discretion. History of trachea-oesophageal fistula or any other type of fistula (e.g. abdominal), gastrointestinal perforation, intra-abdominal abscess; 11. Interstitial pneumonia or extensive symptomatic fibrosis of the lungs; 12. Serious, non-healing wound, ulcer, or bone fracture; significant traumatic injury in the 4 weeks prior to enrolment (complete recover must have occurred); 13. Major surgery (e.g. laparotomy) in the 4 weeks prior to study randomization; 14. Minor surgery in the 2 weeks prior to study randomization. Insertion of a central vascular access device for chemotherapy infusion must be done at least 2 days prior to the start of treatment. Patients will be randomized only if they have recovered from all surgery related toxicities; 15. Bleeding diathesis or coagulopathy; 16. Pulmonary embolism or any arterial thromboembolism; 17. Deep vein thrombosis or other significant thromboembolic event; 18. Clinically significant peripheral vascular disease; 19. Previous organ transplantation that requires immunosuppressive therapy; 20. Need for chronic oral steroid use ( ≥10 mg/day of methylprednisolone or equivalent) for the treatment of a nonmalignant condition other than intermittent prophylactic use as an antiemetic and inhaled steroid use; 21. Chronic use of aspirin (\> 325 mg/day) or other non steroidal anti-inflammatory agents (those known to inhibit platelet function at doses used to treat chronic inflammatory diseases); 22. In treatment with antiplatelets agents (i.e clopidogrel \> 75 mg/day, ticlopidine,dipyridamole); 23. Undergoing treatment with sorivudine or its chemically-related analogues (such as brivudine); 24. Full-dose oral or parenteral anticoagulants or thrombolytic treatment for therapeutic purposes ≤10 days prior to study randomization; 25. Geographic inaccessibility; 26. Any radiation therapy completed ≤ 4 weeks prior to study randomization. If the radiated lesion/s is/are the only site of disease, and if it/they show progression after the radiotherapeutic procedure, the patient will become eligible for the study; 27. Previous embolization or thermoablation of metastases ≤ 30 days prior to study randomization. If these lesions are the only site of disease, and if they show progression after the embolization or thermoablation procedure, the patient will become eligible for the study; 28. Laboratory abnormality or medical or psychiatric disorders that would interfere with informed consent or compliance, or which could indicate a contraindication to patient enrolment into the study (also known dihydropyrimidine dehydrogenase deficit); 29. HIV-positivity, whether or not symptomatic.