This study is to verify the advantage of FOLFOXIRI plus cetuximab over FOLFOXIRI plus bevacizumab as the first-line therapy in metastatic colorectal cancer patients with RAS wild-type tumors.

This study is to verify the advantage of FOLFOXIRI plus cetuximab over FOLFOXIRI plus bevacizumab as the first-line therapy in metastatic colorectal cancer patients with RAS wild-type tumors. In this study the investigators employed deepness of response as a primary endpoint.

Inclusion Criteria:

• Histologically confirmed colorectal cancer

• RAS wild-type

• Measurable lesion by RECIST (Ver.1.1)

• No past history of chemotherapy in the case of unresectable primary lesion/distant metastasis/lymph node metastasis.In the case of recurrence, no treatment for the first recurrence lesion after operation

• Eastern Cooperative Oncology Group (ECOG) Performance status 0-1.The case >=71 years is PS0.

• Life expectancy of more than 6 months

• Patients have enough organ function for study treatment within 14 days before enrollment;

  1. White blood cell (WBC)>=3,000/mm3, <12,000/mm3.
  2. Neu>=1,500/mm3.
  3. Platelet count (PLT) >=10.0x104/mm3.
  4. Hb>=9.0g/dL.
  5. Total Bilirubin<=1.5x Upper Limited Normal (ULN)
  6. aspartate aminotransferase (AST) <=2.5xULN.
  7. alanine aminotransferase (ALT) <=2.5xULN.
  8. Creatinine<=1.5xULN.
  9. Proteinuria<=1+.
  10. prothrombin time-international normalized ratio (PT-INR) <=1.5

• Must be able to swallow tablets

• Written informed consent

Exclusion Criteria:

• Synchronous multiple malignancy or metachronous multiple malignancy within 5 years disease free interval
• Lynch syndrome
• Brain metastases
• Infectious disease
• Interstitial lung disease or pulmonary fibrosis
• Comorbidity or history of serious heart failure
• History of thromboembolic events
• Cerebrovascular disease
• History of hemoptysis/hematemesis
• Uncontrolled hypertension (systolic BP>180mmHg, or diastolic BP>100mmHg)
• Sensory alteration or paresthesia interfering with function
• Large quantity of pleural, abdominal or cardiac effusion
• Severe comorbidity (renal failure, liver failure, hypertension, etc)
• Prior radiotherapy for primary and metastases leision
• Men/women who are unwilling to avoid pregnancy
• Women who are pregnant or breastfeeding
• Women with a positive pregnancy test
• History of severe allergy
• HBsAg positive or active viral hepatitis
• Administration of blood products/ Granulocyte-Colony Stimulating Factor (G-CSF), and blood transfusion within 14 days
• Surgical procedure or such as skin-open biopsy, trauma surgery, or other more intensive surgery within 28 days
• Systematic administration of antiplatelet drug or non steroid anti-inflammatory drugs (NSAIDs)
• Diathesis of bleeding (history of hemoptysis, including cavitation and/or necrosis in lung metastasis confirmed by imaging), coagulopathy
• History of gastrointestinal perforation within 1 year
• Unhealed traumatic bone fracture
• Uncontrolled diarrhea
• History of organ recipient
• Prior cetuximab/bevacizumab/Irinotecan/Oxaliplatin treatment (Adjuvant therapy by Oxaliplatin is excluded)
• Administration of atazanavir sulfate
• Jaundice
• Ileus or bowel obstruction
• Clinical diagnosis of Alzheimer's Disease
• Insulin dependent diabetes
• Thyroid disease
• Any other cases who are regarded as inadequate for study enrollment by investigators