Evidence suggests that the addition of cetuximab or bevacizumab to doublet regimens could improve response rate and resectability rate of liver metastases and survival in colorectal liver metastases (CRLM). Moreover, it is observed that FOLFOXIRI yields higher response and resection rates compared with doublet regimens. However, which is better in conversion therapy of RAS/BRAF wild-type initially unresectable CRLM, FOLFOXIRI plus cetuximab or bevacizumab, remains unknown.

In this study, RAS/BRAF wild-type colorectal cancer patients with initially unresectable liver-only metastases, as prospectively confirmed by a local multidisciplinary team (MDT) according to predefined criteria, will be randomised between modified FOLFOXIRI (mFOLFOXIRI) plus cetuximab and mFOLFOXIRI plus bevacizumab. Patient imaging will be reviewed for resectability by MDT, consisting of at least one radiologist and three liver surgeons every assessment. MDT review will be performed prior to randomization as well as during treatment, as described in the protocol.

Patients will be stratified for primary tumor location (right-sided or left sided) and numbers of liver metastases (<5 or ≥5).

Patients with RAS/BRAF wild-type primary tumors will be randomized between mFOLFOXIRI plus cetuximab (cetuximab 500 mg/m^2 in 60 minutes i.v., followed by oxaliplatin 85 mg/m^2 i.v. in 120 minutes, followed by irinotecan 165 mg/m^2 i.v. in 60 minutes, together with leucovorin 400 mg/m^2 i.v. in 120 minutes, followed by continuous infusion of 5-fluorouracil 2400 mg/m^2 in 46 hours, every 2 weeks) or mFOLFOXIRI plus bevacizumab (Bevacizumab 5 mg/kg in 15-30 minutes i.v., followed by oxaliplatin 85 mg/m^2 i.v. in 120 minutes, followed by irinotecan 165 mg/m^2 i.v. in 60 minutes, together with leucovorin 400 mg/m^2 i.v. in 120 minutes, followed by continuous infusion of 5-fluorouracil 2400 mg/m^2 in 46 hours, every 2 weeks).

Patients will be evaluated every 8 weeks by MRI or CT scan for disease status. The assigned systemic treatment should be continued for at least 6 months or earlier in case of resectability, progression of disease, unacceptable toxicity, or patient refusal. If after 6 months MDT concludes that the patient is still not resectable, it is highly unlikely that resectability will be achieved at all. Therefore the chemotherapy regimen may be reconsidered after 6 months of treatment.

In patients who will become resectable and undergo secondary surgery of liver metastases, the total duration of preoperative and postoperative treatment together should be 6 months. However, the postoperative chemotherapy regimen was determined by the investigator.

After 70% of patients were enrolled and conversion therapy were finished, a mid-term analysis will be performed.

Inclusion Criteria:

1. The primary tumor was confirmed by histology as colorectal adenocarcinoma
2. Initially unresectable liver metastases suggested by MDT
3. RAS/BRAF gene wild-type states
4. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
5. Life expectancy ≥ 3 months
6. Good hematological function: neutrophil ≥ 1.5x109 / L and platelet count ≥ 100x109 / L; HB ≥ 9g / dl (within one week before randomization)
7. Normal liver and kidney function: serum bilirubin ≤ 1.5x normal upper limit (ULN), alkaline phosphatase ≤ 5x ULN, serum transaminase (AST or ALT) ≤ 5x ULN (within one week before randomization);
8. Sign the written informed consent to participate in the experiment

Exclusion Criteria:

1. Patients with liver metastases from colorectal cancer who have previously received targeted therapy, chemotherapy, radiotherapy or interventional therapy
2. Known or suspected extrahepatic metastasis
3. Patients with known hypersensitivity to any component of the study treatment
4. Clinical related coronary heart disease or history of myocardial infarction in the last 12 months or left ventricular ejection fraction below normal range
5. Acute or subacute intestinal obstruction
6. Pregnancy (no pregnancy confirmed by serum / urine β - hCG) or breastfeeding.
7. Other malignant tumors within 5 years, except for those with skin basal cell carcinoma or cervical cancer
8. Known drug / alcohol abuse
9. No legal capacity or limited legal capacity