Cetuximab/FOLFIRI With or Without Oxaliplatin and FOLFOXIRI With or Without Bevacizumab in Neoadjuvant Treatment of Non-resectable Colorectal Liver Metastases

Patients with liver metastases from colorectal and without known extrahepatic metastases will be screened for this study including ras status (b-raf status according to local standard). Patients receive chemotherapy according to the allocation and are re-evaluated for resectability every 8 weeks for a maximum of 6 months. Resectable patients will be resected and receive an adjuvant treatment to complete 12 cycles. In certain circumstances, a second resection is allowed within the study. Patients will be randomized using a web-based computer system that allows randomization if the key basic characteristics are entered. Patients with ras wild-type tumours will be randomized to receive: * Cetuximab/FOLFIRI or * Cetuximab/FOLFOXIRI Patients with ras mutations will be randomized to receive: * FOLFOXIRI or * FOLFOXIRI/bevacizumab Chemotherapy doses are adjusted to the risk of toxicity in all treatment arms. Stratification will be performed according to: * Number of metastases (\< 5 vs. ≥ 5 metastases) * Primary tumour in situ * Centre Treatment regimens For dose reductions and conditions to continue please refer to the full protocol. All drugs are used within the label and approved doses. B-raf mutations are determined according to local standard. If a b-raf mutation is known before randomization, the investigator can consider the patient as ras wildtype OR as ras mutant patient. Cetuximab/FOLFIRI : Cetuximab 400 mg/m² (first dose, 2 h), then 250 mg/m² (1 h) weekly Irinotecan 180 mg/m², d-l Folinic acid 400 mg/m² (2 h), 5-FU 400 mg/m² (Bolus), 5-FU 2400 mg/m² (46 h) every 2 weeks Cetuximab/FOLFOXIRI: Cetuximab 400 mg/m² (first dose, 2 h), then 250 mg/m² (1 h) weekly Irinotecan 125 mg/m² , Oxaliplatin 85 mg/m² (2 h), d-l Folinic acid 400 mg/m² (2 h), 5-FU 3200 mg/m² (46 h) every 2 weeks FOLFOXIRI: Irinotecan 165 mg/m², Oxaliplatin 85 mg/m² (2 h), d-l Folinic acid 400 mg/m² (2 h), 5-FU 3200 mg/m² (46 h) every 2 weeks Bevacizumab/FOLFOXIRI: Bevacizumab 5 mg/kg (90 - 30 min i.v.), Irinotecan 165 mg/m², Oxaliplatin 85 mg/m² (2 h), d-l Folinic acid 400 mg/m² (2 h), 5-FU 3200 mg/m² (46 h) every 2 weeks Evaluation for response and resections Patients are evaluated for response by the same imaging technique as at baseline every 8 weeks. The findings will be discussed for resectability within two weeks after tumour assessment in a local multidisciplinary team. Technically resectable patients should be offered liver resection. The treatment will continue until liver resection or for a maximum of six months (12 cycles). Adjuvant treatment After liver resection, an adjuvant treatment is recommended with the same schedule as preoperatively, for a maximum combined pre- and postoperative treatment of 12 cycles. If less than three postoperative cycles remain, no postoperative treatment will be started (see chapter 9.10). Follow up After resection, patients will be followed up for 5 years after randomization. This includes * imaging and clinical investigation every three months for the first 2 years, then every six months (patients without tumour progression / recurrence) * survival status and surgical/medical treatment every three months for the first 2 years and then every six months (all patients)