Study Hypothesis

• As well as in animal models as in patients with colorectal cancer resection of the primary tumor resulted in increase in vascular density, metabolism and secondary tumor growth of the distant metastases. These data strongly suggest an inhibitory effect of the primary tumor on the outgrowth of its metastases.

In this study we investigate whether pre-operative treatment with the anti-angiogenic agent bevacizumab and/or chemotherapy before resection of the primary colorectal tumor shifts the balance between angiogenic and anti-angiogenic factors in favor of the anti-angiogenic factors and results in reduced growth of the liver metastases.

Eligibility

• Histological proven colorectal cancer without signs of bowel obstruction or bleeding
• Synchronous liver metastases
• WHO performance status 0-1

Treatment

• Arm A: immediate surgery of the primary colorectal tumor, no neoadjuvant therapy
• Arm B: neoadjuvant treatment with bevacizumab during 7 weeks prior to surgery of the colorectal primary
• Arm C: neoadjuvant treatment with CAPOX during 7 weeks prior to surgery of the colorectal primary
• Arm D: neoadjuvant treatment with bevacizumab and CAPOX during 7 weeks prior to surgery of the colorectal primary

Primary endpoint Difference in response of liver metastases to resection of the primary tumor between the experimental groups and the control group, as determined by histopathological scoring of vascular density, apoptotic and mitotic index and by measurement of the metabolic activity of liver metastases by FDG-PET and SUV measurements.

Secondary endpoints Toxicity of neo-adjuvant treatment Complications of surgery

Inclusion Criteria:

• Patients with histological proven primary colorectal cancer and synchronous unresectable liver metastases with or without additional extrahepatic disease (primary tumor in situ). Unresectable liver metastases defined as too extensive hepatic involvement or extrahepatic disease.
• Measurable liver metastases on CT scan (RECIST), positive signal of liver metastases on FDG-PET scan
• Age: 18-80 years
• WHO performance scale 0-1
• ASA category I or II
• Negative pregnancy test in women with childbearing potential
• Life expectancy > 12 weeks
• Laboratory values obtained ≤ 3 weeks prior to study entry, disease evaluation performed ≤ 3 weeks prior to study entry. Adequate bone marrow function (Hb > 6.5 mmol/L, absolute neutrophil count > 1.5 x 109/L, platelets > 100 x 109/L), renal function (serum creatinine < 1.5 x ULN or creatinine clearance ≥ 50 mL/min (calculated according to Cockroft and Gault), liver function (ASAT and ALAT ≤ 3 x upper normal limit, serum bilirubin ≤ 2 x upper normal limit)
• Written informed consent

Exclusion Criteria:

• Signs of bowel obstruction or bleeding from primary tumor
• Prior chemotherapy treatment for advanced disease, prior treatment with anti-angiogenic drugs
• Resectable liver metastases
• Diabetes mellitus
• Continuous use of immunosuppressive agents
• Pregnancy or lactation
• Contra-indications for systemic therapy with bevacizumab (Avastin)/ chemotherapy (Xelox)
• Concurrent severe or uncontrolled disease (i.e. uncontrolled hypertension, congestive heart failure, myocardial infarction < 12 months, chronic active infection)
• Sensory neuropathy > grade 1
• Serious non-healing wound or ulcer
• Patients (M/F) with reproductive potential not implementing adequate contraceptive measures
• Major surgical procedure, open biopsy or significant traumatic injury within 28 days prior to start of bevacizumab
• Bleeding disorders or coagulopathy or need for full-dose anticoagulation
• Signs or symptoms of brain metastases
• Cerebrovascular accident or transient ischemic attack within the past 12 months
• Impairment of gastrointestinal function or -disease that may significantly impair the absorption of oral drugs (i.e. uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, bowel obstruction, or inability to swallow tablets)
• Presence of proteinuria at baseline as defined by: patients with > 1 g of protein/24 hr by a 24-hour urine collection.
• Any concomitant disorder preventing the safe administration of study drugs or surgical procedure.