FOLFOX Via HAI Plus Intravenous Irinotecan With or Without Bevacizumab Versus Systemic FOLFOXIRI With or Without Bevacizumab in Initially Unresectable RAS-mutated CRLM Patients

Inclusion criteria

• Histologically confirmed colorectal adenocarcinoma
• Imaging or pathological confirmation of liver metastases
• The multidisciplinary team determined that the liver metastases were unresectable, defined as (i) ≥5 metastases; (ii) inability to perform R0 resection; (iii) insufficient volume of liver expected to remain after resection; (iv) failure to preserve all 3 hepatic veins after resection, failure to ensure that blood flow to and from the liver and bile ducts can be preserved, and failure to preserve 2 adjacent liver segments. If any of the above criteria are met, it can be considered as initially unresectable liver metastases.
• Patients with mutated RAS and BrafV600E
• No previous treatment for liver metastases, including chemotherapy, surgery, radiotherapy, transarterial chemoembolization (TACE) and targeted therapy
• No extrahepatic metastases confirmed by CT, MRI, or PET/CT (if necessary) (consider enrollment if there is a lung or lymph node lesion less than 10 mm and metastases are difficult to identify)
• Normal hematological function (platelets \>90×109/L; white blood cells \>3×109/L; neutrophils \>1.5×109/L)
• Serum bilirubin ≤ 1.5 times the upper limit of normal value (ULN), transaminases ≤ 5 times ULN
• No ascites, normal coagulation function, albumin ≥35g/L
• Liver function Child-Push grade A
• Serum creatinine less than upper limit of normal (ULN) or calculated creatinine clearance \>50 ml/min (using Cockcroft-Gault formula)
• ECOG score 0-1
• Life expectancy \> 3 months
• Signed written informed consent

Exclusion criteria

• Patients meeting any of the following criteria will be excluded from the study):
• Presence of any extrahepatic metastases and/or primary tumor not amenable to radical surgical resection
• Development of liver metastases within 1 year after completion of adjuvant chemotherapy with FOLFOX or XELOX
• Severe arterial embolism or ascites
• Bleeding tendency or coagulation disorder
• Hypertensive crisis or hypertensive encephalopathy
• Severe uncontrolled systemic complications such as infections or diabetes mellitus
• Clinically significant cardiovascular disease such as cerebrovascular accident (within 6 months prior to enrollment), myocardial infarction (within 6 months prior to enrollment), uncontrolled hypertension despite appropriate medication, unstable angina pectoris, congestive heart failure (NYHA class 2-4), arrhythmias requiring medication
• History or physical examination revealing a central nervous system disease (e.g., primary brain tumor, epilepsy not manageable by standard therapy, presence of brain metastases, or history of stroke)
• Previous malignancy within the last 5 years (except post-radical surgery basal cell carcinoma of the skin and/or carcinoma in situ of the cervix)
• Treatment using any investigational drug within the last 28 days prior to the study
• Any residual toxicity from prior chemotherapy (except alopecia), such as peripheral neuropathy ≥ NCI CTC v3.0 grade 2, will not be considered for treatment with oxaliplatin-containing regimens
• History of allergy to any of the drugs in the study
• Women of childbearing potential (\<2 years after last menstruation) or men of childbearing potential who are not using or have refused to use an effective non-hormonal contraceptive (IUD, barrier method combined with spermicidal gel or sterilization) during pregnancy and lactation
• Unable or unwilling to comply with the study protocol
• Presence of any other disease, dysfunction due to metastatic lesions, or suspicious medical findings that suggest a possible contraindication to the use of the study drug or that would place the patient at risk of treatment-related complications