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

This prospective, randomized, controlled clinical study aims to evaluate the objective remission rate of FOLFOX hepatic artery infusion chemotherapy (HAI) in combination with systemic irinotecan with or without bevacizumab versus systemic intravenous FOLFOXIRI with or without bevacizumab in initially unresectable RAS-mutated colorectal cancer patients with liver metastases.

Inclusion Criteria:Histologically confirmed colorectal adenocarcinomaImaging or pathological confirmation of liver metastasesThe 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 BrafV600ENo previous treatment for liver metastases, including chemotherapy, surgery, radiotherapy, transarterial chemoembolization (TACE) and targeted therapyNo 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 ULNNo ascites, normal coagulation function, albumin ≥35g/LLiver function Child-Push grade ASerum creatinine less than upper limit of normal (ULN) or calculated creatinine clearance >50 ml/min (using Cockcroft-Gault formula)ECOG score 0-1Life expectancy > 3 monthsSigned written informed consentExclusion 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 resectionDevelopment of liver metastases within 1 year after completion of adjuvant chemotherapy with FOLFOX or XELOXSevere arterial embolism or ascitesBleeding tendency or coagulation disorderHypertensive crisis or hypertensive encephalopathySevere uncontrolled systemic complications such as infections or diabetes mellitusClinically 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 medicationHistory 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 studyAny 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 regimensHistory of allergy to any of the drugs in the studyWomen 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 lactationUnable or unwilling to comply with the study protocolPresence 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