Fruquintinib With or Without HAI-FOLFOX for Refractory Colorectal Cancer

Inclusion Criteria:

* Aged between 18 and 75 years.
* Histologically confirmed colorectal adenocarcinoma.
* Radiologically or pathologically confirmed liver metastasis.
* At least one measurable lesion (per RECIST v1.1 criteria).
* No extrahepatic metastasis confirmed by CT, MRI, or PET/CT (if necessary). Patients with minimal extrahepatic metastatic burden (defined as the presence of lung metastasis and/or lymph node metastasis with lung lesion diameter not exceeding 1 cm, and lymph node metastasis with the longest diameter less than 2 cm) can be included.
* Disease progression within 3 months or intolerance to standard treatment with fluoropyrimidine, irinotecan, oxaliplatin combined with targeted therapy (including bevacizumab and cetuximab (RAS/BRAF wild-type)), with previous oxaliplatin-induced neurotoxicity \< Grade 2.
* Normal hematologic function (platelets \>90×10\^9/L; white blood cells \>3×10\^9/L; neutrophils \>1.5×10\^9/L).
* Serum bilirubin ≤1.5 times the upper limit of normal (ULN), transaminases ≤5 times ULN, alkaline phosphatase ≤2.5 times ULN, no ascites, coagulation function: prothrombin time (PT) ≤1.5 ULN; international normalized ratio (INR) ≤1.5 ULN; activated partial thromboplastin time (APTT) ≤1.5 ULN, albumin ≥35 g/L.
* Child-Pugh grade A liver function.
* Serum creatinine less than ULN, or calculated creatinine clearance \>50 ml/min (using Cockcroft-Gault formula).
* ECOG performance status 0-1.
* Expected survival \>3 months.
* Signed written informed consent.
* Willing and able to undergo follow-up until death or study completion/termination.

Exclusion Criteria:

* Severe arterial embolism.
* Bleeding tendency or coagulation disorders.
* Hypertensive crisis or hypertensive encephalopathy.
* Severe uncontrolled systemic complications such as infection or diabetes.
* Clinically significant cardiovascular diseases such as cerebrovascular accident (within 6 months prior to enrollment), myocardial infarction (within 6 months prior to enrollment), uncontrolled hypertension despite appropriate medical therapy, unstable angina, congestive heart failure (NYHA Class 2-4), or arrhythmias requiring medication.
* History or physical examination indicative of central nervous system diseases (e.g., primary brain tumors, uncontrolled seizures, any history of brain metastasis or stroke).
* Other malignancies within the past 5 years (except for radically treated basal cell carcinoma of the skin and/or carcinoma in situ of the cervix).
* Received any investigational drug treatment within 28 days prior to the study.
* Residual toxicity from previous chemotherapy (excluding alopecia), such as peripheral neuropathy ≥ Grade 2 (NCI CTCAE v5.0), if considering an oxaliplatin-containing regimen.
* Allergy to any of the study drugs.
* Pregnant or breastfeeding women.
* Women of childbearing potential not using or refusing to use effective non-hormonal contraception (intrauterine device, barrier method combined with spermicide, or sterilization) or men with reproductive potential.
* Inability or unwillingness to comply with the study protocol.
* Presence of any other diseases, functional impairment due to metastatic lesions, or findings on physical examination suggesting a contraindication to the use of the study drugs or putting the participant at high risk for treatment-related complications.