A total of 116 patients who meet the inclusion criteria and are chemotherapy-naïve for their metastatic disease, will be randomly assigned to either the treatment group (DEBIRI plus systemic chemotherapy) or the control group (systemic chemotherapy alone).

After 4 cycles of chemotherapy and 2 cycles of DEBIRI, patient reassessment to evaluate treatment response, based on RECIST criteria, will be performed using MRI or CT scan within 1-3 months of treatment initiation.

The feasibility of secondary tumor resection, as primary endpoint, will be reassessed at a three-month follow-up multidisciplinary team (MDT) meeting, guided by established clinical guidelines.

Upon acquiring ethical approval, patients with histologically proven, unresectable or borderline resectable liver metastases from colorectal origin who are referred to the hepatobiliary clinic between September 2024 and September 2026 will be enrolled to the study. Informed consent will be obtained for their participation prior to enrollment.

A total of 116 patients who are chemotherapy-naïve for their metastatic disease, will be randomly assigned to either the treatment group or the control group.

With the aim of controlling major confounding factors, Stratified randomization will be performed based on synchronous/metachronous liver metastases and unresectable/borderline resectable status.

Targeted therapy administration for each treatment group in based on oncologist's decision and will be tailored to the tumor's biological characteristics and the patient's clinical status. Ultimately, patients will be categorized into one of the two following treatment groups:

Group 1: DEBIRI+ standard systemic chemotherapy ± Targeted therapy Group 2: Standard systemic chemotherapy ± Targeted therapy The Tumor characteristics, including the number, size, and anatomical location, as well as the presence or absence of extrahepatic metastases, will be assessed based on initial imaging (MRI).

The treatment protocol is defined as the administration of a chemotherapy regimen on days 0 and 14, followed by DEBIRI on days 7 and 21. Each patient of the treatment arm will receive at least two doses of DEBIRI unless treatment-limiting adverse events occur.

After 4 cycles of chemotherapy and 2 cycles of DEBIRI, patient reassessment to evaluate treatment response will be performed using MRI or CT scan within 1-3 months of treatment initiation. All imagings will be reviewed by 2 radiologists who are blinded to clinical information regarding treatment arm. Treatment response will be determined using RECIST criteria.

Conversion to resectability, as primary endpoint, will be evaluated at a three-month follow-up multidisciplinary team (MDT) meeting, guided by established clinical guidelines.

Secondary endpoints of the study will encompass evaluation of treatment tolerability and adverse event rate, alongside analyzing progression-free survival and overall survival.

Inclusion Criteria:

• unresectable/borderline resectable colorectal cancer liver metastases, chemotherapy-naïve for metastatic disease, Eastern Cooperative Oncology Group (ECOG) performance status of 2 or less adequate hematologic, hepatic, and renal function ( absolute neutrophil count ≥ 1.5 × 10^9/L, platelet ≥ 75 ×10^9/L, international normalized ratio ≤ 1.3, Total bilirubin ≤ 2.0 mg/dL, aspartate aminotransferase and alanine aminotransferase ≤ 5 × the upper limit of normal (ULN), Albumin ≥ 2.5 g/dL, Creatinine ≤ 2.0 mg/dL)

Exclusion Criteria:

• candidates for curative surgery without the need for neoadjuvant therapy, Liver involvement of ≥ 70%, brain metastases or Peritoneal carcinomatosis, cirrhosis, presence or History of an allergic reaction to any of the study drugs Chronic viral hepatitis B or C