Postoperative Hepatic Arterial Oxaliplatin Infusion Combined with Systemic Chemotherapy for High‑Risk Resected Colorectal Liver Metastases: A Randomized Phase II Trial

The primary objective is to assess the efficacy of postoperative hepatic arterial infusion (HAI) of oxaliplatin combined with systemic intravenous chemotherapy on progression-free survival (PFS) in patients who have undergone curative‑intent resection of colorectal liver metastases (CRLM) and are at high risk of recurrence. Secondary objectives include:

• Evaluation of overall survival (OS) between treatment arms.
• Evaluation of hepatic recurrence‑free survival (RFS) between treatment arms.
• Comparison of the pattern of recurrence or progression between arms.
• Assessment of the feasibility of HAI of oxaliplatin by selective angiography.
• Assessment of toxicity, focusing on catheter‑related complications and peripheral sensory neuropathy.
• Documentation of the types of treatments administered after recurrence.
• Evaluation of tumor response following re‑introduction of chemotherapy after recurrence.
• Assessment of patients’ quality of life.

The trial enrolled adult participants (age ≥ 18 years) of both sexes, including individuals classified as vulnerable, who had undergone curative‑intent resection (R0/R1) of liver metastases originating from colorectal cancer. All subjects were required to have an Eastern Cooperative Oncology Group performance status of 0‑1, adequate hematologic and hepatic function, and no macroscopic residual disease on postoperative imaging. Eligibility was determined through a multidisciplinary tumor‑board review and required confirmation of eligibility for hepatic arterial infusion of oxaliplatin, absence of contraindications to the chemotherapeutic agents, and compliance with contraception requirements for patients of childbearing potential. Participants needed to demonstrate partial response or disease stability to preoperative chemotherapy, and to be able to adhere to the study protocol, including scheduled visits and laboratory assessments. The sponsor did not provide information regarding the total number of participants enrolled in the study.

The study is a Phase III randomized, double‑blind, controlled trial evaluating postoperative hepatic arterial infusion of oxaliplatin combined with intravenous fluorouracil, folinic acid, calcium levofolinate and irinotecan in patients who have undergone curative‑intent resection of colorectal liver metastases and are at high risk of recurrence. After signing informed consent, participants attend a screening visit for eligibility assessment, laboratory testing, and baseline imaging; eligible subjects are then randomized and begin the treatment protocol, which consists of four cycles of oxaliplatin administered via hepatic arterial catheter (85 mg/m²) and concurrent intravenous chemotherapy (fluorouracil 2800 mg/m², folinic acid 400 mg/m², calcium levofolinate 200 mg/m², irinotecan 150 mg/m²) given every two weeks. Follow‑up visits occur every eight weeks during the first six months to monitor safety, dose intensity, and disease status, and subsequently every three months until the end‑of‑study visit, scheduled approximately 24 months after randomization, at which time final imaging, laboratory assessments, and quality‑of‑life questionnaires are collected. Participant involvement therefore spans roughly two years, including treatment and surveillance phases. Early termination may occur if a patient experiences disease progression, grade ≥ 3 toxicity per CTCAE v5.0, withdrawal of consent, loss to follow‑up, or any major protocol deviation, in which case the patient is withdrawn and final assessments are performed.

The study evaluates postoperative hepatic arterial infusion (HAI) of oxaliplatin combined with intravenous (IV) chemotherapy following curative‑intent resection of colorectal liver metastases in patients at high risk of recurrence.

Oxaliplatin is administered via the hepatic artery at a dose of 85 mg/m² per infusion. An additional IV dose of 85 mg/m² may be given according to the protocol schedule. The infusion is performed on the day designated for HAI, with dosing repeated per treatment cycle as defined in the study protocol.

Fluorouracil is delivered intravenously at 2800 mg/m² per cycle. The infusion is administered after the oxaliplatin HAI and is repeated according to the cycle schedule established in the protocol.

Folinic acid is given intravenously at 400 mg/m² per cycle, administered immediately prior to fluorouracil to enhance cytotoxic activity. Dosing follows the same cycle frequency as the other IV agents.

Calcium levofolinate is administered intravenously at 200 mg/m² per cycle. It is provided as part of the IV chemotherapy regimen and is dosed in alignment with the fluorouracil‑folinic acid schedule.

Irinotecan is infused intravenously at 150 mg/m² per cycle. The administration occurs on the same day as the other IV agents, adhering to the predefined cycle intervals.

All investigational drugs are prepared and administered by qualified personnel in a controlled clinical setting. Dosing calculations are based on body surface area, and infusion times are recorded to ensure compliance with the protocol. Participant adherence to the dosing schedule is monitored through infusion logs, electronic case report forms, and periodic review of medication administration records.

Efficacy will be evaluated primarily by progression‑free survival, defined as the interval from randomization to the first oncological event (local or metastatic recurrence, disease progression, or death from any cause) as determined by imaging assessments performed in accordance with RECIST v1.1 criteria. Time‑to‑event data will be analyzed using standard survival methods, with censoring applied at the date of last follow‑up for patients without an event.

Secondary efficacy parameters include overall survival (time from randomization to death from any cause), hepatic recurrence‑free survival (time from randomization to first hepatic relapse or death), and the pattern of disease progression (hepatic versus extra‑hepatic recurrence as the initial event). Tumor response rate will be assessed by RECIST v1.1 after reintroduction of chemotherapy in the setting of recurrence. Health‑related quality of life will be measured with the European Organization for Research and Treatment of Cancer core questionnaire (EORTC QLQ-C30) together with the liver colorectal metastasis module (QLQ‑LMC21). All secondary endpoints will be analyzed using appropriate statistical techniques, including Kaplan‑Meier estimation for survival outcomes and descriptive statistics for response rates and quality‑of‑life scores.