Liver-directed Chemotherapy After Surgery of Liver Metastases of Colorectal Cancer in Patients With High Risk of Recurrence of Their Disease

Inclusion Criteria:

* Patient must have signed a written informed consent prior to any trial specific procedures. When the patient is physically unable to give their written consent, a trusted person of their choice, independent from the investigator or the sponsor, can confirm in writing the patient's consent
* Age \> 18 years
* ECOG performance status 0-1
* Histologically confirmed stage IV pMMR CRC
* Resected CRLM by one- or two-stage procedures including reverse strategy
* Partial Response or Stability Disease (RECIST 1.1) to preoperative cytotoxic doublet or triplet IV chemotherapy +/- targeted agent before surgery
* Curative-intent ( R0/R1 resection ± local ablation) surgery of 4 or higher CRLM
* No macroscopic residual (hepatic or extra-hepatic) disease on postoperative CT scan within 4 weeks after surgery confirmed during local multidisciplinary tumor board (except up to 3 lung nodules \< 10 mm deemed amenable to curative-intent resection/local ablation and non-resected primary tumor with no or mild symptoms)
* Eligible to HAI of oxaliplatin by (permanent or selective) catheterization defined as the absence of medical (any contraindication to oxaliplatin administration, mainly residual peripheral sensory neuropathy grade \< 2) and technical (vascular anatomy to perform HAI chemotherapy) contraindications to administer oxaliplatin-based doublet or triplet chemotherapy within 8 weeks from surgery during at least 4 cycles evaluated by interventional radiologist and medical oncologist
* Normal liver function (bilirubin \< 1.5 x upper limit of normal values (ULN), aminotransferases \< 5 ULN, alkaline phosphatase \< 5 ULN, International normalized ratio (INR) \< 1.5 ULN, platelets \> 100,000/mm3)
* Women of childbearing potential must have a negative pregnancy test done within 30 days before randomisation
* Potentially reproductive patients must agree to use an effective contraceptive method or practice adequate methods of birth control or practice complete abstinence while on treatment, and for at least 6 months after the last dose of study drug
* Patients must be willing and able to comply with the protocol for the duration of the study including scheduled visits, treatment plan, laboratory tests and other study procedures
* Patients must be affiliated to a Social Security System (or equivalent)

Exclusion Criteria:

* Stage IV dMMR CRC
* Progressive Disease (RECIST 1.1) to preoperative cytotoxic doublet or triplet IV chemotherapy +/- targeted
* Incomplete (R2) surgery or residual (hepatic or extrahepatic) disease on postoperative CT scan within 4 weeks after surgery or symptomatic primary tumours in case of reverse strategy
* Extra hepatic metastasis disease, except ≤ 3 lung nodules \< 10 mm deemed amenable to curative-intent resection/local ablation and non-resected primary tumor with no or mild symptoms
* Impossibility to receive at least 4 postoperative cycles with oxaliplatin
* Patients with contraindications for HAI or IV doublet or triplet administration as limiting anatomical variations of hepatic artery, peripheral sensory neuropathy ≥ grade 2 (NCI-CTAE v.5.0), gastric/duodenal ulcer or significant chronic liver disease (resulting in portal hypertension and/or liver failure)
* Peripheral neuropathy grade ≥ 2
* Patient with a dihydropyrimidine dehydrogenase deficiency (DPD)
* Medical history of other concomitant or previous malignant disease, except adequately treated in situ carcinoma of the uterine cervix, basal or squamous cell carcinoma of the skin, or cancer in complete remission for ≥5 years
* Pregnant women or women who are breast-feeding
* Participation in another therapeutic trial within the 30 days prior to randomisation
* Patients unwilling or unable to comply with the medical follow-up required by the trial because of geographic, familial, social, or psychological reasons
* Persons deprived of their liberty or under protective custody or guardianship