The investigators propose to conduct a randomised phase III trial evaluating a maintenance strategy comparing hepatic arterial injection of Yttrium-90 resin microspheres plus continuing simplified chemotherapy with/without targeted therapy versus continuing simplified chemotherapy with/without targeted therapy alone for patient with dominant or exclusive and unresectable liver mCRC controlled after 3-6 months of chemotherapy induction.

The aim of the study is to investigate whether an intensified maintenance treatment of SIRT + simplified maintenance chemotherapy has a benefit in terms of time to progression (TTP) compared to simplified chemotherapy maintenance alone, in patients with stable disease after 3-6 months induction therapy. We would like to demonstrate the feasibility and safety of this approach and to investigate if this strategy has the potential to increase the outcome of the patient.

Primary end-point:

- Time to first progression (TTP1 overall)

Secondary end-points:

• Time to global progression (TTP1 + TTP2), Time to second progression (TTP2), TTP1 liver only
• Progression Free Survival (PFS)
• Overall Survival (OS)
• Safety
• Ro resection rate
• Quality of Life

Exploratory analysis:

- Prediction and evaluation of SIR-spheres treatment response (only for Belgian centres)

Inclusion criteria:

1. Willing and able to provide written informed consent

2. Histologically confirmed adenocarcinoma of the colon or rectum, with or without primary tumour in situ. Unequivocal and measurable (RECIST 1.1) CT evidence of liver metastases which are not treatable by surgical resection and/or local ablation with curative intent at the time of trial entry.

3. Partial response or stable disease (RECIST 1.1 criteria, controlled metastatic disease) after chemotherapy induction with oxaliplatin and/or irinotecan based induction chemotherapy (doublet or triplet combinations) +/- targeted therapies during 3 to 6 months.

4. Trial inclusion must be performed between 3 and 6 months since the date of the first course of chemotherapy (induction) administration.

5. Limited extra-hepatic metastases in the lung and/or lymph nodes are permitted. Metastases in the lung must either be not more than five nodules in number with no individual nodule more than 1 cm in diameter or 1 single lesion of up to 1.7 cm in diameter. Involvement of lymph nodes in 1 single anatomic region (pelvis, abdomen or chest) are permitted provided their longest diameter measures less than 2 cm.

6. All imaging evidence used as part of the screening process must be within 28 days prior to the time of randomisation.

7. Suitable for either treatment regimen as determined by clinical assessment undertaken by the Investigator.

8. Patients may have received adjuvant chemotherapy or (neo-) adjuvant chemo-radiotherapy to the pelvis, provided the last dose of chemotherapy was administered at least 6 months prior to begin chemotherapy induction. Previous radiotherapy to the pelvis is not an exclusion criterion.

9. WHO performance status 0 - 1

10. Adequate hematological, renal and hepatic function as follows:

    Hematological Neutrophils > 1.5 x 109/L Platelets > 100 x 109/L Renal Creatinine < 1.5 x ULN (Upper Limit Normal) Hepatic Bilirubin ≤ 1.0 X ULN Albumin ≥ 30g/L ALT ≤ 5.0 x ULN AST ≤ 5.0 x ULN LDH ≤ 2.5 x ULN The date of blood tests must be within 28 days prior to the time of randomisation.

11. Age 18 years or older.

12. Female patients must either be postmenopausal, sterile (surgically or radiation- or chemically-induced), or if sexually active using an acceptable method of contraception.

13. Male patients must be surgically sterile or if sexually active and having a pre-menopausal partner must be using an acceptable method of contraception.

14. Life expectancy of at least 3 months without any active treatment.

Exclusion criteria

1. Evidence of ascites, cirrhosis, portal hypertension, main portal venous tumour involvement or thrombosis as determined by clinical or radiological assessment.
2. More than 6 months since last chemotherapy administration before trial inclusion.
3. Previous radiotherapy delivered to the upper abdomen.
4. Non-malignant disease that would render the patient unsuitable for treatment according to this protocol.
5. Prior major liver resection: remnant liver < 50% of the initial liver volume. Patient with a biliary stent can be included.
6. Liver tumor involvement > 80% before study inclusion (not at diagnosis but when trial inclusion for the patient is planned).
7. Resectable metastatic disease at trial inclusion.
8. Progressive disease during first-line metastatic chemotherapy. Adjuvant chemotherapy for colorectal cancer is not an exclusion criterion provided that it was completed more than 6 months prior to start of 1st line chemotherapy.
9. No oxaliplatin or irinotecan use during the first 3 to 6 months induction chemotherapy.
10. Pregnant or breast feeding.
11. Concurrent or prior history of cancer other than adequately treated non melanoma skin cancer or carcinoma in situ of the cervix.
12. Severe allergy to non-ionic contrast agents which would prevent contrast media use during the study.