Table 1 List of eligibility criteria of the SULTAN study

1. Histologically confirmed CRC, and radiologic or histologic proof of CRLM not amenable to a curative intent-treatment after 2 months to 6 months of first-line induction chemotherapy

2. First-line chemotherapy with oxaliplatin and/or irinotecan combined with a fluoropyrimidine and a targeted therapy (e.g., anti-EGFR or antiangiogenic antibody) for metastatic disease (patients ending their adjuvant chemotherapy after primary tumor resection since more than 6 months should also have received first-line chemotherapy for metastatic disease)

3. Unresectability of the CRLM will be confirmed by a centralized multidisciplinary expert panel (composed of surgeons, radiologists, interventional radiologists and medical oncologists). The panel will review the CT scan and MRI of the patients (weekly web conference). Non-resectability criteria (one of the following criteria):

 ✓ Upfront R0/R1 resection of all CRLM (that leaves at least two adequately perfused and drained segments) is not possible

 ✓ and/or metastases in contact with major vessels of the remnant liver which would require resection of the vessel for an R0 resection (i.e., tumor involvement of main portal right and left portal veins, of the three main hepatic veins, or of the retrohepatic vena cava)

 ✓ and/or documented progressive disease on imaging (according to the RECIST v1.1 criteria) or doubling of serum levels of carcinoembryonic antigen (CEA) or CA 19.9 following ≥2 months of induction chemotherapy

4. At least one measurable liver metastasis according to the RECIST v1.1

5. Age ≥ 18 years

6. ECOG performance status 0–1

7. Normal liver function: bilirubin < 1.5 x upper limit of normal values (ULN), aminotransferases < 5 ULN, alkaline phosphatase < 5 ULN

8. International normalized ratio (INR) < 1.5 ULN

9. Neutrophils > 1500/mm³, platelets > 100,000/mm³, hemoglobin > 9 g/dL (transfusion allowed)

10. Calculated creatinine clearance > 50 mL/min (Cockcroft and Gault formula)

11. Informed consent signed by the patient or his/her legal representative

12. Patient affiliated to a social security regimen

13. 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

1. Patient eligible for curative-intent treatment of CRLM (i.e. resection and/or thermoablation), according to local multidisciplinary team and/or central review

2. Definitive anatomical contraindication to complete surgical resection:

 a. More than two lesions in all liver segments

 b. Bilobar liver metastasis and more than three lesions > 3 cm in the hepatic lobe the least affected (i.e. the future remnant liver)

 c. Bilobar liver metastasis and disease liver extend > 50%

3. Extrahepatic metastases (except ≤3 lung nodules < 10 mm deemed amenable to curative-intent resection/thermoablation and non-resected primary tumor with no or mild symptoms)

4. Patient with contraindication for trial drugs; contraindication limited to targeted therapy (e.g., anti-EGFR or antiangiogenic antibody) are allowed

5. Disease progression after FOLFOXIRI/FOLFIRINOX

6. Sensory neuropathy ≥ grade 2 (NCI-CTAE v.4.0)

7. If patients received bevacizumab, following non-inclusion criteria must be respected:

 a. Proteinuria > 1 g

 b. Gastro-intestinal fistulae or perforation

 c. Hypersensitivity to Chinese hamster ovary cell products or other human recombinant antibody

 d. Major surgery in the last 28 days

8. If patients received panitumumab, following non-inclusion criteria must be respected:

a. Interstitial lung disease

b. Pulmonary fibrosis

9. Significant chronic liver disease (resulting in portal hypertension and/or liver failure)

10. Allergy to contrast media that cannot be managed with standard care

11. Previous organ transplantation, HIV or other immunodeficiency syndromes

12. Concomitant or past history of cancer within 5 years prior to entry into the trial (except treated basal-cell skin cancer or in situ carcinoma of the cervix)

13. Patients with clinically significant active heart disease or myocardial infarction in the last 6 months

14. Concomitant medications/comorbidities that may prevent the patient from receiving study treatments as uncontrolled intercurrent illness (for instance: active infection, active inflammatory disorders, inflammatory bowel disease, intestinal obstruction, uncontrolled hypertension systolic > 15 and diastolic > 9, symptomatic congestive heart failure…)

15. Ionic disorders as:

 a. Kalemia ≤1 x ULN

 b. Magnesemia <0.5 mmol/L

 c. Calcemia <2 mmol/L

16. Patient with a dihydropyrimidine dehydrogenase deficiency (DPD): the test should be done for all patients before first 5-FU administration, according recommendations about the high risk of no testing DPD in patient before 5-FU administration

17. QT/QTc > 450 msec (men) and > 470 msec (women)

18. Concomitant intake of St. John’s wort

19. Patient already included in another clinical trial with an experimental treatment

20. Pregnancy or lactation

21. Patients deprived of liberty or under guardianship

22. Patients unable to undergo medical monitoring for geographical, social or psychological reasons