The objective of the SIM trial is to investigate whether using the Surefire Infusion System during holmium-166 radioembolization increases the posttreatment tumor to non-tumor activity concentration ratio, compared with using a standard end-hole microcatheter.

Study design: clinical within-subject randomized controlled trial.

Study population: 25 patients with unresectable, chemorefractory, liver-dominant colorectal liver metastases.

Intervention: scout and therapeutic doses of holmium-166 microspheres will be administered in the left and right hepatic artery during two sequential angiography procedures on the same day. In all subjects, the use of the Surefire Infusion System and the standard end-hole catheter will be randomly allocated to the infusion site (left and right hepatic artery).

Baseline and follow-up investigation: at baseline and during follow-up, patients will undergo physical examination and laboratory investigations for toxicity assessment, and a whole-body 18F-FDG-PET + dual-phase liver CT (at baseline and 3-months follow-up) for tumor response assessment. After the scout procedure and therapeutic procedure, a holmium-166 SPECT/CT will be obtained for the assessment of the microsphere distribution.

Main study parameters/endpoints:

The primary endpoint is the tumor to non-tumor activity concentration ratio on SPECT/CT.

Secondary endpoints include mean absorbed doses of radioactivity in tumorous and healthy liver tissue, tumor response, the predictive value of holmium-166 scout dose and infusion efficiency. These endpoints will be compared between the Surefire Infusion System and standard microcatheter infusions. A dose-response relationship, clinical toxicity and overall survival will be assessed for the entire cohort.

Inclusion Criteria:

• Written informed consent
• Histopathologically confirmed diagnosis of adenocarcinoma of the colon or rectum
• Hepatic metastases with measurable morphological appearance (≥ 1 cm) on cross sectional imaging, located in the right and left hepatic arterial perfusion territory
• Unresectable, liver dominant disease
• Progressive disease after second line chemotherapy or no further chemotherapeutical treatment options due to severe side effects or unwillingness of the patient to undergo systemic chemotherapy
• Age ≥ 18 years
• Expected adequacy of follow-up

Exclusion Criteria:

• World health organization performance score > 2
• Inadequate bone marrow function (hemoglobin < 6.0 mmol/l, leukocyte count < 3.0 x 109/l, platelet count < 75x 109/l), inadequate liver function (bilirubin > 35 µmol/l, aspartate aminotransferase / alanine aminotransferase (AST/ALT) > 5 x upper limit of normal (ULN)) or inadequate renal function (creatinine > 1.5 x ULN)
• Prior hemihepatectomy
• Compromised biliary system (biliary stent or hepaticojejunostomy)
• Child Pugh score B7 or worse
• Active hepatitis B or C
• Main portal vein thrombosis on CT (or previous portal vein embolization)
• Severe celiac axis stenosis on CT
• Unsuitable hepatic arterial anatomy on CT
• Treatment with systemic chemotherapy within 4 weeks prior to radioembolization
• Previous participation in a study classified as class III by a radiation safety committee
• Bleeding diathesis
• Pregnancy or breast feeding
• Life expectancy < 3 months
• Patients who are declared incompetent
• Any condition that prevents from safe treatment with radioembolization