Safety and Feasibility of Radioembolization Using Ho-166 in Patients With Unresectable Hepatocellular Carcinoma

Background: Hepatocellular carcinoma (HCC) accounts for 90% of primary liver cancers and represents a growing health problem worldwide. Most patients present locally advanced disease and are candidates for palliative transarterial locoregional treatment. Transarterial radioembolization (TARE) using 90Y has been used for more than a decade for patients with advanced disease. The use of 166Ho could offer a more personalized approach in terms of imaging and dosimetry. Aim: to evaluate the feasibility and safety of TARE using 166Ho in a selected population of HCC patients and assess the biological peripheral response to this therapy. Materials and methods: In this open-label, prospective, non-randomized, singlecenter pilot study, 20 patients with unresectable hepatocellular carcinoma will undergo TARE using 166Ho. The primary outcome is the feasibility of 166Ho radioembolization as well as the assessment of safety and toxicity profiles (CTAE V5.0). Secondary outcomes include the evaluation of efficacy of 166Ho radioembolization in unresectable hepatocellular carcinoma, according to mRECIST and metabolic criteria, as well as the impact on the tumor marker alpha-fetoprotein (AFP), assessment of biodistribution/dosimetry using a "scout dose" and time to progression (TTP). A substudy will assess the hepatic function using 99mTc-IDA hepato-biliary scintigraphy (HBS) and the comparison between "pre-scout" HBS and HBS just after "scout dose". Finally, blood samples will be collected at different time points in order to explore the biological peripheral response to these therapies. Perspectives: The newly developed 166Ho-microspheres have distinctive advantages over the existing 90Ymicrospheres with improved dosimetry that represents a prerequisite for optimal safety and efficacy.

Inclusion Criteria:Patients must have given written informed consentAdults ≥ 18 years-oldTypical imaging or biopsy proven HCC according to EASL-EORTC guidelines (1)Unresectable disease, BCLC B, or contraindicated for ablation, resection or transplantation, BCLC A, or BCLC C patients with no extra-hepatic extension, patients on the waiting list for resection or transplantation.At least one measurable lesion on multiphasic CT or MRIPreserved liver function with Child- Pugh score≤ B7ECOG performance status ≤ 1 (Table 2)Life expectancy ≥3 monthsEfficient contraception for womenPlatelets ≥ 50000/m3 and PT≥ 50%Hemoglobin ≥8.5 g/dlBilirubin ≤ 2 mg/dlASAT/ALAT levels ≤ 5x upper normal limitCreatinine ≤ 1.5x upper normal limitExclusion Criteria:Before work-up:History of progressive, uncontrolled cancer other than HCC presenting liver metastasis.>50% of liver involvementPortal vein thrombosis of the main branch diagnosed on contrast enhanced images. Involvement of the right or left portal main branches and more distal is acceptedEvidence of extrahepatic diseaseUnmanageable intolerance to contrast mediumContraindication to hepatic angiographyDigestive hemorrhage due to portal hypertension in the 30 days preceding treatmentPrevious systemic treatment, radiation therapy, transarterial loco-regional therapy or ablation therapy for HCCActive infection or untreated active hepatitis (if detectable viral HBV load, treatment with a nucleoside analog should be instituted).Pregnancy or breast feedingAscitisTransjugular intrahepatic portosystemic shunt (TIPS) or portacaval shuntMajor surgery withing 4 weeks or incompletely healed surgical incision before starting study therapyPatients suffering from psychic disorders that make a comprehensive judgement impossible, such as psychosis, hallucinations and/or severe depression.Patients who are declared incapacitatedAfter work-up:Lung absorbed dose > 30 Gy, as calculated using the 166Ho scout dose or 99mTc MAAUncorrectable extrahepatic deposition of the scout dose activity. Activity in the falciform ligament, portal lymph nodes and gallbladder is accepted.