Study Protocol: Adjuvant Holmium-166 Radioembolization After Radiofrequency Ablation in Early-Stage Hepatocellular Carcinoma Patients-A Dose-Finding Study (HORA EST HCC Trial)

Pim Hendriks, Daphne D D Rietbergen, Arian R van Erkel, Minneke J Coenraad, Mark J Arntz, Roel J Bennink, Andries E Braat, A Stijn L P Crobach, Otto M van Delden, Tom van der Hulle, Heinz-Josef Klümpen, Rutger W van der Meer, J Frank W Nijsen, Carla S P van Rijswijk, Joey Roosen, Bastian N Ruijter, Frits Smit, Mette K Stam, R Bart Takkenberg, Maarten E Tushuizen, Floris H P van Velden, Lioe-Fee de Geus-Oei, Mark C Burgmans, Dutch Hepatocellular Cholangiocarcinoma Group, Pim Hendriks, Daphne D D Rietbergen, Arian R van Erkel, Minneke J Coenraad, Mark J Arntz, Roel J Bennink, Andries E Braat, A Stijn L P Crobach, Otto M van Delden, Tom van der Hulle, Heinz-Josef Klümpen, Rutger W van der Meer, J Frank W Nijsen, Carla S P van Rijswijk, Joey Roosen, Bastian N Ruijter, Frits Smit, Mette K Stam, R Bart Takkenberg, Maarten E Tushuizen, Floris H P van Velden, Lioe-Fee de Geus-Oei, Mark C Burgmans, Dutch Hepatocellular Cholangiocarcinoma Group

Abstract

Purpose: To investigate the biodistribution of holmium-166 microspheres (166Ho-MS) when administered after radiofrequency ablation (RFA) of early-stage hepatocellular carcinoma (HCC). The aim is to establish a perfused liver administration dose that results in a tumoricidal dose of holmium-166 on the hyperaemic zone around the ablation necrosis (i.e. target volume).

Materials and methods: This is a multicentre, prospective, dose-escalation study in HCC patients with a solitary lesion 2-5 cm, or a maximum of 3 lesions of ≤ 3 cm each. The day after RFA patients undergo angiography and cone-beam CT (CBCT) with (super)selective infusion of technetium-99 m labelled microalbumin aggregates (99mTc-MAA). The perfused liver volume is segmented from the CBCT and 166Ho-MS is administered to this treatment volume 5-10 days later. The dose of holmium-166 is escalated in a maximum of 3 patient cohorts (60 Gy, 90 Gy and 120 Gy) until the endpoint is reached. SPECT/CT is used to determine the biodistribution of holmium-166. The endpoint is met when a dose of ≥ 120 Gy has been reached on the target volume in 9/10 patients of a cohort. Secondary endpoints include toxicity, local recurrence, disease-free and overall survival.

Discussion: This study aims to find the optimal administration dose of adjuvant radioembolization with 166Ho-MS after RFA. Ultimately, the goal is to bring the efficacy of thermal ablation up to par with surgical resection for early-stage HCC patients.

Trial registration: Clinicaltrials.gov identifier: NCT03437382.

Keywords: Early-stage HCC; Hepatocellular carcinoma; Holmium-166; Radioembolization; Radiofrequency ablation; TARE; Thermal ablation.

Conflict of interest statement

M.C. Burgmans has received an educational grant from Boston Scientific. None are related to the current project. J.F.W. Nijsen is co-founder and part time scientific director of Quirem Medical which has been acquired by Terumo Europe NV in July 2020. Nijsen is entitled to certain milestone payments from Terumo which are related to Quirem’s financial, operational and regulatory performance in the future. Furthermore, Nijsen is inventor on the patents related to radioactive microspheres that are assigned to University Medical Center Utrecht Holding BV, Quirem Medical or BASF Corp. The activities of J.F.W. Nijsen within Quirem Medical are approved and supported by the Board of Directors of the Radboudumc. All other authors declare that they have no conflict of interest.

© 2022. The Author(s).

Figures

Fig. 1
Fig. 1
Schematic drawings of the study procedure. A HCC lesion of 2–5 cm. B Thermal ablation of HCC lesion. C Potential sites of LTP due to heat-sink effect, impaired heat propagation or satellite nodules. D Target zone for adjuvant TARE. E Deposition of 166Ho-MS with preferential flow of microspheres to the hyperaemic zone surrounding the ablation area. F Perfused liver volume after 166Ho-MS TARE (i.e. treatment volume)
Fig. 2
Fig. 2
Participants timeline of the treatment period. After the angiography procedure and the acquisition of the Tc-99 m MAA SPECT/CT, the dose calculation was performed and 166Ho-MS were ordered

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