Holmium-166 radioembolization for the treatment of patients with liver metastases: design of the phase I HEPAR trial

BACKGROUND: Intra-arterial radioembolization with yttrium-90 microspheres ( (90)Y-RE) is an increasingly used therapy for patients with unresectable liver malignancies. Over the last decade, radioactive holmium-166 poly(L-lactic acid) microspheres ( (166)Ho-PLLA-MS) have been developed as a possible alternative to (90)Y-RE. Next to high-energy beta-radiation, (166)Ho also emits gamma-radiation, which allows for imaging by gamma scintigraphy. In addition, Ho is a highly paramagnetic element and can therefore be visualized by MRI. These imaging modalities are useful for assessment of the biodistribution, and allow dosimetry through quantitative analysis of the scintigraphic and MR images. Previous studies have demonstrated the safety of (166)Ho-PLLA-MS radioembolization ( (166)Ho-RE) in animals. The aim of this phase I trial is to assess the safety and toxicity profile of (166)Ho-RE in patients with liver metastases. METHODS: The HEPAR study (Holmium Embolization Particles for Arterial Radiotherapy) is a non-randomized, open label, safety study. We aim to include 15 to 24 patients with liver metastases of any origin, who have chemotherapy-refractory disease and who are not amenable to surgical resection. Prior to treatment, in addition to the standard technetium-99m labelled macroaggregated albumin ( (99m)Tc-MAA) dose, a low radioactive safety dose of 60-mg (166)Ho-PLLA-MS will be administered. Patients are treated in 4 cohorts of 3-6 patients, according to a standard dose escalation protocol (20 Gy, 40 Gy, 60 Gy, and 80 Gy, respectively). The primary objective will be to establish the maximum tolerated radiation dose of (166)Ho-PLLA-MS. Secondary objectives are to assess tumour response, biodistribution, performance status, quality of life, and to compare the (166)Ho-PLLA-MS safety dose and the (99m)Tc-MAA dose distributions with respect to the ability to accurately predict microsphere distribution. DISCUSSION: This will be the first clinical study on (166)Ho-RE. Based on preclinical studies, it is expected that (166)Ho-RE has a safety and toxicity profile comparable to that of (90)Y-RE. The biochemical and radionuclide characteristics of (166)Ho-PLLA-MS that enable accurate dosimetry calculations and biodistribution assessment may however improve the overall safety of the procedure. TRIAL REGISTRATION: ClinicalTrials.gov NCT01031784