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

Maarten L J Smits, Johannes F W Nijsen, Maurice A A J van den Bosch, Marnix G E H Lam, Maarten A D Vente, Julia E Huijbregts, Alfred D van het Schip, Mattijs Elschot, Wouter Bult, Hugo W A M de Jong, Pieter C W Meulenhoff, Bernard A Zonnenberg, Maarten L J Smits, Johannes F W Nijsen, Maurice A A J van den Bosch, Marnix G E H Lam, Maarten A D Vente, Julia E Huijbregts, Alfred D van het Schip, Mattijs Elschot, Wouter Bult, Hugo W A M de Jong, Pieter C W Meulenhoff, Bernard A Zonnenberg

Abstract

Background: Intra-arterial radioembolization with yttrium-90 microspheres ( 90Y-RE) is an increasingly used therapy for patients with unresectable liver malignancies. Over the last decade, radioactive holmium-166 poly(L-lactic acid) microspheres ( 166Ho-PLLA-MS) have been developed as a possible alternative to 90Y-RE. Next to high-energy beta-radiation, 166Ho 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 166Ho-PLLA-MS radioembolization ( 166Ho-RE) in animals. The aim of this phase I trial is to assess the safety and toxicity profile of 166Ho-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 ( 99mTc-MAA) dose, a low radioactive safety dose of 60-mg 166Ho-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 166Ho-PLLA-MS. Secondary objectives are to assess tumour response, biodistribution, performance status, quality of life, and to compare the 166Ho-PLLA-MS safety dose and the 99mTc-MAA dose distributions with respect to the ability to accurately predict microsphere distribution.

Discussion: This will be the first clinical study on 166Ho-RE. Based on preclinical studies, it is expected that 166Ho-RE has a safety and toxicity profile comparable to that of 90Y-RE. The biochemical and radionuclide characteristics of 166Ho-PLLA-MS that enable accurate dosimetry calculations and biodistribution assessment may however improve the overall safety of the procedure.

Trial registration: ClinicalTrials.gov NCT01031784.

Figures

Figure 1
Figure 1
Scanning electron microscope image of holmium microspheres.
Figure 2
Figure 2
Schematic overview of the administration system for 166Ho-RE.The administration system consists of the following components: iodine contrast agent (Visipaque ®, GE Healthcare) (1), saline solution (2), 20-ml syringe (Luer-Lock) (3), three-stopcock manifold (4), one-way valve (5), inlet line (6), administration vial containing the 166Ho-PLLA-MS (7), outlet line (8), flushing line (9), Y-connector (10) and catheter (11).
Figure 3
Figure 3
Timeline for study participants. *only in 18F-FDG-avid tumours.

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