title: Holmium-166 radioembolization for the treatment of patients with liver metastases: design of the phase I HEPAR trial.
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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Radiology and Nuclear Medicine, University Medical Center Utrecht, Heidelberglaan 100, E01,132, 3584 CX Utrecht, The Netherlands.
authors.forename: Maarten L J
authors.initials: ML
authors.lastname: Smits
authors.forename: Johannes F W
authors.initials: JF
authors.lastname: Nijsen
authors.forename: Maurice A A J
authors.initials: MA
authors.lastname: van den Bosch
authors.forename: Marnix G E H
authors.initials: MG
authors.lastname: Lam
authors.forename: Maarten A D
authors.initials: MA
authors.lastname: Vente
authors.forename: Julia E
authors.initials: JE
authors.lastname: Huijbregts
authors.forename: Alfred D
authors.initials: AD
authors.lastname: van het Schip
authors.forename: Mattijs
authors.initials: M
authors.lastname: Elschot
authors.forename: Wouter
authors.initials: W
authors.lastname: Bult
authors.forename: Hugo W A M
authors.initials: HW
authors.lastname: de Jong
authors.forename: Pieter C W
authors.initials: PC
authors.lastname: Meulenhoff
authors.forename: Bernard A
authors.initials: BA
authors.lastname: Zonnenberg
mesh_terms: D004621:Embolization, Therapeutic; D005500:Follow-Up Studies; D006695:Holmium / Q000627:therapeutic use*; D006801:Humans; D008113:Liver Neoplasms / Q000000981:diagnostic imaging / Q000532:radiotherapy* / Q000556:secondary*; D008863:Microspheres; D011379:Prognosis; D011877:Radionuclide Imaging; D019275:Radiopharmaceuticals / Q000627:therapeutic use*; D012107:Research Design; D013668:Technetium Tc 99m Aggregated Albumin / Q000627:therapeutic use; D015021:Yttrium Radioisotopes
chemical_list: D019275:Radiopharmaceuticals; D013668:Technetium Tc 99m Aggregated Albumin; D015021:Yttrium Radioisotopes; D006695:Holmium