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

Smits et al. Journal of Experimental & Clinical Cancer Research 2010, 29:70 http://www.jeccr.com/content/29/1/70 Open Access RESEARCH Holmium-166 radioembolization for the treatment of patients with liver metastases: design of the phase I HEPAR trial Research Maarten LJ Smits1, Johannes FW Nijsen*1, Maurice AAJ van den Bosch1, Marnix GEH Lam1, Maarten AD Vente1, Julia E Huijbregts1, Alfred D van het Schip1, Mattijs Elschot1, Wouter Bult1, Hugo WAM de Jong1, Pieter CW Meulenhoff2 and Bernard A Zonnenberg1 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 betaradiation, 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 chemotherapyrefractory 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 166HoPLLA-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 166HoPLLA-MS that enable accurate dosimetry calculations and biodistribution assessment may however improve the overall safety of the procedure. Trial registration: ClinicalTrials.gov NCT01031784 Background The liver is a common site of metastatic disease. Hepatic metastases can originate from a wide range of primary tumours (e.g. colorectal-, breast- and neuroendocrine tumours) [1]. It is estimated that 50% of all patients with a * Correspondence: 1 Department of Radiology and Nuclear Medicine, University Medical Center Utrecht, Heidelberglaan 100, E01.132, 3584 CX Utrecht, The Netherlands Full list of author information is available at the end of the article primary colorectal tumour will in due course develop hepatic metastases [2]. Once a primary malignancy has spread to the liver, the prognosis of many of these patients deteriorates significantly. Potentially curative treatment options for hepatic metastases consist of subtotal hepatectomy or, in certain cases, radiofrequency ablation. Unfortunately, only 20-30% of patients are eligible for these potentially curative treatment options, mainly because hepatic metastases are often multiple and © 2010 Smits et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Smits et al. Journal of Experimental & Clinical Cancer Research 2010, 29:70 http://www.jeccr.com/content/29/1/70 Page 2 of 11 in an advanced stage at the time of presentation [3]. The majority of patients are therefore left with palliative treatment options. Palliative therapy consists primarily of systemic chemotherapy. In spite of the many promising developments on cytostatic and targeted biological agents over the last ten years, there are still certain tumour types that do not respond adequately and the long-term survival rate for patients with unresectable metastatic liver disease remains low [4-8]. Moreover, systemic chemotherapy can be associated with substantial side effects that lie in the non-specific nature of this treatment. Cytostatic agents are distributed over the entire body, destroying cells that divide rapidly, both tumour cells and healthy cells. For these reasons, a significant need for new treatment options is recognized. A relatively recently developed therapy for primary and secondary liver cancer is radioembolization with yttrium90 microspheres ( 90Y-RE). 90Y-RE is a minimally invasive procedure during which radioactive microspheres are instilled selectively into the hepatic artery using a catheter. The high-energy beta-radiation emitting microspheres subsequently strand in the arterioles (mainly) of the tumour, and a tumoricidal radiation absorbed dose is delivered. The clinical results of this form of internal radiation therapy are promising [9,10]. The only currently clinically available microspheres for radioembolization loaded with 90Y are made of either glass (TheraSphere ®, MDS Nordion Inc., Kanata, Ontario Canada) or resin (SIR-Spheres ®, SIRTeX Medical Ltd., Sydney, New South Wales, Australia). Although 90Y-RE is evermore used and considered a safe and effective treatment, 90Y-MS have a drawback: following administration the actual biodistribution cannot be accurately visualized. For this reason, holmium-166 loaded poly(L-lactic acid) microspheres ( 166Ho-PLLAMS) have been developed at our centre [11,12]. Like 90Y, 166Ho emits high-energy beta particles to eradicate tumour cells but 166Ho also emits low-energy (81 keV) gamma photons which allows for nuclear imaging. As a consequence, visualization of the microspheres is feasible. This is very useful for three main reasons. Firstly, prior to administration of the treatment dose, a small scout dose of 166Ho-PLLA-MS can be administered for prediction of the distribution of the treatment dose. This provides a theoretical advantage over 90Y-RE, for which the distribution assessment depends on a scout dose of 99mTc-MAA, with a disputable distribution correlation with the actual microspheres [13]. Secondly, quantitative analysis of the nuclear images would allow assessment of the radiation dose delivered on both (...truncated)