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Methods for calculating the activity to be administered during yttrium-90 radioembolization (RE) are largely based on empirical toxicity and efficacy analyses, rather than dosimetry. At the same time, it is recognized that treatment planning based on proper dosimetry is of vital importance for the optimization of the results of RE. The heterogeneous and often clustered intrahepatic biodistribution of millions of point-source radioactive particles poses a challenge for dosimetry. Several studies found a relationship between absorbed doses and treatment outcome, with regard to both toxicity and efficacy. This should ultimately lead to improved patient selection and individualized treatment planning. New calculation methods and imaging techniques and a new generation of microspheres for image-guided RE will all contribute to these improvements. The aim of this review is to give insight into the latest and most important developments in RE dosimetry and to suggest future directions on patient selection, individualized treatment planning, and study designs.

Purpose: To assess the radiation exposure to individuals coming from patients after treatment with holmium-166 ((166)Ho) microspheres., Materials and Methods: Holmium-166 radioembolization (RE) with escalating whole-liver doses of 20 Gy, 40 Gy, 60 Gy, and 80 Gy was administered to 15 patients. Exposure rates (μSv/h) from patients were measured at 1.0 m distance from a lateral and frontal position at 0, 3, 6, 24, and 48 hours after infusion. The total effective dose equivalent (TEDE) to a maximally exposed contact was calculated in accordance with guidelines of the U.S. Nuclear Regulatory Commission (NRC). Results were extrapolated to a whole-liver dose of 60 Gy used in future treatments., Results: The median exposure rate at discharge, 48 hours after infusion, measured from a lateral position was 26 μSv/h (range, 7-45 μSv/h). Extrapolated to a whole-liver dose of 60 Gy, none of the exposure rates for the NRC contact scenario, at any time, frontal or lateral, would lead to a TEDE > 5 mSv; all patients may be released directly after treatment. Release after 6 hours is possible without contact restrictions for patients who received up to 7 GBq., Conclusions: The TEDE to a contact of patients treated with (166)Ho RE would not exceed the NRC limit of 5 mSv. Contact restrictions 6 hours after treatment are unnecessary for infused activities < 7 GBq., (Copyright © 2014 SIR. Published by Elsevier Inc. All rights reserved.)

Unlabelled: (166)Ho-poly(l-lactic acid) microspheres allow for quantitative imaging with MR imaging or SPECT for microsphere biodistribution assessment after radioembolization. The purpose of this study was to evaluate SPECT- and MR imaging-based dosimetry in the first patients treated with (166)Ho radioembolization., Methods: Fifteen patients with unresectable, chemorefractory liver metastases of any origin were enrolled in this phase 1 study and were treated with (166)Ho radioembolization according to a dose escalation protocol (20-80 Gy). The contours of all liver segments and all discernible tumors were manually delineated on T2-weighted posttreatment MR images and registered to the posttreatment SPECT images (n = 9) or SPECT/CT images (n = 6) and MR imaging-based R2* maps (n = 14). Dosimetry was based on SPECT (n = 15) and MR imaging (n = 9) for all volumes of interest, tumor-to-nontumor (T/N) activity concentration ratios were calculated, and correlation and agreement of MR imaging- and SPECT-based measurements were evaluated., Results: The median overall T/N ratio was 1.4 based on SPECT (range, 0.9-2.8) and 1.4 based on MR imaging (range, 1.1-3.1). In 6 of 15 patients (40%), all tumors had received an activity concentration equal to or higher than the normal liver (T/N ratio ≥ 1). Analysis of SPECT and MR imaging measurements for dose to liver segments yielded a high correlation (R(2) = 0.91) and a moderate agreement (mean bias, 3.7 Gy; 95% limits of agreement, -11.2 to 18.7)., Conclusion: With the use of (166)Ho-microspheres, in vivo dosimetry is feasible on the basis of both SPECT and MR imaging, which enables personalized treatment by selective targeting of inadequately treated tumors.

Purpose: Quantitative imaging of the radionuclide distribution is of increasing interest for microsphere radioembolization (RE) of liver malignancies, to aid treatment planning and dosimetry. For this purpose, holmium-166 ((166)Ho) microspheres have been developed, which can be visualized with a gamma camera. The objective of this work is to develop and evaluate a new reconstruction method for quantitative (166)Ho SPECT, including Monte Carlo-based modeling of photon contributions from the full energy spectrum., Methods: A fast Monte Carlo (MC) simulator was developed for simulation of (166)Ho projection images and incorporated in a statistical reconstruction algorithm (SPECT-fMC). Photon scatter and attenuation for all photons sampled from the full (166)Ho energy spectrum were modeled during reconstruction by Monte Carlo simulations. The energy- and distance-dependent collimator-detector response was modeled using precalculated convolution kernels. Phantom experiments were performed to quantitatively evaluate image contrast, image noise, count errors, and activity recovery coefficients (ARCs) of SPECT-fMC in comparison with those of an energy window-based method for correction of down-scattered high-energy photons (SPECT-DSW) and a previously presented hybrid method that combines MC simulation of photopeak scatter with energy window-based estimation of down-scattered high-energy contributions (SPECT-ppMC+DSW). Additionally, the impact of SPECT-fMC on whole-body recovered activities (A(est)) and estimated radiation absorbed doses was evaluated using clinical SPECT data of six (166)Ho RE patients., Results: At the same noise level, SPECT-fMC images showed substantially higher contrast than SPECT-DSW and SPECT-ppMC+DSW in spheres ≥ 17 mm in diameter. The count error was reduced from 29% (SPECT-DSW) and 25% (SPECT-ppMC+DSW) to 12% (SPECT-fMC). ARCs in five spherical volumes of 1.96-106.21 ml were improved from 32%-63% (SPECT-DSW) and 50%-80% (SPECT-ppMC+DSW) to 76%-103% (SPECT-fMC). Furthermore, SPECT-fMC recovered whole-body activities were most accurate (A(est) = 1.06 × A - 5.90 MBq, R(2) = 0.97) and SPECT-fMC tumor absorbed doses were significantly higher than with SPECT-DSW (p = 0.031) and SPECT-ppMC+DSW (p = 0.031)., Conclusions: The quantitative accuracy of (166)Ho SPECT is improved by Monte Carlo-based modeling of the image degrading factors. Consequently, the proposed reconstruction method enables accurate estimation of the radiation absorbed dose in clinical practice.

Objective: To investigate clinical and laboratory toxicity in patients with unresectable liver metastases, treated with yttrium-90 radioembolization ((90)Y-RE)., Methods: Patients with liver metastases treated with (90)Y-RE, between February 1(st) 2009 and March 31(st) 2012, were included in this study. Clinical toxicity assessment was based on the reporting in patient's charts. Laboratory investigations at baseline and during a four-month follow-up were used to assess laboratory toxicity according to the Common Terminology Criteria for Adverse Events version 4.02. The occurrence of grade 3-4 laboratory toxicity was stratified according to treatment strategy (whole liver treatment in one session versus sequential sessions). Response assessment was performed at the level of target lesions, whole liver and overall response in accordance with RECIST 1.1 at 3- and 6 months post-treatment. Median time to progression (TTP) and overall survival were calculated by Kaplan-Meier analysis., Results: A total of 59 patients, with liver metastases from colorectal cancer (n = 30), neuroendocrine tumors (NET) (n = 6) and other primary tumors (n = 23) were included. Clinical toxicity after (90)Y-RE treatment was confined to grade 1-2 events, predominantly post-embolization symptoms. No grade 3-4 clinical toxicity was observed, whereas laboratory toxicity grade 3-4 was observed in 38% of patients. Whole liver treatment in one session was not associated with increased laboratory toxicity. Three-months disease control rates for target lesions, whole liver and overall response were 35%, 21% and 19% respectively. Median TTP was 6.2 months for target lesions, 3.3 months for the whole liver and 3.0 months for overall response. Median overall survival was 8.9 months., Conclusion: The risk of severe complications or grade 3-4 clinical toxicity in patients with liver metastases of various primary tumors undergoing (90)Y-RE is low. In contrast, laboratory toxicity grade 3-4 can be expected to occur in more than one-third of patients without any clinical signs of radiation induced liver disease.

Radioembolization using yttrium-90 microspheres (⁹⁰Y-RE) is an emerging treatment option for breast cancer liver metastases (BCLM) patients if other locoregional and systemic treatment options fail. The purpose of this study was to provide a systematic overview of the current literature concerning ⁹⁰Y-RE for BCLM patients. A systematic search for relevant articles was performed in MEDLINE, EMBASE, and The Cochrane Library (January 2012) by combining an extensive list of synonyms for the determinants 'radioembolization', 'yttrium-90' and 'microsphere' with synonyms for the domain 'liver'. Data on tumor response, survival and toxicity were extracted and collected from all relevant articles. The search yielded 4078 studies, of which six were finally included for analysis, concerning a total of 198 patients. Tumor response was scored in five studies using either RECIST (n=3) or WHO criteria (n=2). Overall disease control rates (complete response, partial response and stable disease) at 2-4 months post treatment ranged from 78% to 96%. Median survival, available in four studies, ranged from 10.8 to 20.9 months. In total, gastric ulceration was reported in ten patients (5%) and treatment related mortality in three patients (2%). The results from the analyzed studies consistently show that ⁹⁰Y-RE is a safe and effective treatment option for BCLM patients. Comparative studies, especially combining ⁹⁰Y-RE with systemic therapy are strongly encouraged., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Purpose: Holmium-166 acetylacetonate microspheres ((166)Ho-AcAc-MS) are proposed as an intratumoral radioablation device. This article presents a pilot study in housecats with unresectable liver cancer. Feasibility and tolerability of intratumoral administrations of (166)Ho-AcAc-MS was investigated., Methods and Materials: Three cats with unresectable liver tumors of different histotype were included. One cat had hepatocellular carcinoma (HCC), one had cholangiocarcinoma (CC), and one had a malignant epithelial liver tumor (MELT) of unspecified histotype. (166)Ho-AcAc-MS were injected percutaneously under ultrasound guidance into the tumors. Followup consisted of physical examinations and hematologic and biochemical analyses., Results: (166)Ho-AcAc-MS were administered to three liver tumor-bearing cats. The treatment was well tolerated and the clinical condition, that is body weight, alertness, mobility, and coat condition of the animals improved markedly. Most biochemical and hematologic parameters normalized shortly after treatment. Life of all cats was extended and associated with a good quality of life. The HCC cat that received 33-Gy tumor-absorbed dose was euthanized 6 months after the first administration owing to disease progression. The MELT cat received 99-Gy tumor dose and was euthanized 3 months posttreatment owing to bacterial meningitis. The CC cat received 333Gy and succumbed 4 months after the first treatment owing to the formation of a pulmonary embolism., Conclusions: Percutaneous intratumoral injection of radioactive (166)Ho-AcAc-MS is feasible in liver tumor-bearing cats. The findings of this pilot study indicate that (166)Ho-AcAc-MS may constitute safe brachytherapeutic microspheres and warrant studies to confirm the clinical utility of this novel brachytherapy device., (Copyright © 2013 American Brachytherapy Society. Published by Elsevier Inc. All rights reserved.)

Objectives: To demonstrate the feasibility of MRI-based assessment of the intrahepatic Ho-PLLA-MS biodistribution after radioembolisation in order to estimate the absorbed radiation dose., Methods: Fifteen patients were treated with holmium-166 ((166)Ho) poly(L-lactic acid)-loaded microspheres (Ho-PLLA-MS, mean 484 mg; range 408-593 mg) in a phase I study. Multi-echo gradient-echo MR images were acquired from which R (2) maps were constructed. The amount of Ho-PLLA-MS in the liver was determined by using the relaxivity r (2) of the Ho-PLLA-MS and compared with the administered amount. Quantitative single photon emission computed tomography (SPECT) was used for comparison with MRI regarding the whole liver absorbed radiation dose., Results: R (2) maps visualised the deposition of Ho-PLLA-MS with great detail. The mean total amount of Ho-PLLA-MS detected in the liver based on MRI was 431 mg (range 236-666 mg) or 89 ± 19 % of the delivered amount (correlation coefficient r = 0.7; P < 0.01). A good correlation was found between the whole liver mean absorbed radiation dose as assessed by MRI and SPECT (correlation coefficient r = 0.927; P < 0.001)., Conclusion: MRI-based dosimetry for holmium-166 radioembolisation is feasible. Biodistribution is visualised with great detail and quantitative measurements are possible.

Background: The efficacy of radioembolisation for the treatment of liver tumours depends on the selective distribution of radioactive microspheres to tumorous tissue. The distribution of holmium-166 ((166)Ho) poly(L-lactic acid) microspheres can be visualised in vivo by both single-photon-emission CT (SPECT) and MRI. In this phase 1 clinical trial, we aimed to assess the safety and the maximum tolerated radiation dose (MTRD) of (166)Ho-radioembolisation in patients with liver metastases., Methods: Between Nov 30, 2009, and Sept 19, 2011, patients with unresectable, chemorefractory liver metastases were enrolled in the Holmium Embolization Particles for Arterial Radiotherapy (HEPAR) trial. Patients were treated with intra-arterial (166)Ho-radioembolisation in cohorts of three patients, with escalating aimed whole-liver absorbed doses of 20, 40, 60, and 80 Gy. Cohorts were extended to a maximum of six patients if dose-limiting toxicity occurred. Patients were assigned a dose in the order of study entry, with dose escalation until dose-limiting toxicity was encountered in at least two patients of a dose cohort. Clinical or laboratory toxicities were scored according to the National Cancer Institute's Common Terminology Criteria for Adverse Events version 3.0. The primary endpoint was the MTRD. Analyses were per protocol. This study is registered with ClinicalTrials.gov, number NCT01031784., Findings: 15 patients underwent (166)Ho-radioembolisation at doses of 20 Gy (n=6), 40 Gy (n=3), 60 Gy (n=3), and 80 Gy (n=3). Mean estimated whole-liver absorbed doses were 18 Gy (SD 2) for the 20 Gy cohort, 35 Gy (SD 1) for the 40 Gy cohort, 58 Gy (SD 3) for the 60 Gy cohort, and 73 Gy (SD 4) for the 80 Gy cohort. The 20 Gy cohort was extended to six patients because of the occurrence of dose-limiting toxicity in one patient (pulmonary embolism). In the 80 Gy cohort, dose-limiting toxicity occurred in two patients: grade 4 thrombocytopenia, grade 3 leucopenia, and grade 3 hypoalbuminaemia in one patient, and grade 3 abdominal pain in another patient. The MTRD was identified as 60 Gy. The most frequently encountered laboratory toxicities (including grade 1) were lymphocytopenia, hypoalbuminaemia, raised alkaline phosphatase, raised aspartate aminotransferase, and raised gamma-glutamyltransferase, which were all noted in 12 of 15 patients. Stable disease or partial response regarding target lesions was achieved in 14 of 15 patients (93%, 95% CI 70-99) at 6 weeks and nine of 14 patients (64%, 95% CI 39-84) at 12 weeks after radioembolisation. Compared with baseline, the average global health status and quality of life scale score at 6 weeks after treatment had decreased by 13 points (p=0·053) and by 14 points at 12 weeks (p=0·048). In all patients, technetium-99m ((99m)Tc)-macro-aggregated albumin SPECT, (166)Ho scout dose SPECT, and (166)Ho treatment dose SPECT showed similar patterns of the presence or absence of extrahepatic deposition of activity., Interpretation: (166)Ho-radioembolisation is feasible and safe for the treatment of patients with unresectable and chemorefractory liver metastases and enables image-guided treatment. Clinical (166)Ho-radioembolisation should be done with an aimed whole-liver absorbed dose of 60 Gy., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Purpose: To investigate the potential of magnetic resonance imaging (MRI) for accurate assessment of the three-dimensional (166)Ho activity distribution to estimate radiation-absorbed dose distributions in (166)Ho-loaded poly (L-lactic acid) microsphere ((166)Ho-PLLA-MS) liver radioembolization., Methods and Materials: MRI, computed tomography (CT), and single photon emission CT (SPECT) experiments were conducted on an anthropomorphic gel phantom with tumor-simulating gel samples and on an excised human tumor-bearing liver, both containing known amounts of (166)Ho-PLLA-MS. Three-dimensional radiation-absorbed dose distributions were estimated at the voxel level by convolving the (166)Ho activity distribution, derived from quantitative MRI data, with a (166)Ho dose point-kernel generated by MCNP (Monte Carlo N-Particle transport code) and from Medical Internal Radiation Dose Pamphlet 17. MRI-based radiation-absorbed dose distributions were qualitatively compared with CT and autoradiography images and quantitatively compared with SPECT-based dose distributions. Both MRI- and SPECT-based activity estimations were validated against dose calibrator measurements., Results: Evaluation on an anthropomorphic phantom showed that MRI enables accurate assessment of local (166)Ho-PLLA-MS mass and activity distributions, as supported by a regression coefficient of 1.05 and a correlation coefficient of 0.99, relating local MRI-based mass and activity calculations to reference values obtained with a dose calibrator. Estimated MRI-based radiation-absorbed dose distributions of (166)Ho-PLLA-MS in an ex vivo human liver visually showed high correspondence to SPECT-based radiation-absorbed dose distributions. Quantitative analysis revealed that the differences in local and total amounts of (166)Ho-PLLA-MS estimated by MRI, SPECT, and the dose calibrator were within 10%. Excellent agreement was observed between MRI- and SPECT-based dose-volume histograms., Conclusions: Quantitative MRI was demonstrated to provide accurate three-dimensional (166)Ho-PLLA-MS activity distributions, enabling localized intrahepatic radiation-absorbed dose estimation by convolution with a (166)Ho dose point-kernel for liver radioembolization treatment optimization and evaluation., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Purpose: To evaluate the incidence of extrahepatic deposition of technetium-99m-labeled albumin macroaggregates ((99m)Tc-MAA) after pretreatment angiography, before yttrium-90 radioembolizaton ((90)Y-RE), and to report on technical solutions that can be used to ensure safe delivery of (90)Y-microspheres in patients with initial extrahepatic deposition., Materials and Methods: A retrospective analysis of 26 patients with primary and secondary liver malignancies, who were scheduled for treatment with (90)Y-RE in our institution in 2009, was performed. The angiograms and single-photon emission computed tomography images of all patients were reviewed by an interventional radiologist and a nuclear medicine physician, respectively, to identify and localize extrahepatic deposition of (99m)Tc-MAA when present. Subsequently, the technical solutions were used to successfully perform (90)Y-RE in these patients were evaluated and described., Results: Extrahepatic deposition of (99m)Tc-MAA was observed in 8 of 26 patients (31%). In 7 of 8 patients, a second pretreatment angiography was performed to detect the cause of extrahepatic deposition. The technical solutions to enable safe (90)Y microspheres delivery included more distal placement of the microcatheter in the proper/right hepatic artery in 4 of 7 (57%) patients; (super)selective catheterization of multiple segmental branches in 2 of 7 (29%); and additional coiling of a newly detected branch in the remaining patient (14%). This was confirmed by a second MAA procedure. (90)Y-RE was eventually performed in 25 of 26 (96%) patients. No procedure-related complications (<30 days) were observed., Conclusion: Extrahepatic deposition of (99m)Tc-MAA after pretreatment angiography did occur in 8 of 26 (31%) patients. The technical solutions as presented allowed safe (90)Y-RE delivery in 25 of 26 (96%) patients.

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.

Poly(L-lactic acid) microspheres loaded with holmium-166 acetylacetonate (166Ho-PLLA-MS) are a novel microdevice for intra-arterial radio-embolization in patients with unresectable liver malignancies. The neutron activation in a nuclear reactor, in particular the gamma heating, damages the 166Ho-PLLA-MS. The degree of damage is dependent on the irradiation characteristics and irradiation time in a particular reactor facility. The aim of this study was to standardize and objectively validate the activation procedure in a particular reactor. The methods included light- and scanning electron microscopy (SEM), particle size analysis, differential scanning calorimetry, viscometry, thermal neutron flux measurements and energy deposition calculations. Seven hours-neutron irradiation results in sufficient specific activity of the 166Ho-PLLA-MS while structural integrity is preserved. Neutron flux measurements and energy deposition calculations are required in the screening of other nuclear reactors. For the evaluation of microsphere quality, light microscopy, SEM and particle size analysis are appropriate techniques.

Purpose: The aim of this study was to develop microspheres with an ultra high holmium content which can be neutron activated for radioablation of malignancies. These microspheres are proposed to be delivered selectively through either intratumoral injections into solid tumors or administered via an intravascularly placed catheter., Methods: Microspheres were prepared by solvent evaporation, using holmium acetylacetonate (HoAcAc) crystals as the sole ingredient. Microspheres were characterized using light and scanning electron microscopy, coulter counter, titrimetry, infrared and Raman spectroscopy, differential scanning calorimetry, X-ray powder diffraction, magnetic resonance imaging (MRI), and X-ray computed tomography (CT)., Results: Microspheres, thus prepared displayed a smooth surface. The holmium content of the HoAcAc microspheres (44% (w/w)) was higher than the holmium content of the starting material, HoAcAc crystals (33% (w/w)). This was attributed to the loss of acetylacetonate from the HoAcAc complex, during rearrangement of acetylacetonate around the holmium ion. The increase of the holmium content allows for the detection of (sub)microgram amounts of microspheres using MRI and CT., Conclusions: HoAcAc microspheres with an ultra-high holmium content were prepared. These microspheres are suitable for radioablation of tumors by intratumoral injections or treatment of liver tumors through transcatheter administration.

The worldwide incidence of hepatic malignancies, both primary and secondary, exceeds 1 000 000 new cases each year. The poor prognosis of patients suffering from hepatic malignancies has lead to the development of a liver directed therapy which consists of intra-arterial administration of radioactive particles through a catheter. Yttrium-90 ((90)Y) microspheres are increasingly applied for this purpose, and up to now nearly all clinical experience with radioembolization has been obtained with these microspheres. The response rate is very promising in both patients with primary and metastatic liver malignancies. Currently, two commercially available (90)Y microsphere devices are in use clinically, both as a first-line treatment and in a salvage setting. Unfortunately, the use of a pure beta-emitter like (90)Y hampers acquisition of high quality nuclear images for pre-treatment work-up and follow-up. This issue was addressed by the development of holmium-166 ((166)Ho) and rhenium-188 ((188)Re) microspheres, which emit both beta-particles for therapeutic purposes and gamma-photons for nuclear imaging. Moreover, since holmium is paramagnetic it allows for magnetic resonance imaging. (166)Ho loaded poly(L-lactic acid) microspheres have been thoroughly investigated in a preclinical setting, and recently the first clinical results for (188)Re microspheres were reported. This review provides an overview of the current status and (pre-)clinical developments of radioactive microspheres for treatment of liver malignancies.

Radioembolization with yttrium-90 microspheres ((90)Y-RE), either glass- or resin-based, is increasingly applied in patients with unresectable liver malignancies. Clinical results are promising but overall response and survival are not yet known. Therefore a meta-analysis on tumor response and survival in patients who underwent (90)Y-RE was conducted. Based on an extensive literature search, six groups were formed. Determinants were cancer type, microsphere type, chemotherapy protocol used, and stage (deployment in first-line or as salvage therapy). For colorectal liver metastases (mCRC), in a salvage setting, response was 79% for (90)Y-RE combined with 5-fluorouracil/leucovorin (5-FU/LV), and 79% when combined with 5-FU/LV/oxaliplatin or 5-FU/LV/irinotecan, and in a first-line setting 91% and 91%, respectively. For hepatocellular carcinoma (HCC), response was 89% for resin microspheres and 78% for glass microspheres. No statistical method is available to assess median survival based on data presented in the literature. In mCRC, (90)Y-RE delivers high response rates, especially if used neoadjuvant to chemotherapy. In HCC, (90)Y-RE with resin microspheres is significantly more effective than (90)Y-RE with glass microspheres. The impact on survival will become known only when the results of phase III studies are published.

Primary and secondary liver cancer have longtime been characterized by an overall poor prognosis since the majority of patients are not candidates for surgical resection with curative intent, systemic chemotherapy alone has rarely resulted in long-term survival, and the role of conventional external beam radiation therapy has traditionally been limited due to the relative sensitivity of the liver parenchyma to radiation. Therefore, a host of new treatment options have been developed and clinically introduced, including radioembolization techniques, which are the main topic of this paper. In these locoregional treatments liver malignancies are passively targeted because, unlike the normal liver, the blood supply of intrahepatic tumors is almost uniquely derived from the hepatic artery. These internal radiation techniques consist of injecting either yttrium-90 ((90)Y) microspheres, or iodine-131 ((131)I) or rhenium-188 ((188)Re) labeled lipiodol into the hepatic artery. Radioactive lipiodol is used exclusively for treatment of primary liver cancer, whereas (90)Y microsphere therapy is applied for treatment of both primary and metastatic liver cancers. Favorable clinical results have been achieved, particularly when (90)Y microspheres were used in conjunction with systemic chemotherapy. The main advantages of radiolabeled lipiodol treatment are that it is relatively inexpensive (especially (188)Re-HDD-lipiodol) and that the administration procedure is somewhat less complex than that of the microspheres. Holmium-166 ((166)Ho) loaded poly(L-lactic acid) microspheres have also been developed and are about to be clinically introduced. Since (166)Ho is a combined beta-gamma emitter and highly paramagnetic as well, it allows for both (quantitative) scintigraphic and magnetic resonance imaging.

Purpose: To investigate the use of magnetic resonance (MR) imaging in the administration and biodistribution of holmium-loaded poly(L-lactic acid) microspheres (Ho-PLLA-MS) in liver tumors., Materials and Methods: MR imaging measurements were obtained in phantoms, three ex vivo rabbit livers, and four livers in living rabbits. When applicable, measurements were compared with those on scintigraphic images. The transverse relaxivity R2* of the Ho-PLLA-MS was determined in a phantom study. The in vivo animal experiments were performed by using rabbits with an implanted VX2 tumor. Detection of passing Ho-PLLA-MS to estimate lung shunting was performed in a scaled model of the vena cava., Results: In the ex vivo liver experiments, the feasibility of real-time MR imaging during administration of microspheres was demonstrated. The in vivo rabbit experiments demonstrated that MR imaging can depict radioactive, nonradioactive, and decayed Ho-PLLA-MS after treatment for as long as they remain in the body. Furthermore, this study showed the ability of dynamic MR imaging to detect single doses of passing Ho-PLLA-MS., Conclusion: Ho-PLLA-MS used for internal radionuclide therapy can be imaged clearly in vivo with MR imaging.

Since one of the most frequent sites of human metastatic cancer is the liver, particularly in colon and rectum carcinoma, there is a special need for the development of an effective therapy. This study describes the parameters for reproducible production of poly lactic acid (PLA) microspheres with an average diameter of 37 microm and labelled with neutron-activated holmium-166 (Emax=1.84 MeV, t1/2=26. 8 h), suitable for use in internal radionuclide therapy of liver metastases. It is demonstrated that holmium-loaded PLA microspheres can be prepared by a relatively simple method, with incorporation of 17.0%+/-0.6% holmium (n=5), and that 20 GBq can be obtained from 400 mg neutron activatable microspheres. In order to produce this high amount of activity, the microspheres must be free of water and irradiation must be performed in a polyethylene vial, with a relatively low neutron flux (5x10(13) cm-2 s-1) within 1 h. Under these well-defined conditions minor surface changes were seen which barely affected total volume and consequently total radioactivity of the microspheres with a diameter of 20-50 microm. Overall structural integrity was maintained in terms of form and size. In vitro analyses showed that >99.3% of 166Ho activity was retained in the microspheres after 192 h incubation in PBS, plasma and leucocytes, while in liver homogenate retention was still 98.4%.