A.D. van het Schip

Yttrium-90 microsphere radioembolization for the treatment of liver malignancies: a structured meta-analysis

Radioembolization with yttrium-90 microspheres (90Y-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 90Y-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 90Y-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, 90Y-RE delivers high response rates, especially if used neoadjuvant to chemotherapy. In HCC, 90Y-RE with resin microspheres is significantly more effective than 90Y-RE with glass microspheres. The impact on survival will become known only when the results of phase III studies are published.

Advances in Nuclear Oncology: Microspheres for Internal Radionuclide Therapy of Liver Tumours

Liver metastases cause the majority of deaths from colorectal cancer, and response to chemotherapy and external radiotherapy is poor. An alternative is internal radionuclide therapy using (90)Y labeled microspheres. These microspheres are very stable and have a proven efficacy in the field of treatment of primary or metastatic hepatic cancer. Whilst these glass spheres showed encouraging results in patients, their high density is a serious drawback. Currently, other materials with lower densities and other radioisotopes are being investigated in order to optimize this promising new therapy. Three major radiolabeled microsphere materials, viz. glass, resin-based and polymer-based, are now available for therapy or are being tested in animals. In this review the preparation, stability and degradation of these spheres are discussed.

Characterization of poly(l-lactic acid) microspheres loaded with holmium acetylacetonate

Holmium-loaded PLLA microspheres are useful systems in radioembolization therapy of liver metastases because of their low density, biodegradability and favourable radiation characteristics. Neutron activated Ho-loaded microspheres showed a surprisingly low release of the relatively small holmium complex. In this paper factors responsible for this behaviour are investigated, in particular by the use of differential scanning calorimetry, scanning electron microscopy, infrared spectroscopy and X-ray diffraction. The holmium complex is soluble in PLLA up to 8% in films and 17% in microspheres. Interactions between carbonyl groups of PLLA, and the Ho-ion in the HoAcAc complex, explain very satisfactorily the high stability of holmium-loaded microspheres.

Influence of neutron irradiation on holmium acetylacetonate loaded poly(l-lactic acid) microspheres

Holmium-loaded microspheres are useful systems in radio-embolization therapy of liver metastases. For administration to a patient, the holmium-loaded microspheres have to be irradiated in a nuclear reactor to become radioactive. In this paper. the influence of neutron irradiation on poly(L-lactic acid) (PLLA) microspheres and films, with or without holmium acetylacetonate (HoAcAc), is investigated, in particular using differential scanning calorimetry (MDSC), scanning electron microscopy, gel permeation chromatography (GPC), infrared spectroscopy, and X-ray diffraction. After irradiation of the microspheres, only minor surface changes were seen using scanning electron microscopy, and the holmium complex remained immobilized in the polymer matrix as reflected by a relatively small release of this complex. GPC and MDSC measurements showed a decrease in molecular weight and crystallinity of the PLLA, respectively, which can be ascribed to radiation induced chain scission. Irradiation of the HoAcAc loaded PLLA matrices resulted in evaporation of the non-coordinated and one coordinated water molecule of the HoAcAc complex, as evidenced by MDSC and X-ray diffraction analysis. Infrared spectroscopy indicated that some degradation of the acetylacetonate anion occurred after irradiation. Although some radiation induced damage of both the PLLA matrix and the embedded HoAcAc-complex occurs, the microspheres retain their favourable properties (no marginal release of Ho, preservation of the microsphere size), which make these systems interesting candidates for the treatment of tumours by radio-embolization.

Neutron activation of holmium poly(L-lactic acid) microspheres for hepatic arterial radioembolization: a validation study

Poly(L-lactic acid) microspheres loaded with holmium-166 acetylacetonate (166Ho-PLLA-MS) are a novel microdevice for intra-arterial radioembolization 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.

Lanthanide bearing microparticulate systems for multi-modality imaging and targeted therapy of cancer.

The rapid developments of high-resolution imaging techniques are offering unique possibilities for the guidance and follow up of recently developed sophisticated anticancer therapies. Advanced biodegradable drug delivery systems, e.g. based on liposomes and polymeric nanoparticles or microparticles, are very effective tools to carry these anticancer agents to their site of action. Elements from the group of lanthanides have very interesting physical characteristics for imaging applications and are the ideal candidates to be co-loaded either in their non-radioactive or radioactive form into these advanced drug delivery systems because of the following reasons: Firstly, they can be used both as magnetic resonance imaging (MRI) and computed tomography (CT) contrast agents and for single photon emission computed tomography (SPECT). Secondly, they can be used for radionuclide therapies which, importantly, can be monitored with SPECT, CT, and MRI. Thirdly, they have a relatively low toxicity, especially when they are complexed to ligands. This review gives a survey of the currently developed lanthanide-loaded microparticulate systems that are under investigation for cancer imaging and/or cancer therapy.

Microspheres with ultrahigh holmium content for radioablation of malignancies

PurposeThe 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.MethodsMicrospheres 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).ResultsMicrospheres, 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.ConclusionsHoAcAc 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.

Can bone marrow scintigraphy predict platelet toxicity after treatment with 186Re-HEDP?

The toxicity of 186Re-1,1-hydroxyethylidene diphosphonate (186Re-HEDP) therapy in patients with painful bone metastases is mainly limited to thrombocytopaenia. The aim of this study was to investigate the influence of bone marrow scintigraphy on the prediction of decreased platelet counts after 186Re-HEDP therapy. Twenty-nine prostatic cancer patients with multiple painful bone metastases were included in the study. From a pre-therapy nanocolloid bone marrow scintigram, the bone marrow index (BMI) was determined as an indicator of the extent of bone marrow involvement. The influence of the BMI on the prediction of percent decrease in platelet counts was investigated. The mean BMI was 59 +/- 20. Regression analysis showed that the BMI does not improve the relationship between percent reduction in platelet count and administered dose. In contrast, we previously showed that the bone scan index (BSI) does predict the percent reduction in platelet counts before treatment. We conclude that bone marrow scintigraphy does not provide any additional information on platelet toxicity after a therapeutic dose of 186Re-HEDP. Bone scintigraphy is preferred in the prediction of reduced platelet counts.

Holmium-166 acetylacetonate microspheres as an intratumoral radioablation device

Opportunistic pathogens are ubiquitous and lead to life threatening infection making it a common place for mankind. Localizing occult infection noninvasively, has continued to be as challenging as treating the infection. Pathogenesis of infection is associated with activation of a large number of parameters. Over the past 35 years, a variety of these parameters have been targeted for a development of a most suitable radiopharmaceutical that will image abscesses conveniently and with high sensitivity and specificity. These parameters include polymorphonuclear neutrophil (PMNs), cytokines, bacteria and glycosis to name a few. However, challenges for specificity still arise, not from the lack of availability of agents that will image infection, but from the lack of their versality. The good old Ga‐67‐citrate takes too long to image abscesses before abscesses can be localized after its administration. In‐111‐Oxine, although considered the best, suffers from ex vivo labeling of blood cells, cost and long half life of In‐111. Tc‐99m‐HMPAO elutes off the labeled White blood cells, cytokines specific agents can present toxicity, PMN specific antibodies do not label PMNs with high avidity and bacterial agents do not target bacteria specifically. Radioactive agents that harbor into infection foci nonspecifically through increased capillary permeability are plentiful but of course are nonspecific and the current popular agent F‐18‐FDG does not localize only infection and renders itself nonspecific. Despite the far from ideal circumstances, NM physicians have done a remarkable job, and have continued to provide excellent care for those patients who suffer from bacterial infection or inflammation. Scientists and physician scientists on the other hand have continued to seek new and improved agents that may address some of the present challenges. This presentation will summarize today’s challenges and attempt to present tomorrow’s prospects. OP203 SPECT-CT in the diagnosis of inflammation and infection