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Rhenium-188 Labeled Radiopharmaceuticals: Current Clinical Applications in Oncology and Promising Perspectives

Rhenium-188 ( 188 Re) is a high energy beta-emitting radioisotope with a short 16.9 h physical half-life, which has been shown to be a very attractive candidate for use in therapeutic nuclear medicine. The high beta emission has an average energy of 784 keV and a maximum energy of 2.12 MeV, sufficient to penetrate and destroy targeted abnormal tissues. In addition, the low-abundant gamma emission of 155 keV (15%) is efficient for imaging and for dosimetric calculations. These key characteristics identify 188 Re as an important therapeutic radioisotope for routine clinical use. Moreover, the highly reproducible on-demand availability of 188 Re from the 188 W/ 188 Re generator system is an important feature and permits installation in hospital-based or central radiopharmacies for cost-effective availability of no-carrier-added (NCA) 188 Re. Rhenium-188 and technetium-99 m exhibit similar chemical properties and represent a “theranostic pair.” Thus, preparation and targeting of 188 Re agents for therapy is similar to imaging agents prepared with 99m Tc, the most commonly used diagnostic radionuclide. Over the last three decades, radiopharmaceuticals based on 188 Re-labeled small molecules, including peptides, antibodies, Lipiodol and particulates have been reported. The successful application of these 188 Re-labeled therapeutic radiopharmaceuticals has been reported in multiple early phase clinical trials for the management of various primary tumors, bone metastasis, rheumatoid arthritis, and endocoronary interventions. This article reviews the use of 188 Re-radiopharmaceuticals which have been investigated in patients for cancer treatment, demonstrating that 188Re represents a cost effective alternative for routine clinical use in comparison to more expensive and/or less readily available therapeutic radioisotopes.

radiopharmaceuticals↗

X-Rays Compton Detectors For Biomedical Application

Collimators are usually needed to image sources emitting X-rays that cannot be focused. Alternately, one may employ a Compton Camera (CC) and measure the direction of the incident X-ray by letting it interact with a thin solid, liquid or gaseous material (Tracker) and determine the scattering angle. With respect to collimated cameras, CCs allow higher gamma-ray efficiency in spite of lighter geometry, and may feature comparable spatial resolution. CCs are better when the X-ray energy is high and small setups are required. We review current applications of CCs to Gamma Ray Astronomy and Biomedical systems stressing advantages and drawbacks. As an example, we focus on a particular CC we are developing, which is designed to image small animals administered with marked pharmaceuticals, and assess the bio-distribution and targeting capability of these latter. This camera has to address some requirements: relatively high activity of the imaged objects; detection of gamma-rays of different energies that may range from 140 keV (Tc99m) to 511 keV; presence of gamma and beta radiation with energies up to 2 MeV in case of 188Re. The camera consists of a thin position-sensitive Silicon Drift Detector as Tracker, and a further downstream position-sensitive system employing scintillating crystals and a multi-anode photo-multiplier (Calorimeter). The choice of crystal, pixel size, and detector geometry has been driven by measurements and simulations with the tracking code GEANT4. Spatial resolution, efficiency and scope are discussed.

46 INSTRUMENTATION RELATED TO NUCLEAR SCIENCE AND ↗

Nuclear Data Sheets for A=188☆

Evaluated nuclear structure and decay data for all nuclei with mass number A=188 (Lu, Hf, Ta, W, Re, Os, Ir, Pt, Au, Hg, Tl, Pb, Bi, Po) are presented. The experimental data are compiled and evaluated, and best values for level and gamma-ray energies, quantum numbers, lifetimes, gamma-ray intensities, and other nuclear properties are recommended. Inconsistencies and discrepancies that exist in the literature are noted. This work supersedes the earlier evaluation by Balraj Singh (2002Si10), published in Nuclear Data Sheets 95, 387 (2002). The gamma-ray transition probabilities were calculated using the ENSDF analysis program ruler (www-nds.iaea.org/public/ensdf{sub p}gm/). However, the reader should be warned that the program may produce incorrect results when dealing with non-symmetric uncertainties.

73 NUCLEAR PHYSICS AND RADIATION PHYSICS↗

Radiation Pneumopathy in the Rat After Intravenous Application of {sup 188}Re-Labeled Microspheres

Purpose: To determine the dose dependence and kinetics of pneumopathy after systemic administration of rhenium-188 ({sup 188}Re)-labeled microspheres in a rat model. Methods and Materials: {sup 188}Re-microspheres were injected intravenously into adult Wistar rats (n = 54, age, 8 {+-} 2 months). The rats were divided into 6 groups according to the intended absorbed dose in the lung (maximum 60 Gy). Gamma camera scans were used to estimate the individual whole lung doses. One control group (n = 5) received nonlabeled microspheres. The breathing rate was measured before and weekly after the treatment using whole body plethysmography until 24 weeks. An increase in the breathing rate by 20% compared with the individual pretreatment control value was defined as the quantal endpoint for dose-effect analyses. Results: A biphasic increase in the breathing rate was observed. The first impairment of lung function occurred in Weeks 3-6. For late changes, the interval to onset was clearly dose dependent and was 17 weeks (10-30 Gy) and 10 weeks (50-60 Gy), respectively. The incidence of the response was highly dependent on the estimated lung dose. The median effective dose for an early and late response was virtually identical (19.9 {+-} 0.6 Gy and 20.4 {+-} 3.1 Gy, respectively). A significant correlation was found between the occurrence of an early and a late effect in the same rat, suggesting a strong consequential component. Conclusions: The effects of radiolabeled microspheres can be studied longitudinally in a rat model, using changes in the breathing rate as the functional, clinically relevant response. The isoeffective doses from the present study using radionuclide administration and those from published investigations of homogeneous external beam radiotherapy are almost similar.

62 RADIOLOGY AND NUCLEAR MEDICINE↗

Evaluation of S-values and dose distributions for {sup 90}Y, {sup 131}I, {sup 166}Ho, and {sup 188}Re in seven lobes of the rat liver

Purpose: Rats have been widely used in radionuclide therapy research for the treatment of hepatocellular carcinoma (HCC). This has created the need to assess rat liver absorbed radiation dose. In most dose estimation studies, the rat liver is considered as a homogeneous integrated target organ with a tissue composition assumed to be similar to that of human liver tissue. However, the rat liver is composed of several lobes having different anatomical and chemical characteristics. To assess the overall impact on rat liver dose calculation, the authors use a new voxel-based rat model with identified suborgan regions of the liver. Methods: The liver in the original cryosectional color images was manually segmented into seven individual lobes and subsequently integrated into a voxel-based computational rat model. Photon and electron particle transport was simulated using the MCNPX Monte Carlo code to calculate absorbed fractions and S-values for {sup 90}Y, {sup 131}I, {sup 166}Ho, and {sup 188}Re for the seven liver lobes. The effect of chemical composition on organ-specific absorbed dose was investigated by changing the chemical composition of the voxel filling liver material. Radionuclide-specific absorbed doses at the voxel level were further assessed for a small spherical hepatic tumor. Results: The self-absorbed dose for different liver lobes varied depending on their respective masses. A maximum difference of 3.5% was observed for the liver self-absorbed fraction between rat and human tissues for photon energies below 100 keV. {sup 166}Ho and {sup 188}Re produce a uniformly distributed high dose in the tumor and relatively low absorbed dose for surrounding tissues. Conclusions: The authors evaluated rat liver radiation doses from various radionuclides used in HCC treatments using a realistic computational rat model. This work contributes to a better understanding of all aspects influencing radiation transport in organ-specific radiation dose evaluation for preclinical therapy studies, from tissue composition to organ morphology and activity distribution.

61 RADIATION PROTECTION AND DOSIMETRY↗

A dose point kernel database using GATE Monte Carlo simulation toolkit for nuclear medicine applications: Comparison with other Monte Carlo codes

Purpose: GATE is a Monte Carlo simulation toolkit based on the Geant4 package, widely used for many medical physics applications, including SPECT and PET image simulation and more recently CT image simulation and patient dosimetry. The purpose of the current study was to calculate dose point kernels (DPKs) using GATE, compare them against reference data, and finally produce a complete dataset of the total DPKs for the most commonly used radionuclides in nuclear medicine. Methods: Patient-specific absorbed dose calculations can be carried out using Monte Carlo simulations. The latest version of GATE extends its applications to Radiotherapy and Dosimetry. Comparison of the proposed method for the generation of DPKs was performed for (a) monoenergetic electron sources, with energies ranging from 10 keV to 10 MeV, (b) beta emitting isotopes, e.g., {sup 177}Lu, {sup 90}Y, and {sup 32}P, and (c) gamma emitting isotopes, e.g., {sup 111}In, {sup 131}I, {sup 125}I, and {sup 99m}Tc. Point isotropic sources were simulated at the center of a sphere phantom, and the absorbed dose was stored in concentric spherical shells around the source. Evaluation was performed with already published studies for different Monte Carlo codes namely MCNP, EGS, FLUKA, ETRAN, GEPTS, and PENELOPE. A complete dataset of total DPKs was generated for water (equivalent to soft tissue), bone, and lung. This dataset takes into account all the major components of radiation interactions for the selected isotopes, including the absorbed dose from emitted electrons, photons, and all secondary particles generated from the electromagnetic interactions. Results: GATE comparison provided reliable results in all cases (monoenergetic electrons, beta emitting isotopes, and photon emitting isotopes). The observed differences between GATE and other codes are less than 10% and comparable to the discrepancies observed among other packages. The produced DPKs are in very good agreement with the already published data, which allowed us to produce a unique DPKs dataset using GATE. The dataset contains the total DPKs for {sup 67}Ga, {sup 68}Ga, {sup 90}Y, {sup 99m}Tc, {sup 111}In, {sup 123}I, {sup 124}I, {sup 125}I, {sup 131}I, {sup 153}Sm, {sup 177}Lu {sup 186}Re, and {sup 188}Re generated in water, bone, and lung. Conclusions: In this study, the authors have checked GATE's reliability for absorbed dose calculation when transporting different kind of particles, which indicates its robustness for dosimetry applications. A novel dataset of DPKs is provided, which can be applied in patient-specific dosimetry using analytical point kernel convolution algorithms.

61 RADIATION PROTECTION AND DOSIMETRY↗

Calculation of electron and isotopes dose point kernels with fluka Monte Carlo code for dosimetry in nuclear medicine therapy

Purpose: The calculation of patient-specific dose distribution can be achieved by Monte Carlo simulations or by analytical methods. In this study, fluka Monte Carlo code has been considered for use in nuclear medicine dosimetry. Up to now, fluka has mainly been dedicated to other fields, namely high energy physics, radiation protection, and hadrontherapy. When first employing a Monte Carlo code for nuclear medicine dosimetry, its results concerning electron transport at energies typical of nuclear medicine applications need to be verified. This is commonly achieved by means of calculation of a representative parameter and comparison with reference data. Dose point kernel (DPK), quantifying the energy deposition all around a point isotropic source, is often the one. Methods: fluka DPKs have been calculated in both water and compact bone for monoenergetic electrons (10{sup -3} MeV) and for beta emitting isotopes commonly used for therapy ({sup 89}Sr, {sup 90}Y, {sup 131}I, {sup 153}Sm, {sup 177}Lu, {sup 186}Re, and {sup 188}Re). Point isotropic sources have been simulated at the center of a water (bone) sphere, and deposed energy has been tallied in concentric shells. fluka outcomes have been compared to penelope v.2008 results, calculated in this study as well. Moreover, in case of monoenergetic electrons in water, comparison with the data from the literature (etran, geant4, mcnpx) has been done. Maximum percentage differences within 0.8{center_dot}R{sub CSDA} and 0.9{center_dot}R{sub CSDA} for monoenergetic electrons (R{sub CSDA} being the continuous slowing down approximation range) and within 0.8{center_dot}X{sub 90} and 0.9{center_dot}X{sub 90} for isotopes (X{sub 90} being the radius of the sphere in which 90% of the emitted energy is absorbed) have been computed, together with the average percentage difference within 0.9{center_dot}R{sub CSDA} and 0.9{center_dot}X{sub 90} for electrons and isotopes, respectively. Results: Concerning monoenergetic electrons, within 0.8{center_dot}R{sub CSDA} (where 90%-97% of the particle energy is deposed), fluka and penelope agree mostly within 7%, except for 10 and 20 keV electrons (12% in water, 8.3% in bone). The discrepancies between fluka and the other codes are of the same order of magnitude than those observed when comparing the other codes among them, which can be referred to the different simulation algorithms. When considering the beta spectra, discrepancies notably reduce: within 0.9{center_dot}X{sub 90}, fluka and penelope differ for less than 1% in water and less than 2% in bone with any of the isotopes here considered. Complete data of fluka DPKs are given as Supplementary Material as a tool to perform dosimetry by analytical point kernel convolution. Conclusions: fluka provides reliable results when transporting electrons in the low energy range, proving to be an adequate tool for nuclear medicine dosimetry.

62 RADIOLOGY AND NUCLEAR MEDICINE↗

Rhenium-188: Availability from the W-188/Re-188 Generator and Status of Current Applications

Rhenium-188 is one of the most readily available generator derived and useful radionuclides for therapy emitting - particles (2.12 MeV, 71.1% and 1.965 MeV, 25.6%) and imageable gammas (155 KeV, 15.1%). The 188W/188Re generator is an ideal source for the long term (4-6 months) continuous availability of no carrier added (nca) 188Re suitable for the preparation of radiopharmaceuticals for radionuclide therapy. The challenges associated with the double neutron capture route of production of the parent 188W radionuclide have been a major impediment in the progress of application of 188Re. Tungsten-188 of adequate specific activity can be prepared only in 2-3 of the high flux reactors operating in the World. Several useful technologies have been developed for the preparation of clinical grade 188W/188Re generator. Since the specific activity of 188W used in the generator is relatively low (<5 Ci/g), the eluted 188ReO4- can have low radioactive concentration often insufficient for radiopharmaceutical preparation. However, several efficient post elution concentration techniques have been developed that yield clinically useful 188ReO4-. Rhenium-188 has been used for the preparation of therapeutic radiopharmaceuticals for the management of diseases such as bone metastasis, rheumatoid arthritis and primary cancers. Several early phase clinical studies using radiopharmaceuticals based on 188Re-labeled phosphonates, antibodies, peptides, lipiodol and particulates have been reported. This article reviews the availability, and use of188Re including a discussion of why broader use of 188Re has not progressed as ecpected as a popular radionuclide for therapy.

60 APPLIED LIFE SCIENCES↗

Comparative analysis of 11 different radioisotopes for palliative treatment of bone metastases by computational methods

Purpose: Throughout the years, the palliative treatment of bone metastases using bone seeking radiotracers has been part of the therapeutic resources used in oncology, but the choice of which bone seeking agent to use is not consensual across sites and limited data are available comparing the characteristics of each radioisotope. Computational simulation is a simple and practical method to study and to compare a variety of radioisotopes for different medical applications, including the palliative treatment of bone metastases. This study aims to evaluate and compare 11 different radioisotopes currently in use or under research for the palliative treatment of bone metastases using computational methods. Methods: Computational models were used to estimate the percentage of deoxyribonucleic acid (DNA) damage (fast Monte Carlo damage algorithm), the probability of correct DNA repair (Monte Carlo excision repair algorithm), and the radiation-induced cellular effects (virtual cell radiobiology algorithm) post-irradiation with selected particles emitted by phosphorus-32 ({sup 32}P), strontium-89 ({sup 89}Sr), yttrium-90 ({sup 90}Y ), tin-117 ({sup 117m}Sn), samarium-153 ({sup 153}Sm), holmium-166 ({sup 166}Ho), thulium-170 ({sup 170}Tm), lutetium-177 ({sup 177}Lu), rhenium-186 ({sup 186}Re), rhenium-188 ({sup 188}Re), and radium-223 ({sup 223}Ra). Results: {sup 223}Ra alpha particles, {sup 177}Lu beta minus particles, and {sup 170}Tm beta minus particles induced the highest cell death of all investigated particles and radioisotopes. The cell survival fraction measured post-irradiation with beta minus particles emitted by {sup 89}Sr and {sup 153}Sm, two of the most frequently used radionuclides in the palliative treatment of bone metastases in clinical routine practice, was higher than {sup 177}Lu beta minus particles and {sup 223}Ra alpha particles. Conclusions: {sup 223}Ra and {sup 177}Lu hold the highest potential for palliative treatment of bone metastases of all radioisotopes compared in this study. Data reported here may prompt future in vitro and in vivo experiments comparing different radionuclides for palliative treatment of bone metastases, raise the need for the careful rethinking of the current widespread clinical use of {sup 89}Sr and {sup 153}Sm, and perhaps strengthen the use of {sup 223}Ra and {sup 177}Lu in the palliative treatment of bone metastases.

60 APPLIED LIFE SCIENCES↗

Postlumpectomy Focal Brachytherapy for Simultaneous Treatment of Surgical Cavity and Draining Lymph Nodes

Purpose: The primary objective was to investigate a novel focal brachytherapy technique using lipid nanoparticle (liposome)-carried {beta}-emitting radionuclides (rhenium-186 [{sup 186}Re]/rhenium-188 [{sup 188}Re]) to simultaneously treat the postlumpectomy surgical cavity and draining lymph nodes. Methods and Materials: Cumulative activity distributions in the lumpectomy cavity and lymph nodes were extrapolated from small animal imaging and human lymphoscintigraphy data. Absorbed dose calculations were performed for lumpectomy cavities with spherical and ellipsoidal shapes and lymph nodes within human subjects by use of the dose point kernel convolution method. Results: Dose calculations showed that therapeutic dose levels within the lumpectomy cavity wall can cover 2- and 5-mm depths for {sup 186}Re and {sup 188}Re liposomes, respectively. The absorbed doses at 1 cm sharply decreased to only 1.3% to 3.7% of the doses at 2 mm for {sup 186}Re liposomes and 5 mm for {sup 188}Re liposomes. Concurrently, the draining sentinel lymph nodes would receive a high focal therapeutic absorbed dose, whereas the average dose to 1 cm of surrounding tissue received less than 1% of that within the nodes. Conclusions: Focal brachytherapy by use of {sup 186}Re/{sup 188}Re liposomes was theoretically shown to be capable of simultaneously treating the lumpectomy cavity wall and draining sentinel lymph nodes with high absorbed doses while significantly lowering dose to surrounding healthy tissue. In turn, this allows for dose escalation to regions of higher probability of containing residual tumor cells after lumpectomy while reducing normal tissue complications.

62 RADIOLOGY AND NUCLEAR MEDICINE↗

Evaluation of Heat Transfer and Thermal Stability of Supercritical JP-7 Fuel

A series of electrically heated tube experiments was conducted to investigate the potential of JP-7 as a coolant under conditions relevant to a Mach 8 propulsion system. The heat transfer capabilities, carbon deposition, and material compatibility of JP-7 at surface temperatures up to 1700 F (927 C) were tested in 0.125 in. diameter tubes of 304 SS, Inconel 617, Haynes 188, Haynes 230, and 50150 Moly-Rhenium. The heat transfer to the coolant was modeled well by a Dittus-Boelter correlation at lower heat fluxes. At higher heat fluxes, audible instabilities were observed and corresponded to a significant enhancement in the coolant heat transfer. The carbon deposition rates in these tests were comparable to those in previous experiments at lower heat fluxes and much longer residence times. This result suggests that alternative paths of the deposition mechanism may be enhanced under high heat flux test conditions. Microscopic investigation of the post test tubes indicated that there was a significant layer of ordered carbon deposits that had not been seen in the tests at lower heat flux.

Linne, Diane L.↗

Direct intratumoral infusion of liposome encapsulated rhenium radionuclides for cancer therapy: Effects of nonuniform intratumoral dose distribution

Purpose: Focused radiation therapy by direct intratumoral infusion of lipid nanoparticle (liposome)-carried beta-emitting radionuclides has shown promising results in animal model studies; however, little is known about the impact the intratumoral liposomal radionuclide distribution may have on tumor control. The primary objective of this work was to investigate the effects the intratumoral absorbed dose distributions from this cancer therapy modality have on tumor control and treatment planning by combining dosimetric and radiobiological modeling with in vivo imaging data. Methods: {sup 99m}Tc-encapsulated liposomes were intratumorally infused with a single injection location to human head and neck squamous cell carcinoma xenografts in nude rats. High resolution in vivo planar imaging was performed at various time points for quantifying intratumoral retention following infusion. The intratumoral liposomal radioactivity distribution was obtained from 1 mm resolution pinhole collimator SPECT imaging coregistered with CT imaging of excised tumors at 20 h postinfusion. Coregistered images were used for intratumoral dosimetric and radiobiological modeling at a voxel level following extrapolation to the therapeutic analogs, {sup 186}Re/{sup 188}Re liposomes. Effective uniform dose (EUD) and tumor control probability (TCP) were used to assess therapy effectiveness and possible methods of improving upon tumor control with this radiation therapy modality. Results: Dosimetric analysis showed that average tumor absorbed doses of 8.6 Gy/MBq (318.2 Gy/mCi) and 5.7 Gy/MBq (209.1 Gy/mCi) could be delivered with this protocol of radiation delivery for {sup 186}Re/{sup 188}Re liposomes, respectively, and 37-92 MBq (1-2.5 mCi)/g tumor administered activity; however, large intratumoral absorbed dose heterogeneity, as seen in dose-volume histograms, resulted in insignificant values of EUD and TCP for achieving tumor control. It is indicated that the use of liposomes encapsulating radionuclides with higher energy beta emissions, dose escalation through increased specific activity, and increasing the number of direct tumor infusion sites improve tumor control. For larger tumors, the use of multiple infusion locations was modeled to be much more efficient, in terms of activity usage, at improving EUD and TCP to achieve a tumoricidal effect. Conclusions: Direct intratumoral infusion of beta-emitting radionuclide encapsulated liposomes shows promise for cancer therapy by achieving large focally delivered tumor doses. However, the results of this work also indicate that average tumor dose may underestimate tumoricidal effect due to substantial heterogeneity in intratumoral liposomal radionuclide distributions. The resulting intratumoral distribution of liposomes following infusion should be taken into account in treatment planning and evaluation in a clinical setting for an optimal cancer therapy.

60 APPLIED LIFE SCIENCES↗