RESUMEN
Rationale: Alpha particle emitting radiopharmaceuticals are generating considerable interest for the treatment of disseminated metastatic disease. Molecular imaging of the distribution of these agents is critical to safely and effectively maximize the clinical potential of this emerging drug class. The present studies aim to investigate the feasibility and limitations of quantitative SPECT for 223Ra, 225Ac and 227Th. Methods: Three state-of-the-art SPECT/CT systems were investigated: the GE Discovery NM/CT 670, the GE Optima NM/CT 640, and the Siemens Symbia T6. A series of phantoms, including the NEMA IEC Body phantom, were used to compare and calibrate each camera. Additionally, anthropomorphic physical tumor and vertebrae phantoms were developed and imaged to evaluate the quantitative imaging protocol. Results: This work describes and validates a methodology to calibrate each clinical system. The efficiency of each gamma camera was analyzed and compared. Using the calibration factors obtained with the NEMA phantom, we were able to quantify the activity in 3D-printed tissue phantoms with an error of 2.1%, 3.5% and 11.8% for 223Ra, 225Ac, and 227Th, respectively. Conclusion: The present study validates that quantitative SPECT/CT imaging of 223Ra, 225Ac, and 227Th is achievable but that careful considerations for camera configuration are required. These results will aid in future implementation of SPECT-based patient studies and will help to identify the limiting factors for accurate image-based quantification with alpha particle emitting radionuclides.
Asunto(s)
Procesamiento de Imagen Asistido por Computador/métodos , Radiofármacos/farmacocinética , Tomografía Computarizada por Tomografía Computarizada de Emisión de Fotón Único/métodos , Actinio/farmacocinética , Partículas alfa/uso terapéutico , Animales , Disponibilidad Biológica , Calibración , Humanos , Fantasmas de Imagen , Radioisótopos , Radio (Elemento)/farmacocinética , Torio/farmacocinética , Tomografía Computarizada por Rayos X/métodosRESUMEN
Thorium-227 (227Th) is a long-lived (T1/2 = 18.7 d) α-emitter that has emerged as candidate for radioimmunotherapy. Imaging of patients treated with thorium-227 conjugates is challenging due to the low activity administered and to photon emissions with low yields. In addition, the radioactive daughter radium-223 (223Ra) have photon emissions in the same energy range as 227Th. The long half-life of 223Ra (T1/2 = 11.4 d) and the possibility of redistribution motivates efforts to separate 227Th and 223Ra. The aim of this study was to investigate the feasibility of imaging of patients treated with 227Th-labeled-monoclonal antibody (mAb) and to determine acquisition and image processing parameters to enable discrimination between 227Th and 223Ra. Imaging was performed with a GE Discovery 670 NM/CT γ-camera. Radionuclide separation with different energy windows (EW) and collimators was studied in images of vials with either 227Th or 223Ra. Phantom acquisitions with clinically relevant activities were performed to assess image quality and the usefulness of background subtraction and spatial filtering. Two patients treated with 227Th-labeled-mAb were imaged. Imaging of vials showed that 223Ra can be distinguished from 227Th using multiple energy windows. Medium- and high-energy collimators showed similar performance of sensitivity and spatial resolution, whereas the low-energy collimator had higher sensitivity but poor resolution due to collimator penetration. Visually, the image quality was improved with background subtraction and spatial filtering. The patient images exhibited the expected image quality and a possibility to separate 227Th and 223Ra. γ-Camera imaging of patients treated with 227Th-mAb is feasible and 223Ra can be distinguished from 227Th. Image quality is substantially improved using background subtraction and a spatial smoothing filter. Acquisition settings recommended for planar images are: high-energy general purpose or medium-energy general purpose collimator, 40 min acquisition time and energy windows: (1) 70-100 keV (227Th and 223Ra); (2) 215-260 keV (227Th); (3) 260-290 keV (223Ra); (4) 350-420 keV (223Ra).
Asunto(s)
Radioinmunoterapia/métodos , Radiofármacos/farmacocinética , Radio (Elemento)/farmacocinética , Torio/farmacocinética , Ensayos Clínicos Fase I como Asunto , Estudios de Factibilidad , Cámaras gamma , Semivida , Humanos , Procesamiento de Imagen Asistido por Computador , Fantasmas de Imagen , Radiometría/métodos , Radiofármacos/administración & dosificación , Radio (Elemento)/administración & dosificación , Espectrometría gamma/instrumentación , Espectrometría gamma/métodos , Torio/administración & dosificación , Distribución TisularRESUMEN
Introduction: Thorium-227 is an alpha-emitting radioisotope with potential therapeutic applications in targeted alpha therapy. Thorium-227 decays to Radium-223, which may have an independent biodistribution to that of the parent Thorium-227 radiopharmaceutical. Quantitative in vivo imaging with sodium iodide (NaI) detectors is challenging due to cross-talk between neighboring γ-photopeaks as well as scattered γ-photons. The aim of this work was to validate the use of a spectral analysis technique to estimate the activity of each isotope within a region of interest applied to a pair of conjugate view planar acquisitions, acquired at multiple energy windows. Methods: Energy spectra per unit activity arising from unscattered Thorium-227 photons and Radium-223 photons as well as from scattered photons were modeled. These spectra were scaled until the combination of these component spectra resulted in the closest match to the measured data in four energy windows. Results: Measured estimates of activity followed the known decay curves in phantoms representative of a human torso. The mean errors in estimating Thorium-227 and Radium-223 were 5.1% (range -8.0% to 40.0%) and 3.4% (range -50.0% to 48.7%), respectively. The differences between the integrals of the theoretical and estimated time activity curve were <10% for both Thorium-227 and Radium-223. Conclusion: γ-camera quantification of Thorium-227 and Radium-223 can be achieved by using multiple energy window acquisitions.
Asunto(s)
Modelos Teóricos , Radiofármacos/farmacocinética , Radio (Elemento)/farmacocinética , Torio/farmacocinética , Cámaras gamma , Humanos , Modelos Anatómicos , Fantasmas de Imagen , Radiometría/métodos , Espectrometría gamma/instrumentación , Espectrometría gamma/métodos , Distribución Tisular , Torso/diagnóstico por imagenRESUMEN
Objective: Dose optimization and pharmacokinetic evaluation of α-particle emitting radium-223 dichloride (223RaCl2) by planar γ-camera or single photon emission computed tomography (SPECT) imaging are hampered by the low photon abundance and injected activities. In this study, we demonstrate SPECT of 223Ra using phantoms and small animal in vivo models. Methods: Line phantoms and mice bearing 223Ra were imaged using a dedicated small animal SPECT by detecting the low-energy photon emissions from 223Ra. Localization of the therapeutic agent was verified by whole-body and whole-limb autoradiography and its radiobiological effect confirmed by immunofluorescence. Results: A state-of-the-art commercial small animal SPECT system equipped with a highly sensitive collimator enables collection of sufficient counts for three-dimensional reconstruction at reasonable administered activities and acquisition times. Line sources of 223Ra in both air and in a water scattering phantom gave a line spread function with a full-width-at-half-maximum of 1.45 mm. Early and late-phase imaging of the pharmacokinetics of the radiopharmaceutical were captured. Uptake at sites of active bone remodeling was correlated with DNA damage from the α particle emissions. Conclusions: This work demonstrates the capability to noninvasively define the distribution of 223RaCl2, a recently approved α-particle-emitting radionuclide. This approach allows quantitative assessment of 223Ra distribution and may assist radiation-dose optimization strategies to improve therapeutic response and ultimately to enable personalized treatment planning.
Asunto(s)
Huesos/diagnóstico por imagen , Radiofármacos/farmacocinética , Radio (Elemento)/farmacocinética , Tomografía Computarizada de Emisión de Fotón Único/métodos , Animales , Autorradiografía/métodos , Neoplasias Óseas/radioterapia , Neoplasias Óseas/secundario , Huesos/efectos de la radiación , Humanos , Masculino , Ratones , Modelos Animales , Fantasmas de Imagen , Neoplasias de la Próstata Resistentes a la Castración/diagnóstico por imagen , Neoplasias de la Próstata Resistentes a la Castración/patología , Neoplasias de la Próstata Resistentes a la Castración/radioterapia , Radioisótopos/administración & dosificación , Radioisótopos/farmacocinética , Radiofármacos/administración & dosificación , Radio (Elemento)/administración & dosificación , Distribución Tisular , Tomografía Computarizada de Emisión de Fotón Único/instrumentaciónRESUMEN
PURPOSE: 223Ra-Dichloride is used for treatment of patients with metastatic bone disease from castration-resistant prostate cancer. The uptake and mechanism of action of 223Ra-Dichloride is not well understood. The aim of this work was to develop a compartmental model for 223Ra-Dichloride in patients to improve understanding of the underlying mechanisms. METHODS AND MATERIALS: A compartmental model was developed based on activity retention data from 6 patients (2 treatments of 110 kBq/kg 223Ra-Dichloride) for plasma, bone surfaces, small intestines, large intestines, and excretion data. Rate constants were extracted. Rate constant variability between patients and treatments was assessed. A population model was proposed and compared with the established International Commission on Radiological Protection-67 compartmental model. RESULTS: A single bone compartment cannot accurately describe activity retention in the skeleton. The addition of a second bone compartment improved the fit to skeleton retention data, and the Akaike information criterion decreased. Mean rate constants of 4.0 (range, 1.9-10.9) and 0.15 (0.07-0.39) h-1 were obtained for transport from plasma to first bone compartment and vice versa. Rate constants from first to second bone compartment and back of 0.03 (0.02-0.06) and 0.008 (0.003-0.011) h-1 were calculated. Rate constants for individual patients showed no significant difference between patients and treatments. CONCLUSIONS: The developed compartmental model suggests that 223Ra-Dichloride initially locates at the bone surface and is then incorporated into the bone matrix relatively quickly. This observation could have implications for dosimetry and understanding of the effects of alpha radiation on normal bone tissue. Results suggest that a population model based on patient measurements is feasible.
Asunto(s)
Antineoplásicos/farmacocinética , Neoplasias Óseas/metabolismo , Neoplasias Óseas/secundario , Neoplasias de la Próstata Resistentes a la Castración/patología , Radio (Elemento)/farmacocinética , Partículas alfa , Antineoplásicos/administración & dosificación , Antineoplásicos/sangre , Neoplasias Óseas/sangre , Neoplasias Óseas/radioterapia , Huesos/metabolismo , Humanos , Intestino Grueso/metabolismo , Intestino Delgado/metabolismo , Masculino , Modelos Biológicos , Radioisótopos/administración & dosificación , Radioisótopos/sangre , Radioisótopos/farmacocinética , Radio (Elemento)/administración & dosificación , Radio (Elemento)/sangreRESUMEN
BACKGROUND: Radium-223 is a targeted alpha-particle therapy that improves survival in men with metastatic castration resistant prostate cancer (mCRPC), particularly in men with elevated serum levels of bone alkaline phosphatase (B-ALP). We hypothesized that osteomimicry, a form of epithelial plasticity leading to an osteoblastic phenotype, may contribute to intralesional deposition of radium-223 and subsequent irradiation of the tumor microenvironment. METHODS: We conducted a pharmacodynamic study (NCT02204943) of radium-223 in men with bone mCRPC. Prior to and three and six months after radium-223 treatment initiation, we collected CTCs and metastatic biopsies for phenotypic characterization and CTC genomic analysis. The primary objective was to describe the impact of radium-223 on the prevalence of CTC B-ALP over time. We measured radium-223 decay products in tumor and surrounding normal bone during treatment. We validated genomic findings in a separate independent study of men with bone metastatic mCRPC (n = 45) and publicly accessible data of metastatic CRPC tissues. RESULTS: We enrolled 20 men with symptomatic bone predominant mCRPC and treated with radium-223. We observed greater radium-223 radioactivity levels in metastatic bone tumor containing biopsies compared with adjacent normal bone. We found evidence of persistent Cellsearch CTCs and B-ALP (+) CTCs in the majority of men over time during radium-223 therapy despite serum B-ALP normalization. We identified genomic gains in osteoblast mimicry genes including gains of ALPL, osteopontin, SPARC, OB-cadherin and loss of RUNX2, and validated genomic alterations or increased expression at the DNA and RNA level in an independent cohort of 45 men with bone-metastatic CRPC and in 150 metastatic biopsies from men with mCRPC. CONCLUSIONS: Osteomimicry may contribute in part to the uptake of radium-223 within bone metastases and may thereby enhance the therapeutic benefit of this bone targeting radiotherapy.
Asunto(s)
Biomarcadores de Tumor/genética , Neoplasias Óseas/radioterapia , Terapia Molecular Dirigida/métodos , Neoplasias de la Próstata Resistentes a la Castración/radioterapia , Radio (Elemento)/uso terapéutico , Anciano , Fosfatasa Alcalina/sangre , Fosfatasa Alcalina/genética , Biomarcadores de Tumor/metabolismo , Biopsia , Neoplasias Óseas/genética , Neoplasias Óseas/mortalidad , Neoplasias Óseas/secundario , Huesos/metabolismo , Huesos/patología , Huesos/efectos de la radiación , Cadherinas/genética , Cadherinas/metabolismo , Subunidad alfa 1 del Factor de Unión al Sitio Principal/genética , Subunidad alfa 1 del Factor de Unión al Sitio Principal/metabolismo , Progresión de la Enfermedad , Expresión Génica , Humanos , Masculino , Células Neoplásicas Circulantes/metabolismo , Células Neoplásicas Circulantes/patología , Células Neoplásicas Circulantes/efectos de la radiación , Osteonectina/genética , Osteonectina/metabolismo , Osteopontina/genética , Osteopontina/metabolismo , Próstata/metabolismo , Próstata/patología , Próstata/efectos de la radiación , Neoplasias de la Próstata Resistentes a la Castración/genética , Neoplasias de la Próstata Resistentes a la Castración/mortalidad , Neoplasias de la Próstata Resistentes a la Castración/patología , Radio (Elemento)/sangre , Radio (Elemento)/farmacocinética , Análisis de Supervivencia , Microambiente Tumoral/genética , Microambiente Tumoral/efectos de la radiaciónRESUMEN
This research aimed to assess the radiation absorbed dose produced by 177Lu-iPSMA (177Lu-prostate specific membrane antigen inhibitor), 225Ac-iPSMA and 223RaCl2 to prostate cancer cell nuclei in a simplified model of bone by using an experimental in-vitro prostate cancer LNCaP cell biokinetic study and Monte Carlo simulation with the MCNPX code. Results showed that 225Ac-iPSMA releases a nine hundred-fold radiation dose greater than 177Lu-iPSMA and 14 times more than 223RaCl2 per unit of activity retained in bone. 225Ac-iPSMA could be the best option for treatment of bone metastases in prostate cancer.
Asunto(s)
Actinio/uso terapéutico , Neoplasias Óseas/radioterapia , Neoplasias Óseas/secundario , Lutecio/uso terapéutico , Neoplasias de la Próstata/radioterapia , Neoplasias de la Próstata/secundario , Radioisótopos/uso terapéutico , Radio (Elemento)/uso terapéutico , Actinio/farmacocinética , Antígenos de Superficie , Neoplasias Óseas/metabolismo , Línea Celular Tumoral , Núcleo Celular/metabolismo , Núcleo Celular/efectos de la radiación , Simulación por Computador , Glutamato Carboxipeptidasa II/antagonistas & inhibidores , Humanos , Lutecio/farmacocinética , Masculino , Modelos Biológicos , Método de Montecarlo , Neoplasias de la Próstata/metabolismo , Radioisótopos/farmacocinética , Radiofármacos/farmacocinética , Radiofármacos/uso terapéutico , Dosificación Radioterapéutica , Radio (Elemento)/farmacocinética , Microambiente Tumoral/efectos de la radiaciónRESUMEN
PURPOSE: Despite the effectiveness of 223RaCl2 for treating patients with symptomatic bone metastatic disease, its mechanisms of action are still unclear. Even established dosimetric approaches differ considerably in their conclusions. In silico tumor models bring a new perspective to this situation because they can quantitatively simulate the interaction of α-particles with the target(s). Here, we investigated 3 different mathematical models of tumor growth that consider the radiation effect of radium-223 (223Ra) treatments and compared the results with clinical data. METHODS AND MATERIALS: The well-established Gompertz growth model was applied to simulate metastatic tumor burden. On the basis of published measurements of 223Ra uptake, we have incorporated the radiation effect of α-particles into the model and investigated 3 radium distribution scenarios-uniform exposure, exposure of only an outer layer, and exposure of a constant volume of the tumor. For each scenario, the times for various tumor stages to progress to the first symptomatic skeletal event were calculated. RESULTS: Uniform and outer-layer exposure scenarios showed very poor agreement with the Kaplan-Meier patient curves from clinical data. However, the constant-volume effect predicted outcomes very similar to the observed clinical results, suggesting, depending on the dose rate, that relatively small fractions of the cell population see damage from 223Ra. CONCLUSIONS: The commonly used assumption of uniform 223Ra distribution does not accurately reflect clinical responses. The suggestion that only a subpopulation of the tumor might be affected by 223Ra shows a pressing need to further study the tumor and drug kinetics to schedule more effective treatments in the future.
Asunto(s)
Antineoplásicos/farmacocinética , Neoplasias Óseas/metabolismo , Neoplasias Óseas/secundario , Modelos Biológicos , Radio (Elemento)/farmacocinética , Antineoplásicos/administración & dosificación , Neoplasias Óseas/patología , Neoplasias Óseas/radioterapia , Ensayos Clínicos como Asunto , Relación Dosis-Respuesta en la Radiación , Humanos , Estimación de Kaplan-Meier , Radioisótopos/administración & dosificación , Radioisótopos/farmacocinética , Radio (Elemento)/administración & dosificación , Factores de Tiempo , Carga Tumoral/efectos de la radiaciónRESUMEN
INTRODUCTION: Radium-223 dichloride is the first alpha-particle emitting therapeutic agent approved by FDA and EMA for bone metastatic castration-resistant prostate cancer. We studied its age-dependent biodistribution in mice, and compared it with [99mTc]Tc-MDP and [18F]NaF aiming to identify a potential imaging surrogate to predict [223Ra]RaCl2 whole-body localization. METHODS: Male C57Bl/6 mice dosed with [223Ra]RaCl2 were sacrificed at different time points to explore [223Ra]RaCl2 whole-body distribution. In another experiment, mice at different ages were dosed with [223Ra]RaCl2 to evaluate the aging impact. Finally, [99mTc]Tc-MDP and [18F]NaF were administered to mice, and we compared their biodistributions with [223Ra]RaCl2. Detailed micro-localization of each tracer was visualized using autoradiography and histochemical staining. RESULTS: [223Ra]RaCl2 uptake in bone was rapid and stable. We observed persistent localization at bone epiphyses, as well as the red pulp of the spleen, while its uptake in most soft tissues cleared within 24â¯h. [223Ra]RaCl2 distribution in soft tissues is similar in all age groups tested, while bone activity significantly decreased with aging. Although the diagnostic tracers cleared much faster from soft tissues than the therapeutic radionuclide, [99mTc]Tc-MDP and [18F]NaF both co-localized with [223Ra]RaCl2 in the skeletal compartment. CONCLUSIONS: Radium-223 localization to the bone is dependent on age-varying factors, which implies that radium-223 dosimetry should take patient age into account. [99mTc]Tc-MDP shows a different biodistribution from [223Ra]RaCl2, both in soft tissues and in bone. [18F]NaF presents a high similarity with [223Ra]RaCl2 in skeletal uptake, which validates the potential of [18F]NaF as an imaging surrogate to predict radium-223 radiotherapeutic distribution in bone.
Asunto(s)
Envejecimiento/metabolismo , Imagen Molecular , Radio (Elemento)/farmacocinética , Animales , Masculino , Ratones , Ratones Endogámicos C57BL , Radioisótopos/química , Radioisótopos/farmacocinética , Radio (Elemento)/química , Distribución TisularRESUMEN
PURPOSE: Hypoxic regions of tumors are less sensitive to radio- and chemotherapy, leading to poor prognosis of patients. One option to overcome the radioresistance is the irradiation of hypoxic tumors with high linear energy transfer (LET) α- or Auger electronemitters assuming their radiotoxicity would be less dependent on the cellular oxygenation status. Therefore, the aim of the present study was to determine whether irradiation with the intracellularly distributed Auger electron/γ-emitter 99mTc using the tracer [99mTc]TcHMPAO is a promising therapeutic option for the treatment of hypoxic tumor cells. Thus, the high LET α-particleemitter 223Ra ([223Ra]RaCl2) and the low LET ß-emitter 188Re ([188Re]NaReO4) were studied in comparison to [99mTc]Tc-HMPAO. MATERIALS AND METHODS: A431 tumor cells were incubated with [99mTc]Tc-HMPAO (1-20 MBq/2 mL), [223Ra]RaCl2 (1.4-16.3 kBq/2 mL) or [188Re]NaReO4 (0.3-13.7 MBq/2 mL) under normoxic or hypoxic conditions. The degree of radiotoxicity was analyzed using the colony forming assay (CFA), and the intracellular radionuclide uptake of the radiotracers was quantified. RESULTS: Hypoxic A431 cells are less radiosensitive to irradiation with [99mTc]Tc-HMPAO or [188Re]NaReO4 than normoxic ones. In contrast, the radiosensitivity of A431 cells is almost independent of the oxygen status when treated with the [223Ra]RaCl2. CONCLUSIONS: We demonstrate that the Auger electron/γ-emitter 99mTc ([99mTc]Tc-HMPAO), which does not bound directly to the DNA, is not a promising therapeutic option for hypoxic tumor cells. But the high LET α-particle-emitter 223Ra is more suitable for the treatment of hypoxic tumor cells than irradiation with [99mTc]Tc-HMPAO or the low LET bemitter 188Re. ZIELSETZUNG: Hypoxische Tumorregionen sind bei Radio- und Chemotherapie weniger sensitiv als Tumorregionen mit ausreichender Sauerstoffversorgung. Dies verursacht eine schlechte Prognose für Tumorpatienten. Eine Option die Radioresistenz zu überwinden, stellt die Bestrahlung mit α-Partikel-Emittern oder Auger-Elektronen-Emittern mit einem hohen linearen Energietransfer (LET) dar. In dieser Studie soll untersucht werden, ob die Bestrahlung von hypoxischen Tumorzellen mit dem intrazellulär aufgenommenen γ- sowie Auger-Elektronen-Emitter 99mTc unter Verwendung des Radiotracers [99mTc]Tc-HMPAO eine vielversprechende Therapieoption darstellen könnte. Vergleichend wurde der Hoch-LET α-Partikel-Emitter 223Ra ([223Ra]RaCl2) und der Niedrig-LET ß-Emitter 188Re ([188Re]NaReO4) eingesetzt. METHODEN: A431 Tumorzellen wurden unter normoxischen oder hypoxischen Kulturbedingungen mit [99mTc]Tc-HMPAO (1-20 MBq/2 ml), [223Ra]RaCl2 (1,4-16,3 kBq/2 ml) und [188Re]NaReO4 (0,3-13,7 MBq/2 ml) inkubiert. Zur Detektion der resultierenden strahlenbiologischen Wirkung wurde der Koloniebildungsassay angewendet. Zusätzlich wurde die intrazelluläre Aufnahme der Radiotracer quantifiziert. ERGEBNISSE: Nach Inkubation von [99mTc]Tc-HMPAO sind hypoxische A431-Zellen weniger strahlensensitiv als normoxische Zellen. Im Gegensatz zur Behandlung mit [99mTc]Tc-HMPAO oder [188Re]NaReO4 wurde bei Behandlung mit [223Ra]RaCl2 ein geringerer Einfluss des Sauerstoffstatus auf die Radiosensitivität von A431-Zellen gefunden. SCHLUSSFOLGERUNG: Damit konnte gezeigt werden, dass der nicht direkt an die DNA gebundene Auger-Elektronen-/ γ-Emitter 99mTc ([99mTc]Tc-HMPAO) die Radioresistenz von hypoxischen Tumorzellen nicht überwinden kann. Jedoch stellt der Hoch-LET α-Partikel-Emitter 223Ra ([223Ra]RaCl2) eine bessere Behandlungsoption dar.
Asunto(s)
Partículas alfa/uso terapéutico , Electrones/uso terapéutico , Neoplasias/radioterapia , Hipoxia Tumoral/efectos de la radiación , Línea Celular Tumoral , Supervivencia Celular/efectos de la radiación , Humanos , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Transferencia Lineal de Energía , Neoplasias/metabolismo , Oxígeno/metabolismo , Tolerancia a Radiación , Radioisótopos/farmacocinética , Radioisótopos/uso terapéutico , Radiofármacos/farmacocinética , Radiofármacos/uso terapéutico , Dosificación Radioterapéutica , Radio (Elemento)/farmacocinética , Radio (Elemento)/uso terapéutico , Renio/farmacocinética , Renio/uso terapéutico , Exametazima de Tecnecio Tc 99m/farmacocinética , Exametazima de Tecnecio Tc 99m/uso terapéuticoRESUMEN
OBJECTIVE: The aim of the study was to determine the fraction of administered activity that was excreted and retained by a small cohort of patients who each received treatment with radium-223 dichloride (Ra). Ra is an α-emitting radionuclide that has been approved for use in the treatment of bone metastases that are secondary to castration resistant prostate cancer. PATIENTS AND METHODS: Six patients received two weight-based administrations of Ra 6 weeks apart. Activity excreted in the urine and faeces during the first 48 h following each treatment was assessed by direct counting of the excreta. During the same period the whole-body retention of Ra was also determined using a single probe counting system. The results of the excreta counting and the whole-body counting were compared to determine whether whole-body counting was a suitable surrogate for assessing excretion. Further whole-body retention counts were made at around 3, 4, 7 and 42 days following treatment. RESULTS: Patterns of excretion and retention of Ra varied significantly between patients, but were similar for each patient's pair of treatments. The cumulative maximum activity excreted in the initial 8-h period following the Ra administration was 2.6% that increased to 39% at 48 h. The median excreted activity at ~1 and 6 weeks after treatment was 70 and 86%, respectively. Skeletal retention of Ra at 6 weeks ranged from 11 to 60% of the administered activity.
Asunto(s)
Neoplasias Óseas/radioterapia , Neoplasias Óseas/secundario , Neoplasias de la Próstata Resistentes a la Castración/patología , Radio (Elemento)/farmacocinética , Radio (Elemento)/uso terapéutico , Recuento Corporal Total , Humanos , Masculino , Radioisótopos/administración & dosificación , Radioisótopos/farmacocinética , Radioisótopos/uso terapéutico , Radio (Elemento)/administración & dosificaciónRESUMEN
PURPOSE: The purpose of this study is to identify predictive factors on baseline [18F]NaF positron emission tomography (PET)/computed tomography (CT) of early response to radium-223 dichloride after 3 cycles of treatment in metastatic castration-resistant prostate cancer patients. PROCEDURES: Analysis of 152 metastases was performed in six consecutive patients who underwent [18F]NaF PET/CT at baseline and for early monitoring after 3 cycles of radium-223 dichloride. All metastases depicted on whole-body [18F]NaF PET/CT were contoured and CT (density in Hounsfield units, sclerotic, mixed, or lytic appearance) as well as [18F]NaF [maximum standardized uptake value (SUVmax), SUVmean, and lesion volume (V18F-NaF)] patterns were recorded. Tumor response was defined as percentage change in SUVmax and SUVmean between baseline and post-treatment PET. Bone lesions were defined as stable, responsive, or progressive, according to thresholds derived from a recent multicentre test-retest study in [18F]NaF PET/CT. Total [18F]NaF uptake in metastases, defined as MATV × SUVmean, was correlated to uptake of radium-223 on biodistribution scintigraphy performed 7 days after the first cycle of treatment. RESULTS: Among metastases, 116 involved the axial skeleton and 36 the appendicular skeleton. Lesions were sclerotic in 126 cases and mixed in 26 cases. No lytic lesion was depicted. ROC analysis showed that SUVmax and SUVmean were better predictors of lesion response than V18F-NaF and density on CT (P < 0.0001 and P = 0.001, respectively). SUVmax and SUVmean were predictors of individual tumor response in separate multivariate models (P = 0.01 and P = 0.02, respectively). CT pattern (mixed versus sclerotic) and lesion density were independent predictors only when assessing response with delta SUVmax (P = 0.002 and 0.007, respectively). A good correlation between total [18F]NaF uptake within metastases and their relative radium-223 uptake assessed by two observers 7 days after treatment (r = 0.72 and 0.77, P < 0.0001) was found. CONCLUSIONS: SUVmax and SUVmean on baseline [18F]NaF PET/CT are independent predictors of bone lesions' response to 3 cycles of radium-223 dichloride, supporting the use of NaF to select patients more likely to respond to treatment.
Asunto(s)
Tomografía de Emisión de Positrones , Neoplasias de la Próstata Resistentes a la Castración/diagnóstico por imagen , Radio (Elemento)/farmacocinética , Fluoruro de Sodio/farmacocinética , Anciano , Anciano de 80 o más Años , Radioisótopos de Flúor , Humanos , Modelos Logísticos , Masculino , Análisis Multivariante , Proyectos Piloto , Neoplasias de la Próstata Resistentes a la Castración/patología , Curva ROC , Radioisótopos/farmacocinética , Distribución Tisular , Tomografía Computarizada por Rayos XRESUMEN
PURPOSES: To obtain the necessary acquisition and calibration parameters in order to evaluate the possibility of detecting and quantifying 223Ra uptake in bone metastases of patients treated for castration resistant prostate carcinoma. Furthermore, in the cases in which the activity can be quantified, to determine the absorbed dose. MATERIAL AND METHODS: Acquisitions from a Petri dish filled with 223Ra were performed in the gamma camera. Monte Carlo simulations were also performed to study the partial volume effect. Formulae to obtain the detection and quantification limits of 223Ra uptake were applied to planar images of two patients 7 days post-administration of 55kBq/kg of 223Ra. In order to locate the lesions in advance, whole-body scans and SPECT/CT images were acquired after injecting 99mTc-HDP. RESULTS: The optimal energy window was found to be at 82keV with a medium-energy collimator MEGP. Of the lesions found in the patients, only those that had been detected in both the AP and PA projections could be quantified. These lesions were those which had shown a higher 99mTc-HDP uptake. The estimated values of absorbed doses ranged between 0.7Gy and 7.8Gy. CONCLUSIONS: Of the lesions that can be detected, it is not possible to quantify the activity uptake in some of them, which means that the absorbed dose cannot be determined either. This does not mean that the absorbed dose in these lesions can be regarded as negligible.
Asunto(s)
Adenocarcinoma/secundario , Neoplasias Óseas/secundario , Neoplasias de la Próstata/radioterapia , Radiofármacos/farmacocinética , Radio (Elemento)/farmacocinética , Adenocarcinoma/diagnóstico por imagen , Adenocarcinoma/radioterapia , Adenocarcinoma/cirugía , Neoplasias Óseas/diagnóstico por imagen , Neoplasias Óseas/radioterapia , Terapia Combinada , Simulación por Computador , Difosfonatos , Humanos , Masculino , Método de Montecarlo , Orquiectomía , Compuestos de Organotecnecio , Neoplasias de la Próstata/cirugía , Radioisótopos/farmacocinética , Radioisótopos/uso terapéutico , Radiofármacos/análisis , Radiofármacos/uso terapéutico , Dosificación Radioterapéutica , Radio (Elemento)/análisis , Radio (Elemento)/uso terapéutico , Tomografía Computarizada por Tomografía Computarizada de Emisión de Fotón Único , Imagen de Cuerpo EnteroRESUMEN
PURPOSE: The purpose of this article was to develop, characterize and test (in vivo) dacarbazine microparticles that may be labeled with 99mTc and Ra-223 for both use: diagnostic and therapy of metastatic melanoma. METHODS: We developed by double emulsion solvent evaporation methodology the microparticle. The characterization has been done using, Dynamic Light Scattering (DLS) and Scanning Electron Microscopy (SEM). The labeling with 99mTc and Ra-223 has been done by the direct labeling process. Also the formulation has been tested pre-clinically using Balb/c mice inducted with melanoma, performing the the biodistribution and planar imaging. Cytotoxicity evaluation was also done in M3 V cell line. In order to understand the safety aspects of the microparticles, microbiological study (endotoxin and sterility) has been done. Finally, planar imaging was performed to evaluate the diagnosing aspect. RESULTS: The results showed that a 559 nm microparticles was obtained with a spherical shape. The labeling process with 99mTc reached over 90% of efficacy. On the other hand, the labeling process with Ra-223 showed a 70% efficacy. The results in inducted animals demonstrated that the microparticles were able to reach the tumor with a high rate (20%). Also demonstrated a low recognition by the Mononuclear Phagocytic System. The cytotoxicity and the microbiological control, corroborates the safety aspect of these microparticles. CONCLUSION: The planar image and the possible labeling with Ra-223, corroborates the use as a theragnostic agent for imaging and therapy of Metastatic Melanoma.
Asunto(s)
Antineoplásicos Alquilantes/uso terapéutico , Dacarbazina/uso terapéutico , Melanoma/diagnóstico , Melanoma/tratamiento farmacológico , Radio (Elemento)/uso terapéutico , Tecnecio/uso terapéutico , Animales , Antineoplásicos Alquilantes/farmacocinética , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Dacarbazina/farmacocinética , Sistemas de Liberación de Medicamentos , Femenino , Ratones Endogámicos BALB C , Ratones Desnudos , Radio (Elemento)/farmacocinética , Tecnecio/farmacocinética , Distribución TisularRESUMEN
PURPOSE: The aims of this study were to calculate bone lesion absorbed doses resulting from a weight-based administration of 223Ra-dichloride, to assess the relationship between those doses and corresponding 18F-fluoride uptake and to assess the potential of quantitative 18F-fluoride imaging to predict response to treatment. METHODS: Five patients received two intravenous injections of 223Ra-dichloride, 6 weeks apart, at 110 kBq/kg whole-body weight. The biodistribution of 223Ra in metastatic lesions as a function of time after administration as well as associated lesion dosimetry were determined from serial 223Ra scans. PET/CT imaging using 18F-fluoride was performed prior to the first treatment (baseline), and at week 6 immediately before the second treatment and at week 12 after baseline. RESULTS: Absorbed doses to metastatic bone lesions ranged from 0.6 Gy to 44.1 Gy. For individual patients, there was an average factor difference of 5.3 (range 2.5-11.0) between the maximum and minimum lesion dose. A relationship between lesion-absorbed doses and serial changes in 18F-fluoride uptake was demonstrated (r2 = 0.52). A log-linear relationship was demonstrated (r2 = 0.77) between baseline measurements of 18F-fluoride uptake prior to 223Ra-dichloride therapy and changes in uptake 12 weeks after the first cycle of therapy. Correlations were also observed between both 223Ra and 18F-fluoride uptake in lesions (r = 0.75) as well as between 223Ra absorbed dose and 18F-fluoride uptake (r = 0.96). CONCLUSIONS: There is both inter-patient and intra-patient heterogeneity of absorbed dose estimates to metastatic lesions. A relationship between 223Ra lesion absorbed dose and subsequent lesion response was observed. Analysis of this small group of patients suggests that baseline uptake of 18F-fluoride in bone metastases is significantly correlated with corresponding uptake of 223Ra, the associated 223Ra absorbed dose and subsequent lesion response to treatment.
Asunto(s)
Radioisótopos de Flúor/farmacocinética , Tomografía Computarizada por Tomografía de Emisión de Positrones/métodos , Neoplasias de la Próstata Resistentes a la Castración/diagnóstico por imagen , Radiofármacos/farmacocinética , Radio (Elemento)/farmacocinética , Anciano , Ensayos Clínicos Fase I como Asunto , Humanos , Masculino , Persona de Mediana Edad , Tomografía Computarizada por Tomografía de Emisión de Positrones/normas , Neoplasias de la Próstata Resistentes a la Castración/radioterapia , Radioisótopos/administración & dosificación , Radioisótopos/uso terapéutico , Radiofármacos/administración & dosificación , Radiofármacos/uso terapéutico , Radio (Elemento)/administración & dosificación , Radio (Elemento)/uso terapéuticoRESUMEN
BACKGROUND: Radiation therapy with radium-223 dichloride improves overall survival, reduces symptomatic skeletal events in Caucasian patients with castration-resistant prostate cancer (CRPC) and bone metastases, and is well tolerated. We report here the results of the first efficacy and safety study of radium-223 dichloride in a Japanese population. METHODS: In this open-label, uncontrolled, non-randomized, phase I trial, radium-223 dichloride was given to Japanese patients with CRPC and ≥2 bone metastases in 4-week cycles. The patients were divided into three cohorts, with cohort 1 and the expansion cohort receiving injections of radium-223 dichloride [55 kBq/kg body weight (BW)] every 4 weeks (Q4W) for up to six injections, and cohort 2 receiving an initial single radium-223 dichloride injection of 110 kBq/kg BW followed by up to five injections of 55 kBq/kg BW Q4W. Safety was determined via adverse event (AE) reporting, and biochemical bone markers were assessed for treatment efficacy. RESULTS: In total 19 patients received at least one dose of radium-223 dichloride and 18 patients experienced at least one treatment-emergent AE (TEAE) of which the most common were anemia, thrombocytopenia, and lymphocytopenia. Serious AEs were reported in three patients but none were drug-related. In the patients of cohort 1 + expansion cohort (55 kBq/kg BW Q4W treatment; n = 16), prostate-specific antigen levels remained stable or slightly increased while the bone alkaline phosphatase (ALP) level significantly decreased. The response rates of bone ALP (≥30 and ≥50% reductions) were 81.8 and 36.4% at week 12, and 81.3 and 50.0% at the end of treatment. CONCLUSIONS: Radium-223 dichloride was well tolerated in these Japanese patients and, at a dose of 55 kBq/kg BW, efficacy on biomarkers was as expected. The outcomes in Japanese patients were consistent with those reported in other non-Japanese populations. TRIAL REGISTRATION: ClinicalTrials.gov record NCT01565746.
Asunto(s)
Neoplasias de la Próstata Resistentes a la Castración/patología , Neoplasias de la Próstata Resistentes a la Castración/radioterapia , Radiofármacos/uso terapéutico , Radio (Elemento)/uso terapéutico , Anciano , Fosfatasa Alcalina/sangre , Anemia/inducido químicamente , Pueblo Asiatico , Neoplasias Óseas/metabolismo , Neoplasias Óseas/secundario , Humanos , Masculino , Antígeno Prostático Específico , Radioisótopos/efectos adversos , Radioisótopos/farmacocinética , Radioisótopos/uso terapéutico , Radiofármacos/efectos adversos , Radiofármacos/farmacocinética , Radio (Elemento)/efectos adversos , Radio (Elemento)/farmacocinética , Trombocitopenia/inducido químicamente , Resultado del TratamientoRESUMEN
Metastatic castration-resistant prostate cancer frequently metastasizes to the bone, often resulting in painful skeletal events, reduced quality of life, and reduced survival. Radium-223 is a first-in-class alpha-emitting radiopharmaceutical that has proven to prolong overall survival, delay time to symptomatic skeletal events, and improve quality of life in patients with castration-resistant prostate cancer and symptomatic bone metastases and no visceral metastases. Radium-223 provides survival benefit to patients with castration-resistant prostate cancer and symptomatic bone metastases, regardless of prior docetaxel use. This article gives an overview of the development of radium-223 from the first-in-human trial to current status.
Asunto(s)
Neoplasias Óseas/radioterapia , Neoplasias Óseas/secundario , Neoplasias de la Próstata/patología , Radio (Elemento)/uso terapéutico , Ensayos Clínicos como Asunto , Terapia Combinada , Humanos , Masculino , Radio (Elemento)/farmacocinéticaRESUMEN
INTRODUCTION: A number of drugs have been shown to extend life expectancy in castration-resistant prostate cancer (CRPC). Skeletal related events (SREs) secondary to bone metastases cause significant morbidity for men with CRPC. The α-emitting radiopharmaceutical radium-223 dichloride has been shown to improve overall survival, time to symptomatic skeletal events (SSEs) and quality of life in CRPC. AREAS COVERED: The development of radium-223 from pre-clinical studies to the evidence of efficacy and safety from a phase 3 trial is discussed as well as its pharmacokinetics and metabolism. The integration of radium-223 into routine care for patients with advanced prostate cancer is included including a comparison with other agents in this setting. Expert commentary: The risk/benefit ratio for radium-223 is very similar to that of other agents used in the CRPC setting and is a treatment option for men unsuitable for cytotoxic chemotherapy because of comorbidities. The ALSYMPCA trial demonstrated an improvement in SSEs with radium-223. This is a clinically relevant end-point as not all radiologically-detected SREs are apparent to patients. The correct sequencing of the life-prolonging treatments available to men with CRPC is subject to debate. Radium-223 therapy should be considered before the development of visceral metastases. Drug-combination studies are underway.
Asunto(s)
Antineoplásicos/administración & dosificación , Neoplasias de la Próstata Resistentes a la Castración/tratamiento farmacológico , Radio (Elemento)/administración & dosificación , Animales , Antineoplásicos/efectos adversos , Antineoplásicos/farmacocinética , Neoplasias Óseas/tratamiento farmacológico , Neoplasias Óseas/patología , Neoplasias Óseas/secundario , Humanos , Masculino , Neoplasias de la Próstata Resistentes a la Castración/patología , Calidad de Vida , Radioisótopos/administración & dosificación , Radioisótopos/efectos adversos , Radioisótopos/farmacocinética , Radio (Elemento)/efectos adversos , Radio (Elemento)/farmacocinética , Tasa de Supervivencia , Resultado del TratamientoRESUMEN
OBJECTIVE: This open-label, non-randomized, phase I study examined the pharmacokinetics (PK) and radiation dosimetry of a single dose of radium-223 in Japanese patients with castration-resistant prostate cancer (CRPC) and bone metastases. METHODS: Six male Japanese patients (mean age 72.5 years, range 65-79 years) with histologically or cytologically confirmed stage IV adenocarcinoma of the prostate were recruited. A single IV dose of radium-223 was delivered intravenously (IV) via slow bolus over a 2-5 min period: Cohort 1 received 50 kBq/kg and Cohort 2 received 100 kBq/kg. RESULTS: Following IV injection, radium-223 was rapidly eliminated from the blood in a multi-phasic manner. The fraction of the injected activity of radium-223 retained in the whole body 24 h following injection was 85 %. Biodistribution results showed initial bone uptake was 52 % (range 41-57 %). The maximum activity of radium-223 in the bone was observed within 2 h of dosing. Activity of radium-223 passed through the small intestine within 24 h. No activity was detected in other organs. The major radiation dose from radium-223 was found in osteogenic cells; calculated absorbed doses in osteogenic cells and in the red marrow were 0.76 Gy/MBq and 0.09 Gy/MBq, respectively. CONCLUSIONS: In Japanese patients with CRPC and bone metastases, radium-223 (IV) achieved maximum activity in the bone rapidly and passed through the intestine within 24 h, without signs of activity in other organs. The PK profile and absorbed radiation dose in organs and tissues in Japanese patients were similar to data from non-Japanese patients. Trial registration identification: NCT01565746.
Asunto(s)
Neoplasias Óseas/radioterapia , Neoplasias Óseas/secundario , Neoplasias de la Próstata Resistentes a la Castración/patología , Dosis de Radiación , Radio (Elemento)/farmacocinética , Radio (Elemento)/uso terapéutico , Anciano , Humanos , Masculino , Radioisótopos/sangre , Radioisótopos/farmacocinética , Radioisótopos/uso terapéutico , Radiometría , Dosificación Radioterapéutica , Radio (Elemento)/sangre , Distribución TisularRESUMEN
BACKGROUND: Bone-metastatic, castration-resistant prostate cancer (bmCRPC) represents a lethal stage of the most common noncutaneous cancer in men. The recent introduction of Radium-223 dichloride, a bone-seeking alpha particle (α)-emitting radiopharmaceutical, demonstrates statistically significant survival benefit and palliative effect for bmCRPC patients. Clinical results have established safety and efficacy, yet questions remain regarding pharmacodynamics and dosing for optimized patient benefit. METHODS: We elucidated the biodistribution of (223)Ra as well as interaction with the bone and tumor compartments in skeletally mature mice (C57Bl/6 and CD-1, n = 3-6) and metastasis models (LNCaP and PC3, n = 4). Differences in uptake were evaluated by µCT and histological investigation. Novel techniques were leveraged on whole-mount undecalcified cryosections to determine microdistribution of Radium-223. All statistical tests were two-sided. RESULTS: (223)Ra uptake in the bones (>30% injected activity per gram) at 24 hours was also accompanied by non-negligible remnant activity in the kidney (2.33% ± 0.36%), intestines (5.73% ± 2.04%), and spleen (10.5% ± 5.9%) Skeletal accumulation across strains did not correspond with bone volume or surface area but instead to local blood vessel density (P = .04). Microdistribution analysis by autoradiography and α camera revealed targeting of the ossifying surfaces adjacent to the epiphyseal growth plate. In models of PCa metastasis, radioactivity does not localize directly within tumors but instead at the apposite bone surface. Osteoblastic and lytic lesions display similar intensity, which is comparable with uptake at sites of normal bone remodeling. CONCLUSIONS: Profiling the macro- and microdistribution of (223)Ra in healthy and diseased models has important implications to guide precision application of this emerging α-therapy approach for bmCRPC and other bone metastastic diseases.