RESUMO
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.
Assuntos
Antineoplásicos/farmacocinética , Neoplasias Ósseas/metabolismo , Neoplasias Ósseas/secundário , Neoplasias de Próstata Resistentes à Castração/patologia , Rádio (Elemento)/farmacocinética , Partículas alfa , Antineoplásicos/administração & dosagem , Antineoplásicos/sangue , Neoplasias Ósseas/sangue , Neoplasias Ósseas/radioterapia , Osso e Ossos/metabolismo , Humanos , Intestino Grosso/metabolismo , Intestino Delgado/metabolismo , Masculino , Modelos Biológicos , Radioisótopos/administração & dosagem , Radioisótopos/sangue , Radioisótopos/farmacocinética , Rádio (Elemento)/administração & dosagem , Rádio (Elemento)/sangueRESUMO
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.
Assuntos
Biomarcadores Tumorais/genética , Neoplasias Ósseas/radioterapia , Terapia de Alvo Molecular/métodos , Neoplasias de Próstata Resistentes à Castração/radioterapia , Rádio (Elemento)/uso terapêutico , Idoso , Fosfatase Alcalina/sangue , Fosfatase Alcalina/genética , Biomarcadores Tumorais/metabolismo , Biópsia , Neoplasias Ósseas/genética , Neoplasias Ósseas/mortalidade , Neoplasias Ósseas/secundário , Osso e Ossos/metabolismo , Osso e Ossos/patologia , Osso e Ossos/efeitos da radiação , Caderinas/genética , Caderinas/metabolismo , Subunidade alfa 1 de Fator de Ligação ao Core/genética , Subunidade alfa 1 de Fator de Ligação ao Core/metabolismo , Progressão da Doença , Expressão Gênica , Humanos , Masculino , Células Neoplásicas Circulantes/metabolismo , Células Neoplásicas Circulantes/patologia , Células Neoplásicas Circulantes/efeitos da radiação , Osteonectina/genética , Osteonectina/metabolismo , Osteopontina/genética , Osteopontina/metabolismo , Próstata/metabolismo , Próstata/patologia , Próstata/efeitos da radiação , Neoplasias de Próstata Resistentes à Castração/genética , Neoplasias de Próstata Resistentes à Castração/mortalidade , Neoplasias de Próstata Resistentes à Castração/patologia , Rádio (Elemento)/sangue , Rádio (Elemento)/farmacocinética , Análise de Sobrevida , Microambiente Tumoral/genética , Microambiente Tumoral/efeitos da radiaçãoRESUMO
226Ra is a natural radioelement emitting α and γ radiations. It can be highly concentrated in TENORM materials from the petroleum or fertilizer industries. In Switzerland, 226Ra is currently a radioactive inheritance problem from the watch industry. Furthermore, 223Ra is a radium isotope used in nuclear medicine to treat bone metastasis. There exist several methods to measure radium using alpha or gamma spectrometry or using 222Rn emanation technique. The limitations of these methods are due to the required detection limits and the nature of the samples. When using alpha spectrometry to reach very low detection limits, critical technical hitches often arise because of the difficulties in separating radium from barium, in removing organics eluted from the separating chromatography column, and in plating radium. Moreover, overall chemical recovery of radium is often not reproducible, depending on the studies. Here we propose a method that separates radium from other alkaline-earth cations using cation exchange chromatography and selective complex formation by EDTA and DCTA. Radium is completely free of the 229Th tracer and its daughter products, particularly 225Ac. Organics from the column are removed in a further purification step so that radium can be plated with acceptable yields in a HCl/HNO3/ethanol solution. We successfully applied the method to soil, water, urine and human bone samples and further extended it to the determination of 223Ra in a bone biopsy, using 226Ra as an internal tracer.
Assuntos
Partículas alfa , Osso e Ossos/química , Rádio (Elemento)/análise , Contagem de Cintilação , Osso e Ossos/metabolismo , Osso e Ossos/patologia , Raios gama , Humanos , Rádio (Elemento)/sangue , Rádio (Elemento)/urina , Solo/química , Tório/análise , Tório/sangue , Tório/urina , Poluentes Radioativos da Água/análiseRESUMO
AIM: 223Radium-dichloride (223Ra) administration is an upcoming therapeutic option in patients with castration-resistant metastatic prostate cancer (mCRPC), whose renal and faecal excretion of 223Ra has been primarily estimated from data of a phase-I clinical trial in patients with normal renal function. In the rare case of concomitant renal insufficiency requiring haemodialysis (HD), an estimation of the contamination of dialysate would be beneficial. METHODS: The excretion of 223Ra and its concentration in the dialysate in a patient with mCRPC and end-stage renal disease was examined for six consecutive treatment cycles. Dialysate samples were measured using a commercial system with NaI-scintillation detector. RESULTS: HD showed a residual activity level in the remaining dialysate. The excreted activity was a median of 46.1 kBq (rangeâ =â 42.0- 83.4 kBq) and 11.2 kBq (range = 8.4- 19.9 kBq) for the first (24 h post injection p.i.) and second HD (96 h p.i.), respectively. The activity concentration decreased significantly from a median of 4.18 kBq/l (range = 2.98-5.14 kBq/l) to 0.85 kBq/l (range = 0.69- 1.31 kBq/l, p < 0.0001). For all consecutive time points, the activity concentration further decreased significantly (p < 0.0001). The activity concentration of dialysate from HD performed 125.4 h p.i. [95 % confidence interval = 120.5-130.4 h p.i.] reached the threshold for unrestricted waste disposal. CONCLUSION: The observed extraction of 223Ra by HD exceeded the data determined from the phase-I study. The activity concentration in the dialysate observed for the first HD's p.i. was above the threshold for unrestricted disposal of radioactive waste in Germany. Therefore, the specific requirement for waste handling has to be followed to fulfil the radiation protection regulations.
Assuntos
Neoplasias Ósseas/radioterapia , Neoplasias Ósseas/secundário , Neoplasias de Próstata Resistentes à Castração/patologia , Neoplasias de Próstata Resistentes à Castração/radioterapia , Rádio (Elemento)/isolamento & purificação , Rádio (Elemento)/uso terapêutico , Diálise Renal/métodos , Remoção de Componentes Sanguíneos/métodos , Soluções para Diálise/análise , Soluções para Diálise/química , Humanos , Masculino , Pessoa de Meia-Idade , Doses de Radiação , Proteção Radiológica/métodos , Radioisótopos/sangue , Radioisótopos/isolamento & purificação , Radioisótopos/uso terapêutico , Compostos Radiofarmacêuticos/sangue , Compostos Radiofarmacêuticos/isolamento & purificação , Compostos Radiofarmacêuticos/uso terapêutico , Rádio (Elemento)/sangue , Resultado do TratamentoRESUMO
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.
Assuntos
Neoplasias Ósseas/radioterapia , Neoplasias Ósseas/secundário , Neoplasias de Próstata Resistentes à Castração/patologia , Doses de Radiação , Rádio (Elemento)/farmacocinética , Rádio (Elemento)/uso terapêutico , Idoso , Humanos , Masculino , Radioisótopos/sangue , Radioisótopos/farmacocinética , Radioisótopos/uso terapêutico , Radiometria , Dosagem Radioterapêutica , Rádio (Elemento)/sangue , Distribuição TecidualRESUMO
BACKGROUND: Liposomes carrying chemotherapeutics have had some success in cancer treatment and may also be suitable carriers for therapeutic radionuclides. This study was designed to evaluate the biodistribution and to estimate the radiation doses of the alpha emitter 223Ra loaded into pegylated liposomes in selected tissues. MATERIALS AND METHODS: 223Ra was encapsulated in pegylated liposomal doxorubicin (PLD) by ionophore-mediated loading. The biodistribution of liposomal 223Ra was compared to free cationic 223Ra in Balb/C mice. RESULTS: Liposomal 223Ra circulated in the blood with an initial half-life in excess of 24 hours, which agreed well with that reported for PLD in rodents, while the blood half-life of cationic 223Ra was considerably less than an hour. When liposomal 223Ra was catabolized, the released 223Ra was either excreted or taken up in the skeleton. This skeletal uptake increased up to 14 days after treatment, but did not reach the level seen with free 223Ra. Pre-treatment with non-radioactive PLD 4 days in advance lessened the liver uptake of liposomal 223Ra. Dose estimates showed that the spleen, followed by bone surfaces, received the highest absorbed doses. CONCLUSION: Liposomal 223Ra was relatively stable in vivo and may have potential for radionuclide therapy and combination therapy with chemotherapeutic agents.
Assuntos
Partículas alfa/uso terapêutico , Doxorrubicina/análogos & derivados , Polietilenoglicóis/administração & dosagem , Rádio (Elemento)/administração & dosagem , Animais , Doxorrubicina/administração & dosagem , Doxorrubicina/sangue , Doxorrubicina/química , Doxorrubicina/farmacocinética , Feminino , Meia-Vida , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Polietilenoglicóis/química , Polietilenoglicóis/farmacocinética , Rádio (Elemento)/sangue , Rádio (Elemento)/química , Rádio (Elemento)/farmacocinética , Distribuição TecidualRESUMO
PURPOSE: The main goals were to study the safety and tolerability of the alpha-emitter radium-223 (223Ra) in breast and prostate cancer patients with skeletal metastases. In addition, pain palliation was evaluated. EXPERIMENTAL DESIGN: Fifteen prostate and 10 breast cancer patients enrolled in a phase I trial received a single i.v. injection of 223Ra. Five patients were included at each of the dosages: 46, 93, 163, 213, or 250 kBq/kg and followed for 8 weeks. Palliative response was evaluated according to the pain scale of the European Organization for Research and Treatment of Cancer QLQ C30 questionnaire at baseline and at 1, 4, and 8 weeks after injection. RESULTS: Weekly blood sampling during follow-up revealed mild and reversible myelosuppression with nadir 2 to 4 weeks after the injection. Importantly, for thrombocytes only grade 1 toxicity was reported. Grade 3 neutropenia and leucopenia occurred in two and three patients, respectively. Mild, transient diarrhea was observed in 10 of the 25 patients. Nausea and vomiting was more frequently observed in the highest dosage group. Serum alkaline phosphatase decreased with nadir averages of 29.5% in females and 52.1% in males. Pain relief was reported by 52%, 60%, and 56% of the patients after 7 days, 4, and 8 weeks, respectively. 223Ra cleared rapidly from blood and was below 1% of initial level at 24 hours. Gamma camera images indicated, in accordance with pretreatment (99m)Tc-MDP scans, accumulation of 223Ra in skeletal lesions. Elimination was mainly intestinal. Median survival exceeded 20 months. CONCLUSIONS: 223Ra was well tolerated at therapeutically relevant dosages. Phase II studies have therefore been initiated.
Assuntos
Partículas alfa/uso terapêutico , Neoplasias Ósseas/radioterapia , Rádio (Elemento)/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Fosfatase Alcalina/sangue , Partículas alfa/efeitos adversos , Neoplasias Ósseas/diagnóstico por imagem , Neoplasias Ósseas/secundário , Neoplasias da Mama/patologia , Neoplasias da Mama/radioterapia , Diarreia/etiologia , Relação Dose-Resposta à Radiação , Fadiga/etiologia , Feminino , Seguimentos , Humanos , Injeções Intravenosas , Leucopenia/etiologia , Masculino , Pessoa de Meia-Idade , Náusea/etiologia , Neutropenia/etiologia , Dor/etiologia , Neoplasias da Próstata/patologia , Neoplasias da Próstata/radioterapia , Cintilografia , Rádio (Elemento)/efeitos adversos , Rádio (Elemento)/sangue , Resultado do Tratamento , Vômito/etiologiaRESUMO
A compartmental model of the distribution of radium in humans and young adult beagle dogs (approximately 500-550 d) is presented. The model consists of one soft tissue compartment and seven skeletal compartments for humans, and five skeletal compartments for beagles. The number of transfer parameters to be estimated was reduced by using remodeling rates of bone and imposing several constraints deduced from known features of bone physiology, radium metabolism, and autoradiographic analyses. The model predictions are in good agreement with measured retentions in plasma, whole body, skeleton, and soft tissues of both species. Moreover, for beagles even the retention in individual bones can be predicted quite well if the relevant morphometric parameters are known. While some of the estimated transfer parameters are similar in both species, others differ by an order of magnitude or more. Wherever possible, a comparison of model parameters with those of previous models is given. The new model not only is instrumental for calculating local doses in the skeleton but also can be used for characterizing the microdistribution of radium in this organ.
Assuntos
Medula Óssea/metabolismo , Osso e Ossos/metabolismo , Tecido Conjuntivo/metabolismo , Modelos Biológicos , Radiometria/métodos , Rádio (Elemento)/sangue , Rádio (Elemento)/farmacocinética , Animais , Carga Corporal (Radioterapia) , Cães , Humanos , Cinética , Taxa de Depuração Metabólica , Especificidade de Órgãos , Doses de Radiação , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Especificidade da Espécie , Distribuição TecidualRESUMO
UNLABELLED: The bone-seeking property and the potential exposure of red marrow by the alpha-particle emitter (223)Ra (half-life, 11.43 d) were compared with those of the beta-emitter (89)Sr (half-life, 50.53 d). METHODS: The biodistributions of (223)Ra and (89)Sr were studied in mice. Tissue uptake was determined at 1 h, 6 h, 1 d, 3 d, and 14 d after intravenous administration. Radiation absorbed doses were calculated for soft tissues and for bone. Multicellular-level doses were estimated for bone marrow cavities. RESULTS: Both (89)Sr and (223)Ra selectively concentrated on bone surfaces relative to soft tissues. The measured bone uptake of (223)Ra was slightly higher than that of (89)Sr. At 24 h, the femur uptake of (223)Ra was 40.1% +/- 7.7% of the administered activity per gram of tissue. The uptake in spleen and most other soft tissues was higher for (223)Ra than for (89)Sr. Although predominant clearance of (223)Ra was observed from the soft tissues within the first 24 h, the bone uptake of (223)Ra, which was not significantly different from maximum after only 1 h, was not significantly reduced during the 14 d. Furthermore, little redistribution of (223)Ra daughter products away from bone was found (2% at 6 h and less than 1% at 3 d). Estimates of dose to marrow cavities showed that the (223)Ra alpha-emitter might have a marrow-sparing advantage compared with beta-emitters for targeting osteoid surfaces because the short-range alpha-particles irradiate a significantly lower fraction of the marrow volumes. At the same time, the bone surfaces will receive a therapeutically effective radiation dose. CONCLUSION: The results of this study indicate that (223)Ra is a promising candidate for high-linear-energy transfer alpha-particle irradiation of cancer cells on bone surfaces. (223)Ra can, together with its daughter radionuclides, deliver an intense and highly localized radiation dose to the bone surfaces with substantially less irradiation of healthy bone marrow compared with standard bone-seeking beta-emitters.