RESUMO
153 Sm-DOTMP (CycloSam® ) is a newly-patented radiopharmaceutical for bone tumor treatment. DOTMP (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetramethylene-phosphonate) is a macrocyclic chelating agent with superior binding properties to 153 Sm when compared with EDTMP (Quadramet™, used for palliative treatment of bone cancer). CycloSam® was administered at 1 mCi/kg (37 MBq/kg) in a prospective pilot study to seven dogs with bone cancer resulting in no myelosuppression. Then, 13 dogs were enrolled in a prospective clinical trial study using traditional 3+3 dose escalation and starting at 1.5 mCi/kg. Baseline evaluation included hematologic and biochemical testing, diagnosis confirmation, thoracic and limb radiographs, technetium-99 m-HDP bone scintigraphy, and 18 F-FDG PET scan (SUVmax). Toxicity (primary endpoint) was assessed through weekly blood counts and adverse events. Dogs received 1.5 mCi/kg (n = 4), 1.75 mCi/kg (n = 6), and 2 mCi/kg (n = 3) of 153 Sm-DOTMP. Dose-limiting neutropenia and thrombocytopenia were seen at 2 mCi/kg. No dose-limiting nonhematologic toxicities occurred. Efficacy (secondary endpoint) was assessed by objective lameness measurement (body-mounted inertial sensors), owner quality-of-life (QoL) questionnaire, and repeat PET scan. Objective lameness measurement improved in four dogs (53%-60% decrease) was equivocal in three dogs, and worsened in four dogs (66%-115% increase); two dogs were not evaluable. Repeat 18 F-FDG PET scan results varied and change in lameness did not consistently correlate with SUVmax changes. QoL score worsened (n = 5) or was improved/stable (n = 7). Carboplatin chemotherapy (300 mg/m2 IV every 3 weeks ×4) started 4 weeks after 153 Sm-DOTMP injection. No dog died of chemotherapy-related complications. All dogs completed study monitoring. The recommended dose for CycloSam® in dogs is 1.75 mCi/kg, which resulted in some pain control with minimal toxicity and was safely combined with chemotherapy.
Assuntos
Antineoplásicos , Neoplasias Ósseas , Doenças do Cão , Osteossarcoma , Compostos Radiofarmacêuticos , Animais , Cães , Antineoplásicos/efeitos adversos , Neoplasias Ósseas/diagnóstico por imagem , Neoplasias Ósseas/tratamento farmacológico , Neoplasias Ósseas/veterinária , Doenças do Cão/diagnóstico por imagem , Doenças do Cão/tratamento farmacológico , Fluordesoxiglucose F18 , Coxeadura Animal/diagnóstico por imagem , Coxeadura Animal/tratamento farmacológico , Osteossarcoma/diagnóstico por imagem , Osteossarcoma/tratamento farmacológico , Osteossarcoma/veterinária , Projetos Piloto , Estudos Prospectivos , Qualidade de Vida , Radioisótopos/efeitos adversos , Compostos Radiofarmacêuticos/efeitos adversos , Samário/efeitos adversosRESUMO
Thehuman internal dosimetry of the radionuclidic impurities of samarium-153 in a new bone-seeking radiopharmaceutical, 153Sm-1,4,7,10tetraazacyclododecanetetramethylenephosponic acid (153Sm-DOTMP), has been estimated from preclinical data. The effective dose from the impurities in lower-specific-activity 153Sm is less than 17% of the effective dose from pure Sm-153. It has a background-equivalent radiation time for a dosage of 37 MBq/kg of less than one-half year.
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Radioisótopos , Samário , Compostos OrganofosforadosRESUMO
ABSTRACT: Tin-117m (117mSn) is used to treated dogs with osteoarthritic joints by radiosynoviorthesis. The internal conversion and Auger electrons emitted by the 117mSn provide the therapeutic effect. Sn-117m also emits gamma rays, of which the most significant is 158.6 keV. The external radiation field around a treated dog is of interest to limit the dose to the owners/caretakers of the dog. The dog's torso attenuates the radiation being emitted toward the opposite side of the dog's body. This leads to a radiation field that is significantly non-isotropic. This study characterizes the anisotropy of this field to permit maximum dose rate measurements to be used to calculate the dose to individuals in the vicinity of the dog. Measurements were made in nine directions and at two distances, 0.3 and 1.0 m, to characterize common distances and spatial orientations for human-dog interactions. From these measurements, the percent reduction in the average dose rate compared to the maximum dose rate was determined. From a radiation safety perspective, the important factor is the minimum amount of shielding effectiveness or percent reduction that can be expected. A reasonable measure for this value is the fifth percentile of the shielding effectiveness distribution. The fifth percentile shielding effectiveness measures are 27% and 21% at 0.3 and 1.0 m, respectively.
Assuntos
Elétrons , Osteoartrite , Animais , Anisotropia , Cães , Raios gama , Osteoartrite/radioterapia , Osteoartrite/veterináriaRESUMO
The treatment of pets, service animals, and pre-clinical research subjects with radionuclides raises concern for the safety of the people who interact with the animals after their treatment. Three treatments of skeletal conditions in dogs are considered in this study: Sm-1,4,7,10-tetraazacylcododecanetetramethylenephosphonic acid, which is a bone-seeking radiopharmaceutical; unencapsulated Y permanent interstitial implants, which are sometimes called "liquid brachytherapy"; and Sn radiosynoviorthesis, which is also called radiosynovectomy. External exposure rate readings of the Sm and Sn treatments, and Monte Carlo simulations of Sn at a distance of 1 m and of all three in direct contact with tissue were analyzed for doses. Dogs that have received any of these treatments using typically administered activities may be released from radiation safety isolation immediately after treatment from the standpoint of external exposure. People should avoid prolonged close proximity, such as sleeping with a treated dog, for three weeks following an Y interstitial implant or for a month following Sn radiosynoviorthesis. No such avoidance is necessary after treatment with Sm-1,4,7,10-tetraazacylcododecanetetramethylenephosphonic acid.
Assuntos
Osso e Ossos/efeitos da radiação , Exposição à Radiação/análise , Segurança , Animais , Osso e Ossos/efeitos dos fármacos , Cães , Método de Monte Carlo , Ácidos Fosforosos/química , Ácidos Fosforosos/farmacologiaRESUMO
This longitudinal prospective exploratory study used serial measurements in five dogs to evaluate safety and retention of a tin-117 m (117m Sn) colloid after intra-articular injection in normal elbow joints. Each dog was deemed healthy based on physical examination, laboratory results, and radiographic evaluation of both elbows. While anesthetized, each received an MRI of both elbows, followed by fluorine-18 fluorodeoxyglucose positron emission tomography scans of both elbow joints and associated lymph nodes. Joint fluid (0.5-1.0 mL) was withdrawn aseptically from the left elbow joint, followed by intra-articular injection of 117m Sn colloid (92.5 MBq; 1-1.5 ml). Post-injection assessments included blood counts, serum chemistry panels, urinalyses, radiographs, joint fluid analyses, MRI/positron emission tomography scans, scintigraphy, and biodistribution scans. On day 45-47, each dog was euthanized and a complete postmortem examination was performed. Tissue samples were submitted for histopathology and radioisotope retention studies. Left elbow joints were decalcified and sectioned for future autoradiography. Scintigraphy, 1 day after injection, indicated slight radioisotope escape from the joint to regional lymph nodes. Serial blood, urine, feces, and organ counts indicated >99.1% of the 117m Sn activity was retained in the joint for 45-47 days. Radiation output levels were below patient release levels the day following injection. Maximum standard uptake value for the injected joint decreased. Joint fluid cytology was unchanged. No dog exhibited lameness during the study. Absence of joint damage and lack of systemic effects after injection of the 117m Sn colloid in normal canine elbow joints indicate that this agent may be safely used for radiosynoviorthesis in dogs with osteoarthritis.
Assuntos
Isótopos/efeitos adversos , Compostos Radiofarmacêuticos/efeitos adversos , Estanho/efeitos adversos , Animais , Cães , Injeções Intra-Articulares/veterinária , Isótopos/administração & dosagem , Estudos Longitudinais , Imageamento por Ressonância Magnética/veterinária , Tomografia por Emissão de Pósitrons/veterinária , Estudos Prospectivos , Valores de Referência , Estanho/administração & dosagemRESUMO
A new treatment strategy based on direct injections of (90)Y-hydroxide into the tumor bed in dogs with osteosarcoma was studied. Direct injections of the radiopharmaceutical into the tumor bed were made according to a pretreatment plan established using (18)F-FDG images. Using a special drill, cannulas were inserted going through tissue, tumor and bone. Using these cannulas, direct injections of the radiopharmaceutical were made. The in vivo biodistribution of (90)Y-hydroxide and the anatomical tumor bed were imaged using a time-of-flight (TOF) PET/CT scanner. The material properties of the tissues were estimated from corresponding CT numbers using an electron-density calibration. Radiation absorbed dose estimates were calculated using Monte Carlo methods where the biodistribution of the pharmaceutical from PET images was sampled using a collapsing 3-D rejection technique. Dose distributions in the tumor bed and surrounding tissues were calculated, showing significant heterogeneity with multiple hot spots at injection sites. Dose volume histograms showed that approximately 33.9% of bone and tumor and 70.2% of bone marrow and trabecular bone received an absorbed dose over 200Gy; approximately 3.2% of bone and tumor and 31.0% of bone marrow and trabecular bone received a total dose of over 1000Gy.
RESUMO
OBJECTIVE: Peptide receptor radionuclide therapy with radiolabeled somatostatin analogs is a novel method of treatment in patients with metastatic neuroendocrine tumors (NETs). For the first time in the United States, we present preliminary results of the treatment with Lutetium (177)(Lu) DOTATATE in patients with progressive NETs. METHODS: Thirty-seven patients with grade 1 and grade 2 disseminated and progressive gastroenteropancreatic NET were enrolled in a nonrandomized, phase 2 clinical trial. Repeated cycles of 200 mCi (7.4 GBq; ±10%) were administered up to the cumulative dose of 800 mCi (29.6 GBq; ±10%). RESULTS: Among 32 evaluable patients, partial response and minimal response to treatment were seen in 28% and 3%, respectively, and stable disease was seen in 41% of patients. A total of 28% had progressive disease. A response to treatment was significantly associated with lower burden of disease in the liver. No significant acute or delayed hematologic or kidney toxicity was observed. An impressive improvement of performance status and quality of life were seen after Lu-DOTATATE therapy. CONCLUSIONS: Treatment with multiple cycles of (177)Lu-DOTATATE peptide receptor radionuclide therapy is well tolerated. This treatment results in control of the disease in most patients, whereas systemic toxicities are limited and reversible. Quality of life is also improved.
Assuntos
Neoplasias do Sistema Digestório/radioterapia , Tumores Neuroendócrinos/radioterapia , Octreotida/análogos & derivados , Compostos Organometálicos/uso terapêutico , Compostos Radiofarmacêuticos/uso terapêutico , Receptores de Somatostatina/metabolismo , Adulto , Idoso , Neoplasias do Sistema Digestório/metabolismo , Neoplasias do Sistema Digestório/mortalidade , Neoplasias do Sistema Digestório/patologia , Progressão da Doença , Fracionamento da Dose de Radiação , Feminino , Fluordesoxiglucose F18 , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Imagem Multimodal , Gradação de Tumores , Tumores Neuroendócrinos/metabolismo , Tumores Neuroendócrinos/mortalidade , Tumores Neuroendócrinos/secundário , Octreotida/efeitos adversos , Octreotida/uso terapêutico , Compostos Organometálicos/efeitos adversos , Tomografia por Emissão de Pósitrons , Valor Preditivo dos Testes , Qualidade de Vida , Compostos Radiofarmacêuticos/efeitos adversos , Texas , Fatores de Tempo , Tomografia Computadorizada por Raios X , Resultado do TratamentoAssuntos
Doxiciclina/administração & dosagem , Pulmão/diagnóstico por imagem , Pneumonia , Adulto , Antibacterianos/administração & dosagem , Humanos , Masculino , Pessoa de Meia-Idade , Exame Físico/métodos , Pneumonia/diagnóstico , Pneumonia/tratamento farmacológico , Pneumonia/etiologia , Pneumonia/fisiopatologia , Radiografia , Resultado do TratamentoRESUMO
INTRODUCTION: The therapeutic potential of the bone-seeking radiopharmaceutical 153Sm-labeled 1,4,7,10-tetraazacyclododecanetetramethylenephosphonic acid (153Sm-DOTMP) was assessed by measuring its dosage-dependent skeletal uptake at two chelant-to-metal ratios and its source organ residence times at a chelant-to-metal ratio of 1.5:1. A similar agent, 153Sm-labeled ethylenediaminetetramethylenephosphonic acid (153Sm-EDTMP), has been reported to exhibit dosage-limiting skeletal saturation. METHODS: Sm-DOTMP was prepared with tracer activity of 153Sm and sufficient stable, unenriched Sm to simulate different activities. Cohorts of seven 280-g Sprague-Dawley rats were administered the equivalent of 296, 592, 888, 1184 and 1480 MBq (8, 16, 24, 32 and 40 mCi) at a fixed chelant-to-metal ratio of 1.5:1 and euthanized 3 h after administration. Cohorts of three 128-g Sprague-Dawley rats were administered equivalent dosages of 10.4, 592 and 888 (0.28, 16 and 32 mCi) at a fixed chelant-to-metal ratio of 270:1 and euthanized 2 h after administration. A simulated activity of 1480 MBq (40 mCi) at a chelant-to-metal ratio of 1.5:1 was administered to cohorts of seven rats that were euthanized at 2, 4, 24 or 48 h postadministration. The heart, lungs, liver, spleen, kidneys, small intestine, large intestine, urinary bladder, muscle and a femur were excised, weighed and counted. The data were analyzed to determine skeletal uptake and source organ residence times. RESULTS: No statistically significant skeletal saturation was observed up to human-equivalent dosages of 370 GBq (10 Ci) at a chelant-to-metal ratio of 1.5:1, but the skeletal uptake dropped by 40% over the range of dosages at a chelant-to-metal ratio of 270:1. At a chelant-to-metal ratio of 1.5:1, the preferred ratio, the skeletal uptake fraction in rats was 0.408 (95% confidence interval 0.396-0.419) with an effective half-life of 47.3 h (95% confidence interval 42.3-53.7; the physical half-life of 153Sm is 46.3 h). Extrapolating to an adult human model, 52.9 GBq (1.43 Ci) of 153Sm-DOTMP would deliver 40 Gy to the red marrow. CONCLUSION: 153Sm-DOTMP has dosimetry equivalent to that of 153Sm-EDTMP at low dosages, yet with no skeletal saturation at higher administered activities.
Assuntos
Osso e Ossos/metabolismo , Compostos Organofosforados/metabolismo , Radioisótopos , Compostos Radiofarmacêuticos/metabolismo , Samário , Adulto , Animais , Humanos , Masculino , Compostos Organofosforados/farmacocinética , Radiometria , Compostos Radiofarmacêuticos/farmacocinética , Ratos , Ratos Sprague-DawleyRESUMO
Three 1,4,7,10-tetraazacyclododecane-N,N',N",N"'-tetraacetic acid (DOTA) analogues were evaluated for relative in vivo stability when radiolabeled with (111)In, (90)Y and (177)Lu and conjugated to the monoclonal antibody B72.3. The DOTA analogues evaluated were "NHS-DOTA" [N-hydroxysuccinimdyl (NHS) group activating one carboxylate], "Arm-DOTA" (also known as MeO-DOTA; with a p-NCS, o-MeO-benzyl moiety on the methylene group of one acetic acid arm) and "Back-DOTA" (with a p-NCS-benzyl moiety on a backbone methylene group of the macrocycle). The B72.3 was conjugated to the DOTA analogues to increase the retention time of the radioloabeled conjugates in vivo in mice. The serum stability of the various radiometalated DOTA conjugates showed them to have good stability out to 168 h (all >95% except (111)In-NHS-DOTA-B72.3, which was 91% stable). Hydroxyapatite stability for the (111)In and (177)Lu DOTA-conjugates was >95% at 168 h, while the (90)Y DOTA-conjugates were somewhat less stable (between 90% and 95% at 168 h). The biodistribution studies of the radiometalated DOTA-conjugates showed that no significant differences were observed for the (111)In and (177)Lu analogues; however, the (90)Y analogues showed lower stabilities, as evidenced by their increased bone uptake relative to the other two [2-20% injected dose per gram (% ID/g) for (90)Y and 2-8% ID/g for (111)In and (177)Lu]. The lower stability of the (90)Y analogues could be due to the higher beta energy of (90)Y and/or to the larger ionic radius of Y(3+). Based on the bone uptake observed, the (177)Lu-NHS-DOTA-B72.3 had slightly lower stability than the (177)Lu-Arm-DOTA-B72.3 and (177)Lu-Back-DOTA-B72.3, but not significantly at all time points. For (90)Y, the analogue showing the lowest stability based on bone uptake was (90)Y-Arm-DOTA-B72.3, perhaps because of the metal's larger ionic radius and potential steric interactions minimizing effective complexation. The (111)In analogues all showed similar biological distributions at the various time points. This study suggests that care must be taken when evaluating (90)Y-labeled antibodies and in using NHS-DOTA-antibody conjugates with (177)Lu. All evaluations should be extended to time points relevant to the half-life of the radiometal and the therapy applications.
Assuntos
Anticorpos Antineoplásicos/metabolismo , Osso e Ossos/metabolismo , Compostos Heterocíclicos com 1 Anel/farmacocinética , Radioisótopos/farmacocinética , Animais , Anticorpos Antineoplásicos/química , Osso e Ossos/diagnóstico por imagem , Avaliação Pré-Clínica de Medicamentos , Feminino , Compostos Heterocíclicos com 1 Anel/síntese química , Marcação por Isótopo/métodos , Taxa de Depuração Metabólica , Camundongos , Especificidade de Órgãos , Radioisótopos/química , Cintilografia , Compostos Radiofarmacêuticos/síntese química , Compostos Radiofarmacêuticos/farmacocinética , Distribuição TecidualRESUMO
The radiolanthanides 149Pm, 166Ho, and 177Lu have decay characteristics suitable for radioimmunotherapy (RIT) of cancer. N-Hydroxysulfosuccinimidyl DOTA (DOTA-OSSu) and methoxy-DOTA (MeO-DOTA) were conjugated to the anti-TAG-72 monoclonal antibody CC49 for radiolabeling with 149Pm, 166Ho, and 177Lu. While both DOTA conjugates could be labeled to high specific activity with 177Lu, MeO-DOTA afforded superior conjugate stability, radiolabeling, and radiochemical purity. Pilot biodistributions in nude mice bearing LS174T human colon carcinoma xenografts demonstrated that MeO-DOTA afforded higher tumor uptake and lower kidney retention of 177Lu than DOTA-OSSu. The in vitro stability of 149Pm-, 166Ho-, and 177Lu-MeO-DOTA-CC49 was evaluated using serum and hydroxyapatite assays. Serum stability of radiolanthanide-labeled MeO-DOTA-CC49 followed a trend based on the coordination energies of the radiometals, with 177Lu showing the highest stability after 96 to 168 h at 37 C. In contrast, MeO-DOTA-CC49 labeled with all three radiolanthanides was >92% stable to hydroxyapatite challenge for 168 h at 37 C. Comprehensive biodistributions of 149Pm-, 166Ho-, and 177Lu-MeO-DOTA-CC49 were obtained in LS174T-bearing nude mice. Maximum tumor uptakes were 100.0% ID/g for 149Pm at 96 h, 69.5% ID/g for 166Ho at 96 h, and 132.4% ID/g for 177Lu at 168 h. Normal organ uptakes were generally low, except in the liver, spleen, and kidney at early time points. By 96 to 168 h postinjection, nontarget organ uptake decreased to approximately 7% ID/g (kidney), 12% ID/g (spleen), and 20% ID/g (liver) for each radiolanthanide. When labeled with 149Pm, 166Ho, and 177Lu, MeO-DOTA-CC49 has potential for RIT of colorectal cancer and other carcinomas.