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1.
J Nucl Med ; 2020 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-31924729

RESUMO

Quantitative evaluation of radiolabeled Prostate-Specific Membrane Antigen (PSMA) PET scans may be used to monitor treatment response in patients with prostate cancer (PCa). To interpret longitudinal differences in PSMA uptake, the intrinsic variability of tracer uptake in PCa lesions needs to be defined. The aim of this study was to investigate the repeatability of quantitative 18F-DCFPyL (a second generation 18F-PSMA-ligand) PET/CT measurements in patients with PCa. Methods: Twelve patients with metastatic PCa were prospectively included, of which 2 were excluded from final analyses. Patients received two whole-body 18F-DCFPyL PET/CT scans (median dose 317 MBq; uptake time 120 min), within median 4 days (range 1-11 days). After semi-automatic (isocontour-based) tumor delineation, the following lesion-based metrics were derived: Tumor-to-Blood ratio (TBRmean, TBRpeak, and TBRmax), Standardized Uptake Value (SUVmean, SUVpeak, SUVmax, normalized to bodyweight), tumor volume, and total lesion tracer uptake (TLU). Additionally, patient-based Total Tumor Volume (sum of PSMA-positive tumor volumes; TTV) and Total Tumor Burden (sum of all lesion TLUs; TTB) were derived. Repeatability was analyzed using repeatability coefficients (RC) and intra-class correlations (ICC). Additionally, the effect of point spread function (PSF) image reconstruction on the repeatability of uptake metrics was evaluated. Results: In total, 36 18F-DCFPyL PET positive lesions were analyzed (up to 5 lesions per patient). RCs of TBRmean, TBRpeak, and TBRmax were 31.8%, 31.7%, and 37.3%, respectively. For SUVmean, SUVpeak, SUVmax the RCs were 24.4%, 25.3% and 31.0%, respectively. All ICC were ≥0.97. Tumor volume delineations were well repeatable, with RC 28.1% for individual lesion volumes and RC 17.0% for TTV. TTB had a RC of 23.2% and 33.4%, when based on SUVmean and TBRmean, respectively. Small lesions (<4.2mL) had worse repeatability for volume measurements. The repeatability of SUVpeak, TLU, and all patient-level metrics were not affected by PSF-reconstruction. Conclusion: 18F-DCFPyL uptake measurements are well repeatable and can be used for clinical validation in future treatment response assessment studies. Patient-based TTV may be preferred for multicenter studies since its repeatability was both high and robust to different image reconstructions.

2.
J Neurooncol ; 145(1): 177-184, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31522324

RESUMO

INTRODUCTION: Diffuse intrinsic pontine glioma (DIPG) is a rare clinically, neuro-radiologically, and molecularly defined malignancy of the brainstem with a median overall survival of approximately 11 months. Our aim is to evaluate the current tendency for its treatment in Europe in order to develop (inter)national consensus guidelines. METHODS: Healthcare professionals specialized in DIPG were asked to fill in an online survey with questions regarding usual treatment strategies at diagnosis and at disease progression in their countries and/or their centers, respectively. RESULTS: Seventy-four healthcare professionals responded to the survey, of which 87.8% were pediatric oncologists. Only 13.5% of the respondents biopsy all of their patients, 41.9% biopsy their patients infrequently. More than half of the respondents (54.1%) treated their patients with radiotherapy only at diagnosis, whereas 44.6% preferred radiotherapy combined with chemotherapy. When the disease progresses, treatment strategies became even more diverse, and the tendency for no treatment increased from 1.4% at diagnosis to 77.0% after second progression. 36.5% of the healthcare professionals treat children younger than 3 years differently than older children at diagnosis. This percentage decreased, when the disease progresses. Most of the participants (51.4%) included less than 25% of their patients in clinical trials. CONCLUSION: This survey demonstrates a large heterogeneity of treatment regimens, especially at disease progression. We emphasize the need for international consensus guidelines for the treatment of DIPG, possible by more collaborative clinical trials.

4.
J Nucl Med ; 60(12): 1730-1735, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31000583

RESUMO

Radiolabeled prostate-specific membrane antigen (PSMA) PET has demonstrated promising results for prostate cancer (PCa) imaging. Quantification of PSMA radiotracer uptake is desired as it enables reliable interpretation of PET images, use of PSMA uptake as an imaging biomarker for tumor characterization, and evaluation of treatment effects. The aim of this study was to perform a full pharmacokinetic analysis of 2-(3-(1-carboxy-5-[(6-18F-fluoro-pyridine-3-carbonyl)-amino]-pentyl)-ureido)-pentanedioic acid (18F-DCFPyL), a second-generation 18F-labeled PSMA ligand. On the basis of the pharmacokinetic analysis (reference method), simplified methods for quantification of 18F-DCFPyL uptake were validated. Methods: Eight patients with metastasized PCa were included. Dynamic PET acquisitions were performed at 0-60 and 90-120 min after injection of a median dose of 313 MBq of 18F-DCFPyL (range, 292-314 MBq). Continuous and manual arterial blood sampling provided calibrated plasma tracer input functions. Time-activity curves were derived for each PCa metastasis, and 18F-DCFPyL kinetics were described using standard plasma input tissue-compartment models. Simplified methods for quantification of 18F-DCFPyL uptake (SUVs; tumor-to-blood ratios [TBRs]) were correlated with kinetic parameter estimates obtained from full pharmacokinetic analysis. Results: In total, 46 metastases were evaluated. A reversible 2-tissue-compartment model was preferred for 18F-DCFPyL kinetics in 59% of the metastases. The observed k 4 was small, however, resulting in nearly irreversible kinetics during the course of the PET study. Hence, k 4 was fixated (0.015) and net influx rate, Ki, was preferred as the reference kinetic parameter. Whole-blood TBR provided an excellent correlation with Ki from full kinetic analysis (R 2 = 0.97). This TBR could be simplified further by replacing the blood samples with an image-based, single measurement of blood activity in the ascending aorta (image-based TBR, R 2 = 0.96). SUV correlated poorly with Ki (R 2 = 0.47 and R 2 = 0.60 for SUV normalized to body weight and lean body mass, respectively), most likely because of deviant blood activity concentrations (i.e., tumor tracer input) in patients with higher tumor volumes. Conclusion: 18F-DCFPyL kinetics in PCa metastases are best described by a reversible 2-tissue-compartment model. Image-based TBRs were validated as a simplified method to quantify 18F-DCFPyL uptake and might be applied to clinical, whole-body PET scans. SUV does not provide reliable quantification of 18F-DCFPyL uptake.

6.
Eur J Clin Pharmacol ; 75(6): 825-829, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30729257

RESUMO

PURPOSE: To obtain insight into the feasibility of, and the patients' perspective on, dried blood spot (DBS) self-sampling by patients with chronic myeloid leukemia (CML) using nilotinib. METHODS: Sixty-eight patients with CML using nilotinib participated in this multicenter observational study. Patients were asked to perform blood sampling by means of the DBS method at home just before drug intake (trough level) and to complete a questionnaire including demographics and five questions on their experience with DBS self-sampling. RESULTS: Sixty-one patients (57.5 ± 15.0 years, 49% female) provided 178 DBS samples of which 137 (77%) proved useful in clinical practice. Twenty percent of the samples were rejected because the spot size was too small for analysis. A further 3% were taken at the wrong time. Unsuitable DBS samples were provided by 23 patients. Their educational level was significantly lower than that of patients whose samples were all suitable (p = 0.041). Patients considered DBS self-sampling easy and not painful, and three quarters of the patients performed DBS sampling without additional assistance. Patients' belief in the reliability of DBS self-sampling was moderate to high. It was preferred over venous sampling by 37% of the patients, whereas 39% had no preference. CONCLUSION: DBS self-sampling by CML patients is feasible in clinical practice provided that patients, particularly those with a lower educational level, are adequately instructed about sample collection with emphasis on timing and volume of sample collection.


Assuntos
Antineoplásicos/sangue , Atitude Frente a Saúde , Teste em Amostras de Sangue Seco , Leucemia Mielogênica Crônica BCR-ABL Positiva/sangue , Participação do Paciente , Pirimidinas/sangue , Adulto , Idoso , Antineoplásicos/farmacocinética , Antineoplásicos/uso terapêutico , Monitoramento de Medicamentos/métodos , Feminino , Humanos , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Pirimidinas/farmacocinética , Pirimidinas/uso terapêutico , Autoadministração
7.
Cancer Med ; 7(1): 219-228, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-29168352

RESUMO

Adequate information on oral anticancer agent (OACA) use is an essential element of optimal cancer care. The present study aimed to get insight into the experiences of patients with information on OACA treatment and their characteristics regarding information dissatisfaction. Patients of four Dutch university hospitals using OACA participated in this observational study and completed the Satisfaction with Information about Medicines Scale (SIMS), EORTC Quality of Life Questionnaire-C30, Brief Illness Perception Questionnaire, and Beliefs about Medicines Questionnaire-Specific. Logistic regression analyses were used to determine factors associated with dissatisfaction with information. Patients (n = 208) using capecitabine (35%), lenalidomide (15%), imatinib (14%), temozolomide (12%), sunitinib (11%), thalidomide (5%), dasatinib (4%), erlotinib (2%), and nilotinib (2%) participated. Information on the following SIMS-items was inadequate: how OACA elicit their effect, how long it takes before treatment works, how to conclude that treatment is effective, the risk of side effects and its management, interference with sex life, drowsiness, interference with other medication and alcohol and what to do in case of a missed dose. Younger age, hematological malignancy, dyspnoea, positive perception of consequences of the cancer, low perception of treatment control, and indifferent attitude towards OACA were associated with dissatisfaction with information. In conclusion, a considerable number of patients would have appreciated receiving more information on specific issues relating to the consequences of OACA treatment such as the effects and side effects of OACA and the interference of treatment with various aspects of their daily life. Oncologists, hematologists, lung-oncologists and pharmacists may reconsider the provision of information on OACA treatment.


Assuntos
Antineoplásicos/uso terapêutico , Neoplasias/tratamento farmacológico , Educação de Pacientes como Assunto , Conhecimento do Paciente sobre a Medicação/estatística & dados numéricos , Satisfação do Paciente/estatística & dados numéricos , Administração Oral , Adulto , Idoso , Estudos Transversais , Dinamarca , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Inquéritos e Questionários/estatística & dados numéricos , Adulto Jovem
8.
J Nucl Med ; 59(6): 973-979, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29175983

RESUMO

Transporters such as ABCB1 and ABCG2 limit the exposure of several anticancer drugs to the brain, leading to suboptimal treatment in the central nervous system. The purpose of this study was to investigate the effects of the ABCB1 and ABCG2 inhibitor elacridar on brain uptake using 11C-erlotinib PET. Methods: Elacridar and cold erlotinib were administered orally to wild-type (WT) and Abcb1a/b;Abcg2 knockout mice. In addition, brain uptake was measured using 11C-erlotinib imaging and ex vivo scintillation counting in knockout and WT mice. Six patients with advanced solid tumors underwent 11C-erlotinib PET scans before and after a 1,000-mg dose of elacridar. 11C-erlotinib brain uptake was quantified by pharmacokinetic modeling using volume of distribution (VT) as the outcome parameter. In addition, 15O-H2O scans to measure cerebral blood flow were acquired before each 11C-erlotinib scan. Results: Brain uptake of 11C-erlotinib was 2.6-fold higher in Abcb1a/b;Abcg2 knockout mice than in WT mice, measured as percentage injected dose per gram of tissue (P = 0.01). In WT mice, the addition of elacridar (at systemic plasma concentrations of ≥200 ng/mL) resulted in an increased brain concentration of erlotinib, without affecting erlotinib plasma concentration. In patients, the VT of 11C-erlotinib did not increase after intake of elacridar (0.213 ± 0.12 vs. 0.205 ± 0.07, P = 0.91). 15O-H2O PET showed no significant changes in cerebral blood flow. Elacridar exposure in patients was 401 ± 154 ng/mL. No increase in VT with increased elacridar plasma exposure was found over the 271-619 ng/mL range. Conclusion: When Abcb1 and Abcg2 were disrupted in mice, brain uptake of 11C-erlotinib increased both at a tracer dose and at a pharmacologic dose. In patients, brain uptake of 11C-erlotinib was not higher after administration of elacridar. The more pronounced role that ABCG2 appears to play at the human blood-brain barrier and the lower potency of elacridar to inhibit ABCG2 may be an explanation of these interspecies differences.


Assuntos
Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/antagonistas & inibidores , Acridinas/farmacologia , Barreira Hematoencefálica/efeitos dos fármacos , Barreira Hematoencefálica/diagnóstico por imagem , Cloridrato de Erlotinib , Tomografia por Emissão de Pósitrons , Tetra-Hidroisoquinolinas/farmacologia , Subfamília B de Transportador de Cassetes de Ligação de ATP/antagonistas & inibidores , Animais , Barreira Hematoencefálica/metabolismo , Feminino , Humanos , Masculino , Camundongos , Pessoa de Meia-Idade
9.
Front Oncol ; 7: 254, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29164054

RESUMO

Despite decades of clinical trials for diffuse intrinsic pontine glioma (DIPG), patient survival does not exceed 10% at two years post-diagnosis. Lack of benefit from systemic chemotherapy may be attributed to an intact bloodbrain barrier (BBB). We aim to develop a theoretical model including relevant physicochemical properties in order to review whether applied chemotherapeutics are suitable for passive diffusion through an intact BBB or whether local administration via convection-enhanced delivery (CED) may increase their therapeutic potential. Physicochemical properties (lipophilicity, molecular weight, and charge in physiological environment) of anticancer drugs historically and currently administered to DIPG patients, that affect passive diffusion over the BBB, were included in the model. Subsequently, the likelihood of BBB passage of these drugs was ascertained, as well as their potential for intratumoral administration via CED. As only non-molecularly charged, lipophilic, and relatively small sized drugs are likely to passively diffuse through the BBB, out of 51 drugs modeled, only 8 (15%)-carmustine, lomustine, erlotinib, vismodegib, lenalomide, thalidomide, vorinostat, and mebendazole-are theoretically qualified for systemic administration in DIPG. Local administration via CED might create more therapeutic options, excluding only positively charged drugs and drugs that are either prodrugs and/or only available as oral formulation. A wide variety of drugs have been administered systemically to DIPG patients. Our model shows that only few are likely to penetrate the BBB via passive diffusion, which may partly explain the lack of efficacy. Drug distribution via CED is less dependent on physicochemical properties and may increase the therapeutic options for DIPG.

10.
J Pharm Pharmacol ; 69(10): 1265-1274, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28643375

RESUMO

OBJECTIVES: To compare nilotinib concentrations obtained by venous blood sampling and dried blood spot (DBS) in patients with chronic myeloid leukaemia (CML). It was investigated how to predict nilotinib plasma levels on the basis of DBS. METHODS: Forty duplicate DBS and venous blood samples were collected from 20 patients. Capillary blood was obtained by finger prick and spotted on DMPK-C Whatman sampling paper, simultaneously with venous blood sampling. Plasma concentrations were predicted from DBS concentrations using three methods: (1) individual and (2) mean haematocrit correction and (3) the bias between plasma and DBS concentrations. Results were compared using Deming regression and Bland-Altman analysis. KEY FINDINGS: Nilotinib plasma concentrations ranged from 376 to 2663 µg/l. DBS concentrations ranged from 144 to 1518 µg/l. The slope was 0.56 (95% CI, 0.51 to 0.61) with an intercept of -41.68 µg/l (95% CI, -93.78 to 10.42). Mean differences between calculated and measured plasma concentrations were -14.3% (method 1), -14.0% (method 2) and -0.6% (method 3); differences were within 20% of the mean in 73%, 85% and 80% of the samples, respectively. The slopes were respectively 0.96 (95% CI, 0.86 to 1.06), 0.95 (95% CI, 0.86 to 1.03) and 1.00 (95% CI, 0.91 to 1.09). CONCLUSIONS: Plasma concentrations of nilotinib could be predicted on the basis of DBS. DBS sampling to assess nilotinib concentrations in CML patients seems a suitable alternative for venous sampling.


Assuntos
Teste em Amostras de Sangue Seco/normas , Leucemia Mielogênica Crônica BCR-ABL Positiva/sangue , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Flebotomia/normas , Pirimidinas/sangue , Pirimidinas/uso terapêutico , Adulto , Idoso , Teste em Amostras de Sangue Seco/métodos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Flebotomia/métodos
11.
Clin Pharmacokinet ; 56(10): 1185-1195, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28155137

RESUMO

BACKGROUND: We previously showed the practical and ethical feasibility of using [14C]-microdosing for pharmacokinetic studies in children. We now aimed to show that this approach can be used to elucidate developmental changes in drug metabolism, more specifically, glucuronidation and sulfation, using [14C]paracetamol (AAP). METHODS: Infants admitted to the intensive care unit received a single oral [14C]AAP microdose while receiving intravenous therapeutic AAP every 6 h. [14C]AAP pharmacokinetic parameters were estimated. [14C]AAP and metabolites were measured with accelerator mass spectrometry. The plasma area under the concentration-time curve from time zero to infinity and urinary recovery ratios were related to age as surrogate markers of metabolism. RESULTS: Fifty children [median age 6 months (range 3 days-6.9 years)] received a microdose (3.3 [2.0-3.5] ng/kg; 64 [41-71] Bq/kg). Plasma [14C]AAP apparent total clearance was 0.4 (0.1-2.6) L/h/kg, apparent volume of distribution was 1.7 (0.9-8.2) L/kg, and the half-life was 2.8 (1-7) h. With increasing age, plasma and urinary AAP-glu/AAP and AAP-glu/AAP-sul ratios significantly increased by four fold, while the AAP-sul/AAP ratio significantly decreased. CONCLUSION: Using [14C]labeled microdosing, the effect of age on orally administered AAP metabolism was successfully elucidated in both plasma and urine. With minimal burden and risk, microdosing is attractive to study developmental changes in drug disposition in children.


Assuntos
Acetaminofen/administração & dosagem , Acetaminofen/metabolismo , Analgésicos não Entorpecentes/administração & dosagem , Analgésicos não Entorpecentes/metabolismo , Radioisótopos de Carbono/administração & dosagem , Radioisótopos de Carbono/metabolismo , Fatores Etários , Criança , Pré-Escolar , Relação Dose-Resposta a Droga , Feminino , Humanos , Lactente , Recém-Nascido , Masculino
12.
Cancer Biother Radiopharm ; 32(1): 16-23, 2017 02.
Artigo em Inglês | MEDLINE | ID: mdl-28118029

RESUMO

OBJECTIVE: Rhenium-188-HEDP is an effective radiopharmaceutical for the treatment of painful bone metastases from prostate cancer. The effectiveness of the ß-radiation emitted by 188Re might be enhanced by combination with chemotherapy, using the radiosensitization concept. Therefore, the authors investigated the combined treatment of the taxanes, docetaxel and cabazitaxel, with 188Re in prostate carcinoma cell lines. MATERIALS AND METHODS: The cytotoxic effects of single and combined treatment with taxanes and 188Re were investigated in three human prostate carcinoma cell lines (PC-3, DU 145, and LNCaP), using the colony-forming assay. The half maximal effective concentration (EC50) of all individual agents was determined. The combined treatment was studied at 0.25, 0.5, 1, 2, and 4 times the EC50 of each agent. The interaction was investigated with a regression model. RESULTS: The survival curves showed dose-dependent cell growth inhibition for both the taxanes and 188Re. The regression model showed a good capability of explaining the data. It proved additivity in all combination experiments and confirmed a general trend to a slight subadditive effect. CONCLUSIONS: This proof-of-mechanism study exploring radiosensitization by combining 188Re and taxanes showed no synergism, but significant additivity. This encourages the design of in vivo studies. Future research should explore the potential added value of concomitant treatment of bone metastases with chemotherapy and 188Re-HEDP.


Assuntos
Antineoplásicos/uso terapêutico , Quimiorradioterapia/métodos , Ácido Etidrônico/uso terapêutico , Compostos Organometálicos/uso terapêutico , Neoplasias da Próstata/terapia , Radiossensibilizantes/uso terapêutico , Compostos Radiofarmacêuticos/uso terapêutico , Taxoides/uso terapêutico , Neoplasias Ósseas/secundário , Neoplasias Ósseas/terapia , Linhagem Celular Tumoral , Quimioterapia Adjuvante , Reparo do DNA/efeitos dos fármacos , Reparo do DNA/efeitos da radiação , Docetaxel , Relação Dose-Resposta a Droga , Humanos , Masculino , Neoplasias da Próstata/patologia
13.
J Cereb Blood Flow Metab ; 37(1): 97-105, 2017 01.
Artigo em Inglês | MEDLINE | ID: mdl-26661244

RESUMO

Studies in rodents suggest that flumazenil is a P-glycoprotein substrate at the blood-brain barrier. This study aimed to assess whether [11C]flumazenil is a P-glycoprotein substrate in humans and to what extent increased P-glycoprotein function in epilepsy may confound interpretation of clinical [11C]flumazenil studies used to assess gamma-aminobutyric acid A receptors. Nine drug-resistant patients with epilepsy and mesial temporal sclerosis were scanned twice using [11C]flumazenil before and after partial P-glycoprotein blockade with tariquidar. Volume of distribution, nondisplaceable binding potential, and the ratio of rate constants of [11C]flumazenil transport across the blood-brain barrier (K1/k2) were derived for whole brain and several regions. All parameters were compared between pre- and post-tariquidar scans. Regional results were compared between mesial temporal sclerosis and contralateral sides. Tariquidar significantly increased global K1/k2 (+23%) and volume of distribution (+10%), but not nondisplaceable binding potential. At the mesial temporal sclerosis side volume of distribution and nondisplaceable binding potential were lower in hippocampus (both ∼-19%) and amygdala (both ∼-16%), but K1/k2 did not differ, suggesting that only regional gamma-aminobutyric acid A receptor density is altered in epilepsy. In conclusion, although [11C]flumazenil appears to be a (weak) P-glycoprotein substrate in humans, this does not seem to affect its role as a tracer for assessing gamma-aminobutyric acid A receptor density.


Assuntos
Barreira Hematoencefálica/metabolismo , Epilepsia do Lobo Temporal/diagnóstico por imagem , Flumazenil/farmacocinética , Moduladores GABAérgicos/farmacocinética , Receptores de GABA-A/análise , Esclerose/diagnóstico por imagem , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Adolescente , Adulto , Radioisótopos de Carbono , Resistência a Medicamentos , Humanos , Pessoa de Meia-Idade , Tomografia por Emissão de Pósitrons/métodos , Tomografia por Emissão de Pósitrons/normas , Adulto Jovem
14.
Bone ; 91: 159-79, 2016 10.
Artigo em Inglês | MEDLINE | ID: mdl-27496068

RESUMO

Therapeutic phosphonate-based radiopharmaceuticals radiolabeled with beta, alpha and conversion electron emitting radioisotopes have been investigated for the targeted treatment of painful bone metastases for >35years. We performed a systematic literature search and focused on the pharmaceutical development, preclinical research and early human studies of these radiopharmaceuticals. The characteristics of an ideal bone-targeting therapeutic radiopharmaceutical are presented and compliance with these criteria by the compounds discussed is verified. The importance of both composition and preparation conditions for the stability and biodistribution of several agents is discussed. Very few studies have described the characterization of these products, although knowledge on the molecular structure is important with respect to in vivo behavior. This review discusses a total of 91 phosphonate-based therapeutic radiopharmaceuticals, of which only six agents have progressed to clinical use. Extensive clinical studies have only been described for (186)Re-HEDP, (188)Re-HEDP and (153)Sm-EDTMP. Of these, (153)Sm-EDTMP represents the only compound with worldwide marketing authorization. (177)Lu-EDTMP has recently received approval for clinical use in India. This review illustrates that a thorough understanding of the radiochemistry of these agents is required to design simple and robust preparation and quality control methods, which are needed to fully exploit the potential benefits of these theranostic radiopharmaceuticals. Extensive biodistribution and dosimetry studies are indispensable to provide the portfolios that are required for assessment before human administration is possible. Use of the existing knowledge collected in this review should guide future research efforts and may lead to the approval of new promising agents.


Assuntos
Neoplasias Ósseas/tratamento farmacológico , Neoplasias Ósseas/secundário , Descoberta de Drogas , Terapia de Alvo Molecular , Organofosfonatos/uso terapêutico , Compostos Radiofarmacêuticos/uso terapêutico , Animais , Humanos , Organofosfonatos/química , Compostos Radiofarmacêuticos/química
15.
Nuklearmedizin ; 55(5): 188-95, 2016 Sep 26.
Artigo em Inglês | MEDLINE | ID: mdl-27443809

RESUMO

AIM: Rhenium-188-HEDP ((188)Re-HEDP) is an effective radiopharmaceutical for the palliative treatment of osteoblastic bone metastases. However, only limited data on its routine use are available and its effect on quality of life (QoL) has not been studied. Therefore, we evaluated the clinical benefit of (188)Re-HEDP in routine clinical care. PATIENTS AND METHODS: Prostate or breast cancer patients with painful bone metastases receiving (188)Re-HEDP as a routine clinical procedure were eligible for evaluation. Clinical benefit was assessed in terms of efficacy and toxicity. Pain palliation and QoL were monitored using the visual analogue scale (VAS), corrected for opioid intake, and the EORTC QLQ-C30 Global health status/QoL-scale. Thrombocyte and leukocyte nadirs were used to assess haematological toxicity. RESULTS: 45 and 47 patients were evaluable for pain palliation and QoL, respectively. After a single injection of (188)Re-HEDP, the overall pain response rate was 69% and mean VAS-scores decreased relevantly and significantly (p < 0.05). Repeated treatment resulted in similar pain response. The overall QoL response rate was 68% and mean Global health status/QoL-scores increased relevantly and significantly. Haematological side effects were mild and transient. CONCLUSION: The clinically relevant response on pain and quality of life and the limited adverse events prove clinical benefit of treatment with (188)Re-HEDP and support its use in routine clinical care. Its effectiveness appears comparable to that of external beam radiotherapy.


Assuntos
Neoplasias Ósseas/radioterapia , Neoplasias Ósseas/secundário , Neoplasias da Mama/radioterapia , Dor do Câncer/prevenção & controle , Dor do Câncer/psicologia , Ácido Etidrônico/uso terapêutico , Compostos Organometálicos/uso terapêutico , Neoplasias da Próstata/epidemiologia , Idoso , Neoplasias Ósseas/psicologia , Neoplasias da Mama/epidemiologia , Dor do Câncer/diagnóstico , Comorbidade , Feminino , Humanos , Masculino , Países Baixos/epidemiologia , Cuidados Paliativos , Prevalência , Neoplasias da Próstata/psicologia , Neoplasias da Próstata/radioterapia , Qualidade de Vida/psicologia , Compostos Radiofarmacêuticos/uso terapêutico , Fatores de Risco , Resultado do Tratamento
16.
Front Pharmacol ; 7: 131, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27252651

RESUMO

Selection of the right drug for the right patient is a promising approach to increase clinical benefit of targeted therapy with monoclonal antibodies (mAbs). Assessment of in vivo biodistribution and tumor targeting of mAbs to predict toxicity and efficacy is expected to guide individualized treatment and drug development. Molecular imaging with positron emission tomography (PET) using zirconium-89 ((89)Zr)-labeled monoclonal antibodies also known as (89)Zr-immuno-PET, visualizes and quantifies uptake of radiolabeled mAbs. This technique provides a potential imaging biomarker to assess target expression, as well as tumor targeting of mAbs. In this review we summarize results from initial clinical trials with (89)Zr-immuno-PET in oncology and discuss technical aspects of trial design. In clinical trials with (89)Zr-immuno-PET two requirements should be met for each (89)Zr-labeled mAb to realize its full potential. One requirement is that the biodistribution of the (89)Zr-labeled mAb (imaging dose) reflects the biodistribution of the drug during treatment (therapeutic dose). Another requirement is that tumor uptake of (89)Zr-mAb on PET is primarily driven by specific, antigen-mediated, tumor targeting. Initial trials have contributed toward the development of (89)Zr-immuno-PET as an imaging biomarker by showing correlation between uptake of (89)Zr-labeled mAbs on PET and target expression levels in biopsies. These results indicate that (89)Zr-immuno-PET reflects specific, antigen-mediated binding. (89)Zr-immuno-PET was shown to predict toxicity of RIT, but thus far results indicating that toxicity of mAbs or mAb-drug conjugate treatment can be predicted are lacking. So far, one study has shown that molecular imaging combined with early response assessment is able to predict response to treatment with the antibody-drug conjugate trastuzumab-emtansine, in patients with human epithelial growth factor-2 (HER2)-positive breast cancer. Future studies would benefit from a standardized criterion to define positive tumor uptake, possibly supported by quantitative analysis, and validated by linking imaging data with corresponding clinical outcome. Taken together, these results encourage further studies to develop (89)Zr-immuno-PET as a predictive imaging biomarker to guide individualized treatment, as well as for potential application in drug development.

17.
EJNMMI Res ; 6(1): 10, 2016 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26857779

RESUMO

BACKGROUND: In non-small cell lung cancer (NSCLC) patients off erlotinib therapy, positron emission tomography (PET) using [(11)C]erlotinib distinguished epidermal growth factor receptor (EGFR) mutations from wild-type EGFR. However, tumor uptake of [(11)C]erlotinib during erlotinib therapy is unknown. Therefore, the aims of this study were to evaluate tumor [(11)C]erlotinib uptake in NSCLC patients both on and off erlotinib therapy, to evaluate the effect of erlotinib therapy on tumor perfusion and its correlation to tumor [(11)C]erlotinib uptake, and also, to investigate simplified uptake parameters using arterial and venous blood samples. METHODS: Ten patients were to be scanned twice with a 1-2-week interval, i.e., on (E+) and off (E-) erlotinib therapy. Each procedure consisted of a low-dose CT scan, a 10-min dynamic [(15)O]H2O PET scan, and a 60-min dynamic [(11)C]erlotinib PET scan with arterial and venous sampling at six time points. In patients(E+), the optimal compartment model was analyzed using Akaike information criterion. In patients(E-), the uptake parameter was the volume of distribution (V T), estimated by using metabolite-corrected plasma input curves based on image-derived input functions and discrete arterial and venous blood samples. Tumor blood flow (TBF) was determined by rate constant of influx (K1) of [(15)O]H2O using the 1T2k model and correlated with V T and K1 values of [(11)C]erlotinib. The investigated simplified parameters were standardized uptake value (SUV) and tumor-to-blood ratio (TBR) at 40-60 min pi interval. RESULTS: Of the 13 patients included, ten were scanned twice. In patients(E+), [(11)C]erlotinib best fitted the 2T4k model with V T. In all patients, tumor V T(E+) was lower than V T(E-) (median V T(E-) = 1.61, range 0.77-3.01; median V T(E+) = 1.17, range 0.53-1.74; P = 0.004). Using [(15)O]H2O, five patients were scanned twice. TBF did not change with erlotinib therapy, TBF showed a positive trend towards correlation with [(11)C]erlotinib K1, but not with V T. TBR40-50 and TBR50-60, using both arterial and venous sampling, correlated with V T(E-) (all r s >0.9, P < 0.001), while SUV did not. In patients off and on therapy, venous TBR underestimated arterial TBR by 26 ± 12 and 9 ± 9 %, respectively. CONCLUSIONS: In patients on erlotinib in therapeutic dose, tumor V T decreases with high variability, independent of tumor perfusion. For simplification of [(11)C]erlotinib PET scanning protocols, both arterial and venous TBR 40-60 min post injection can be used; however, arterial and venous TBR values should not be interchanged as venous values underestimate arterial values. TRIAL REGISTRATION: Registered at the Netherlands Trial Registry: NTR3670 .

18.
J Nucl Med ; 57(6): 861-6, 2016 06.
Artigo em Inglês | MEDLINE | ID: mdl-26848174

RESUMO

UNLABELLED: Quantitative assessment of (11)C-erlotinib uptake may be useful in selecting non-small cell lung cancer (NSCLC) patients for erlotinib therapy. The purpose of this study was to find the optimal pharmacokinetic model for quantification of uptake and to evaluate various simplified methods for routine analysis of (11)C-erlotinib uptake in NSCLC patients. METHODS: Dynamic (15)O-H2O and (11)C-erlotinib scans were obtained in 17 NSCLC patients, 8 with and 9 without an activating epidermal growth factor receptor mutation (exon 19 deletion or exon 21-point mutation). Ten of these subjects also underwent a retest scan on the same day. (11)C-erlotinib data were analyzed using single-tissue and 2-tissue-irreversible and -reversible (2T4k) plasma input models. In addition, several advanced models that account for uptake of radiolabeled metabolites were evaluated, including a variation of the 2T4k model without correcting for metabolite fractions in plasma (2T4k-WP). Finally, simplified methods were evaluated-that is, SUVs and tumor-to-blood ratios (TBR)-for several scan intervals. RESULTS: Tumor kinetics were best described using the 2T4k-WP model yielding optimal fits to the data (Akaike preference, 43.6%), acceptable test-retest variability (12%), no dependence on perfusion changes, and the expected clinical group separation (P < 0.016). Volume of distribution estimated using 2T4k-WP and 2T4k were highly correlated (R(2) = 0.94). Similar test-retest variabilities and clinical group separations were found. The 2T4k model did not perform better than an uncorrected model (2T4k-WP), probably because of uncertainty in the estimation of true metabolite fractions. Investigation of simplified approaches showed that SUV curves normalized to patient weight, and injected tracer dose did not reach equilibrium within the time of the scan. In contrast, TBR normalized to whole blood (TBR-WB) appeared to be a useful outcome measure for quantitative assessment of (11)C-erlotinib scans acquired 40-60 min after injection. CONCLUSION: The optimal model for quantitative assessment of (11)C-erlotinib uptake in NSCLC was the 2T4k-WB model. The preferred simplified method was TBR-WB (40-60 min after injection) normalized using several whole-blood samples.


Assuntos
Cloridrato de Erlotinib/metabolismo , Adulto , Idoso , Transporte Biológico , Carcinoma Pulmonar de Células não Pequenas/diagnóstico por imagem , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Feminino , Humanos , Cinética , Neoplasias Pulmonares/diagnóstico por imagem , Neoplasias Pulmonares/metabolismo , Masculino , Pessoa de Meia-Idade , Modelos Biológicos , Imagem Corporal Total
19.
J Nucl Med ; 56(11): 1730-5, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-26294297

RESUMO

UNLABELLED: Overexpression of the multidrug efflux transport P-glycoprotein may play an important role in pharmacoresistance. (11)C-laniquidar is a newly developed tracer of P-glycoprotein expression. The aim of this study was to develop a pharmacokinetic model for quantification of (11)C-laniquidar uptake and to assess its test-retest variability. METHODS: Two (test-retest) dynamic (11)C-laniquidar PET scans were obtained in 8 healthy subjects. Plasma input functions were obtained using online arterial blood sampling with metabolite corrections derived from manual samples. Coregistered T1 MR images were used for region-of-interest definition. Time-activity curves were analyzed using various plasma input compartmental models. RESULTS: (11)C-laniquidar was metabolized rapidly, with a parent plasma fraction of 50% at 10 min after tracer injection. In addition, the first-pass extraction of (11)C-laniquidar was low. (11)C-laniquidar time-activity curves were best fitted to an irreversible single-tissue compartment (1T1K) model using conventional models. Nevertheless, significantly better fits were obtained using 2 parallel single-tissue compartments, one for parent tracer and the other for labeled metabolites (dual-input model). Robust K1 results were also obtained by fitting the first 5 min of PET data to the 1T1K model, at least when 60-min plasma input data were used. For both models, the test-retest variability of (11)C-laniquidar rate constant for transfer from arterial plasma to tissue (K1) was approximately 19%. CONCLUSION: The accurate quantification of (11)C-laniquidar kinetics in the brain is hampered by its fast metabolism and the likelihood that labeled metabolites enter the brain. Best fits for the entire 60 min of data were obtained using a dual-input model, accounting for uptake of (11)C-laniquidar and its labeled metabolites. Alternatively, K1 could be obtained from a 5-min scan using a standard 1T1K model. In both cases, the test-retest variability of K1 was approximately 19%.


Assuntos
Benzazepinas/farmacocinética , Encéfalo/diagnóstico por imagem , Quinolinas/farmacocinética , Compostos Radiofarmacêuticos/farmacocinética , Subfamília B de Transportador de Cassetes de Ligação de ATP/biossíntese , Adulto , Biotransformação , Encéfalo/metabolismo , Radioisótopos de Carbono , Feminino , Voluntários Saudáveis , Humanos , Marcação por Isótopo , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Tomografia por Emissão de Pósitrons/métodos , Reprodutibilidade dos Testes , Adulto Jovem
20.
J Nucl Med ; 56(3): 365-71, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25678491

RESUMO

UNLABELLED: Choline kinase is upregulated in prostate cancer, resulting in increased (18)F-fluoromethylcholine uptake. This study used pharmacokinetic modeling to validate the use of simplified methods for quantification of (18)F-fluoromethylcholine uptake in a routine clinical setting. METHODS: Forty-minute dynamic PET/CT scans were acquired after injection of 204 ± 9 MBq of (18)F-fluoromethylcholine, from 8 patients with histologically proven metastasized prostate cancer. Plasma input functions were obtained using continuous arterial blood-sampling as well as using image-derived methods. Manual arterial blood samples were used for calibration and correction for plasma-to-blood ratio and metabolites. Time-activity curves were derived from volumes of interest in all visually detectable lymph node metastases. (18)F-fluoromethylcholine kinetics were studied by nonlinear regression fitting of several single- and 2-tissue plasma input models to the time-activity curves. Model selection was based on the Akaike information criterion and measures of robustness. In addition, the performance of several simplified methods, such as standardized uptake value (SUV), was assessed. RESULTS: Best fits were obtained using an irreversible compartment model with blood volume parameter. Parent fractions were 0.12 ± 0.4 after 20 min, necessitating individual metabolite corrections. Correspondence between venous and arterial parent fractions was low as determined by the intraclass correlation coefficient (0.61). Results for image-derived input functions that were obtained from volumes of interest in blood-pool structures distant from tissues of high (18)F-fluoromethylcholine uptake yielded good correlation to those for the blood-sampling input functions (R(2) = 0.83). SUV showed poor correlation to parameters derived from full quantitative kinetic analysis (R(2) < 0.34). In contrast, lesion activity concentration normalized to the integral of the blood activity concentration over time (SUVAUC) showed good correlation (R(2) = 0.92 for metabolite-corrected plasma; 0.65 for whole-blood activity concentrations). CONCLUSION: SUV cannot be used to quantify (18)F-fluoromethylcholine uptake. A clinical compromise could be SUVAUC derived from 2 consecutive static PET scans, one centered on a large blood-pool structure during 0-30 min after injection to obtain the blood activity concentrations and the other a whole-body scan at 30 min after injection to obtain lymph node activity concentrations.


Assuntos
Colina/análogos & derivados , Neoplasias da Próstata/diagnóstico por imagem , Compostos Radiofarmacêuticos , Idoso , Calibragem , Colina/química , Humanos , Cinética , Linfonodos/diagnóstico por imagem , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Tomografia por Emissão de Pósitrons , Prostatectomia , Compostos Radiofarmacêuticos/química , Análise de Regressão , Fatores de Tempo , Tomografia Computadorizada por Raios X
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