RESUMEN
BACKGROUND: Hepatocellular carcinoma (HCC) remains one of the leading causes of cancer-related deaths in the world. Liver-directed therapies, including 90Yttrium (90Y) radioembolization, play an integral role in the management of HCC with excellent response rates. This has led to clinical trials of immunotherapy in combination with 90Y. Elevated PD-1 expression and lymphopenia were recently shown as risk factors for disease progression in early-stage HCC treated with liver-directed therapies. The aim of this study was to investigate PD-1 expression dynamics in bridge/downstage to transplant in HCC patients receiving first-cycle 90Y and evaluate the impact of these changes on response rates and time-to-progression (TTP). METHODS: Patients with HCC receiving first-cycle 90Y as a bridge to liver transplantation (n = 99) were prospectively enrolled. Blood specimens were collected before 90Y and again during routine imagining follow-up to analyze PD-1 expression via flow cytometry. Complete and objective response rates (CR and ORR) were determined using mRECIST. RESULTS: In 84/88 patients with available follow-up imaging, 83% had a localized ORR with 63% having localized CR. For overall response, 71% and 54% experienced ORR and CR, respectively. Post-90Y PD-1 upregulation in CD8 + associated with HCC progression and decreased TTP. Treatment with 90Y was associated with an anticipated significant post-treatment drop in lymphocytes (P < 0.001) that was independent of PD-1 expression for either CD4+ or CD8+ T cells (P = 0.751 and P = 0.375) and not associated with TTP risk. The change in lymphocytes was not correlated with PD-1 expression following treatment nor TTP. CONCLUSIONS: Elevated PD-1 expression on peripheral T cells is associated with increased risk of HCC progression and shorter time to progression in bridging/downstaging to transplant HCC patients undergoing first-cycle 90Y. Treatment-induced lymphopenia was not associated with treatment response, or increased progression risk, suggesting this anticipated adverse event does not impact short-term HCC outcomes.
Asunto(s)
Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/radioterapia , Carcinoma Hepatocelular/tratamiento farmacológico , Neoplasias Hepáticas/radioterapia , Neoplasias Hepáticas/tratamiento farmacológico , Receptor de Muerte Celular Programada 1/metabolismo , Linfocitos T CD8-positivos/metabolismo , Resultado del Tratamiento , Radioisótopos de Itrio/uso terapéutico , Radioisótopos de Itrio/metabolismoAsunto(s)
Carcinoma Hepatocelular/terapia , Quimioembolización Terapéutica/métodos , Inmunoterapia/métodos , Radioisótopos de Itrio/uso terapéutico , Carcinoma Hepatocelular/diagnóstico , Carcinoma Hepatocelular/mortalidad , Terapia Combinada/efectos adversos , Terapia Combinada/métodos , Embolización Terapéutica/efectos adversos , Embolización Terapéutica/métodos , Humanos , Inhibidores de Puntos de Control Inmunológico/administración & dosificación , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Neoplasias Hepáticas/patología , Microesferas , Nivolumab/administración & dosificación , Nivolumab/uso terapéutico , Estudios Prospectivos , Seguridad , Resultado del Tratamiento , Radioisótopos de Itrio/administración & dosificación , Radioisótopos de Itrio/metabolismoRESUMEN
BACKGROUND: Therapeutic synergism between radiotherapy and immune checkpoint blockade has been observed in preclinical models of hepatocellular carcinoma. We aimed to study the safety and efficacy of sequential radioembolisation with yttrium-90-resin microspheres (Y90-radioembolisation) followed by nivolumab in patients with advanced hepatocellular carcinoma. METHODS: Patients with Child-Pugh A cirrhosis and advanced hepatocellular carcinoma not suitable for curative surgery were treated with Y90-radioembolisation followed by intravenous nivolumab 240 mg 21 days after Y90-radioembolisation and every 2 weeks thereafter. The primary endpoint, assessed in the per-protocol population, was the objective response rate, determined by RECIST version 1.1, defined as the proportion of patients with a confirmed complete or partial response observed for lesions both within and outside the Y90-radioembolisation field. This study is registered with ClinicalTrials.gov, NCT03033446 and has been completed. FINDINGS: 40 patients were enrolled, of whom 36 received Y90-radioembolisation followed by nivolumab. One (3%) patient had a complete response and ten (28%) had a partial response; the objective response rate was 30·6% (95% CI 16·4-48·1). The most common treatment-related adverse events of any grade were pruritus (18 [50%] of 36 patients) and maculopapular rash (13 [36%]). Two (6%) patients experienced grade 3-4 treatment-related adverse events: one patient had a grade 3 increase in alanine aminotransferase levels, grade 3 bilirubin increase, and grade 4 increase in aspartate aminotransferase levels, while the other had a grade 3 maculopapular rash. Five (14%) patients had a treatment-related serious adverse event (Steven-Johnson syndrome, hepatitis E infection, fever, liver abscesses, and ascites). INTERPRETATION: Y90-radioembolisation followed by nivolumab resulted in an encouraging objective response rate in patients with advanced hepatocellular carcinoma, although the activity observed was not as high as the study was powered for. This strategy should be further evaluated in patients with Barcelona Clinic Liver Clinic (BCLC) stage B hepatocellular carcinoma that is ineligible or refractory to transarterial chemoembolisation and patients with BCLC C disease without extrahepatic spread. FUNDING: National Medical Research Council Singapore, Bristol-Myers Squibb, Sirtex.
Asunto(s)
Carcinoma Hepatocelular/tratamiento farmacológico , Carcinoma Hepatocelular/terapia , Quimioembolización Terapéutica/métodos , Nivolumab/uso terapéutico , Radioisótopos de Itrio/uso terapéutico , Administración Intravenosa , Adulto , Anciano , Carcinoma Hepatocelular/diagnóstico , Terapia Combinada/efectos adversos , Terapia Combinada/métodos , Embolización Terapéutica/efectos adversos , Embolización Terapéutica/métodos , Femenino , Humanos , Inhibidores de Puntos de Control Inmunológico/administración & dosificación , Inhibidores de Puntos de Control Inmunológico/efectos adversos , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Neoplasias Hepáticas/patología , Masculino , Microesferas , Persona de Mediana Edad , Nivolumab/administración & dosificación , Nivolumab/efectos adversos , Supervivencia sin Progresión , Seguridad , Índice de Severidad de la Enfermedad , Singapur/epidemiología , Resultado del Tratamiento , Radioisótopos de Itrio/administración & dosificación , Radioisótopos de Itrio/metabolismoRESUMEN
Introduction: The quality control parameters of in-house-produced 90Y-Acetate from high-level liquid waste (HLLW) using supported liquid membrane (SLM) technology were validated and compared with the pharmacopeia standard. The radiolabeling of DOTATATE yielding 90Y-DOTATATE in acceptable radiochemical purity (RCP), with expected pharmacological behavior in in vivo models, establish the quality of 90Y-Acetate. Clinical translation of 90Y-Acetate in formulation of 90Y-DOTATATE adds support toward its use as clinical-grade radiochemical. Methods: Quality control parameters of 90Y-Acetate, namely radionuclide purity (RNP), were evaluated using ß- spectrometry, γ-spectroscopy, and liquid scintillation counting. RCP and metallic impurities were established using high-performance liquid chromatography and inductively coupled plasma optical emission spectrometry, respectively. The suitability of 90Y-Acetate as an active pharmaceutical ingredient radiochemical was ascertained by radiolabeling with DOTATATE. In vivo biodistribution of 90Y-DOTATATE was carried out in nude mice bearing AR42J xenografted tumor. Clinical efficacy of 90Y-DOTATATE was established after using in patients with large-volume neuroendocrine tumors (NET). Bremsstrahlung imaging was carried out in dual-head gamma camera with a wide energy window setting (100-250 keV). Results: In-house-produced 90Y-Acetate was clear, colorless, and radioactive concentration (RAC) in the range of 40-50 mCi/mL. RCP was >98%. 90Sr content was <0.85 µCi/Ci of 90Y. Gross λ content was <0.8 nCi/Ci of 90Y and no γ peak was observed. Fe3+, Cu2+, Zn2+, Cd2+, and Pb2+ contents were <1.7 µg/Ci. The radiolabeling yield (RLY) of 90Y-DOTATATE was >94%, RCP was >98%. The in vitro stability of 90Y-DOTATATE was up to 72 h postradiolabeling, upon storage at -20°C. Post-therapy (24 h) Bremsstrahlung image of patients with large NET exhibit complete localization of 90Y-DOTATATE in tumor region. Conclusions: This study demonstrates that the in-house-produced 90Y-Acetate from HLLW can be used for the formulation of various therapeutic 90Y-based radiopharmaceuticals. Since 90Y is an imported radiochemical precursor available at a high cost in India, this study which demonstrates the suitability of indigenously sourced 90Y, ideally exemplifies the recovery of "wealth from waste." The Clinical Trial Registration number: (P17/FEB/2019).
Asunto(s)
Radioquímica/métodos , Radioisótopos de Itrio/metabolismo , Animales , Humanos , Masculino , Ratones , Ratones Desnudos , Clasificación del Tumor , Distribución TisularRESUMEN
INTRODUCTION: Selective Internal Radiation Therapy (SIRT) is used for the treatment of hepatic tumors. The aim of this retrospective study was to compare two dosimetric approaches based on 99mTc-MAA SPECT/CT and 90Y PET/CT, using Simplicit90Y™ versus the supplier suggested method of activity calculation. MATERIAL AND METHODS: A total of 19 patients underwent 21 SIRT after baseline angiography and 99mTc-MAA SPECT/CT, followed by 90Y PET/CT. Overlap between 99mTc-MAA and 90Y-microspheres was quantified with different thresholds isocontours. The perfused volume and tumor absorbed dose were estimated using Simplicit90Y™ based on SPECT/CT and PET/CT, then compared with the supplier suggested method. These data were related to overall survival to evaluate their prognostic impact. RESULTS: The overlap between PET/CT and SPECT/CT was dependent on thresholds, decreasing with an increasing threshold. The overlap between the 99mTc-MAA and 90Y-microspheres biodistributions versus the tumor distribution on morphological imaging was suboptimal, in particular for small tumor volume. The tumor absorbed dose estimated after 90Y PET/CT was not different from tumor absorbed dose estimated after SPECT/CT. The Perfused lobe absorbed dose was significantly lower while the volume of the perfused lobe was significantly higher when estimated by Simplicit90Y™ compared to the supplier suggested conventional approach. A statistical parameter based on overlap between tumor and 90Y-microspheres distribution as well as tumoral dosimetry was significantly related to the overall survival. CONCLUSION: Post-treatment imaging remains paramount to estimate the irradiation dosimetry, due to an imperfect overlap. The perfused volume could be estimated from functional imaging, given its impact on dosimetry. Finally, survival seems related to tumoral overlap and dosimetry.
Asunto(s)
Carcinoma Hepatocelular/radioterapia , Neoplasias Hepáticas/radioterapia , Tomografía Computarizada por Tomografía de Emisión de Positrones/métodos , Planificación de la Radioterapia Asistida por Computador/métodos , Tomografía Computarizada por Tomografía Computarizada de Emisión de Fotón Único/métodos , Anciano , Carcinoma Hepatocelular/diagnóstico por imagen , Carcinoma Hepatocelular/metabolismo , Femenino , Humanos , Neoplasias Hepáticas/diagnóstico por imagen , Neoplasias Hepáticas/metabolismo , Masculino , Persona de Mediana Edad , Radioterapia Asistida por Computador/métodos , Estudios Retrospectivos , Radioisótopos de Itrio/metabolismoRESUMEN
A 61-year-old woman with multiple hepatic metastases from uterus cervical cancer received Y radioembolization. The simultaneous time-of-flight (TOF) PET/MR clearly identified the untreated tumor parts on the posttherapeutic Y internal pair-production imaging. After another boosted Y injection, the metastatic hepatic tumors were well covered. The follow-up PET/MR revealed tumor shrinkage. The one-stop-shop TOF PET/MR provided useful follow-up information in patients receiving Y radioembolization.
Asunto(s)
Embolización Terapéutica , Neoplasias Hepáticas/diagnóstico por imagen , Imagen por Resonancia Magnética , Tomografía de Emisión de Positrones , Neoplasias del Cuello Uterino/patología , Radioisótopos de Itrio/metabolismo , Radioisótopos de Itrio/uso terapéutico , Femenino , Humanos , Cinética , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/secundario , Microesferas , Persona de Mediana Edad , Imagen Multimodal , Resinas Sintéticas/química , Radioisótopos de Itrio/químicaRESUMEN
PURPOSE: There are several important positron emission tomography (PET) imaging scenarios that require imaging with very low photon statistics, for which both quantitative accuracy and visual quality should not be neglected. For example, PET imaging with the low photon statistics is closely related to active efforts to significantly reduce radiation exposure from radiopharmaceuticals. We investigated two examples of low-count PET imaging: (a) imaging [90Y]microsphere radioembolization that suffers the very small positron emission fraction of Y-90's decay processes, and (b) cancer imaging with [68Ga]citrate with uptake time of 3-4 half-lives, necessary for visualizing tumors. In particular, we investigated a type of penalized likelihood reconstruction algorithm, block sequential regularized expectation maximization (BSREM), for improving both image quality and quantitative accuracy of these low-count PET imaging cases. PROCEDURES: The NEMA/IEC Body phantom filled with aqueous solution of Y-90 or Ga-68 was scanned to mimic the low-count scenarios of corresponding patient data acquisitions on a time-of-flight (TOF) PET/magnetic resonance imaging system. Contrast recovery, background variation, and signal-to-noise ratio were evaluated in different sets of count densities using both conventional TOF ordered subset expectation (TOF-OSEM) and TOF-BSREM algorithms. The regularization parameter, beta, in BSREM that controls the tradeoff between image noise and resolution was evaluated to find a value for improved confidence in image interpretation. Visual quality assessment of the images obtained from patients administered with [68Ga]citrate (n = 6) was performed. We also made preliminary visual image quality assessment for one patient with [90Y]microspheres. In Y-90 imaging, the effect of 511-keV energy window selection for minimizing the number of random events was also evaluated. RESULTS: Quantitatively, phantom images reconstructed with TOF-BSREM showed improved contrast recovery, background variation, and signal-to-noise ratio values over images reconstructed with TOF-OSEM. Both phantom and patient studies of delayed imaging of [68Ga]citrate show that TOF-BSREM with beta = 500 gives the best tradeoff between image noise and image resolution based on visual assessment by the readers. The NEMA-IQ phantom study with [90Y]microspheres shows that the narrow energy window (460-562 keV) recovers activity concentrations in small spheres better than the regular energy window (425-650 keV) with the beta value of 2000 using the TOF-BSREM algorithm. For the images obtained from patients with [68Ga]citrate using TOF-BSREM with beta = 500, the visual analogue scale (VAS) was improved by 17 % and the Likert score was increased by 1 point on average, both in comparison to corresponding scores for images reconstructed using TOF-OSEM. CONCLUSION: Our investigation shows that the TOF-BSREM algorithm improves the image quality and quantitative accuracy in low-count PET imaging scenarios. However, the beta value in this algorithm needed to be adjusted for each radiopharmaceutical and counting statistics at the time of scans.
Asunto(s)
Algoritmos , Citratos/metabolismo , Radioisótopos de Galio/metabolismo , Galio/metabolismo , Procesamiento de Imagen Asistido por Computador/métodos , Tomografía Computarizada por Tomografía de Emisión de Positrones/métodos , Neoplasias de la Próstata Resistentes a la Castración/patología , Radioisótopos de Itrio/metabolismo , Humanos , Masculino , Microesferas , Fantasmas de Imagen , Neoplasias de la Próstata Resistentes a la Castración/diagnóstico por imagen , Neoplasias de la Próstata Resistentes a la Castración/metabolismo , Radiofármacos/metabolismo , Relación Señal-RuidoRESUMEN
INTRODUCTION: Guidelines on how to adjust activity in patients with a history of liver surgery who are undergoing yttrium-90 radioembolisation (90Y-RE) are lacking. The aim was to study the variability in activity prescription in these patients, between centres with extensive experience using resin microspheres 90Y-RE, and to draw recommendations on activity prescription based on an expert consensus. METHODS: The variability in activity prescription between centres was investigated by a survey of international experts in the field of 90Y-RE. Six representative post-surgical patients (i.e. comparable activity prescription, different outcome) were selected. Information on patients' disease characteristics and data needed for activity calculation was presented to the expert panel. Reported was the used method for activity prescription and whether, how and why activity reduction was found indicated. RESULTS: Ten experts took part in the survey. Recommendations on activity reduction were highly variable between the expert panel. The median intra-patient range was 44 Gy (range 18-55 Gy). Reductions in prescribed activity were recommended in 68% of the cases. In consensus, a maximum DTarget of 50 Gy was recommended. CONCLUSION: With a current lack of guidelines, large variability in activity prescription in post-surgical patients undergoing 90Y-RE exists. In consensus, DTarget ≤50 Gy is recommended. KEY POINTS: ⢠BSA method does not account for a decreased remnant liver volume after surgery. ⢠In post-surgical patients, a volume-based activity determination method is recommended. ⢠In post-surgical patients, a mean D Target of ≤ 50Gy should be aimed for.
Asunto(s)
Embolización Terapéutica/métodos , Neoplasias Hepáticas/radioterapia , Microesferas , Radioisótopos de Itrio/uso terapéutico , Femenino , Humanos , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/cirugía , Masculino , Dosis de Radiación , Encuestas y Cuestionarios , Radioisótopos de Itrio/efectos adversos , Radioisótopos de Itrio/metabolismoRESUMEN
We presented the first example of Cerenkov luminescence imaging (CLI) and radioluminescence imaging (RLI) of human tumor specimens. A patient with a brain meningioma localized in the left parietal region was injected with 166 MBq of 90Y-DOTATOC the day before neurosurgery. The specimens of the tumor removed during surgery were imaged using both CLI and RLI using an optical imager prototype developed in our laboratory. The system is based on a cooled electron multiplied charge coupled device coupled with an f ∕0.95 17-mm C-mount lens. We showed for the first time the possibility of obtaining CLI and RLI images of fresh human brain tumor specimens removed during neurosurgery.
Asunto(s)
Neoplasias Encefálicas/diagnóstico por imagen , Neoplasias Encefálicas/cirugía , Meningioma/diagnóstico por imagen , Meningioma/cirugía , Neurocirugia , Humanos , Luminiscencia , Imagen Óptica , Radioisótopos de Itrio/metabolismoAsunto(s)
Hígado/diagnóstico por imagen , Hígado/metabolismo , Microesferas , Tomografía de Emisión de Positrones , Radioisótopos de Itrio/química , Radioisótopos de Itrio/metabolismo , Adulto , Transporte Biológico , Femenino , Humanos , Masculino , Persona de Mediana Edad , Tomografía Computarizada por Rayos XRESUMEN
OBJECTIVE: To examine yttrium-90 distribution 1 and 72 h following its injection into a knee joint in patients with rheumatoid arthritis (RA). METHODS: In 14 RA patients we injected yttrium-90 into the affected knee joint using lateral approach. To assess the radioisotope distribution in the joint, the superimposed sequential SPECT and CT imaging was performed 1 and 72 h after the injection. We analyzed the percentage of radioisotope distribution in three predefined compartments of the knee joint (lower, upper medial, upper lateral). RESULTS: After 1 and 72 h, the mean percentage distributions were, respectively, 7.14 and 23.07% in lower; 21.42 and 15.38% in upper medial, and 71.42 and 61.53% in upper lateral compartment. The percentage of isotope deposition did not change significantly with time in any of the compartments (all p > 0.26). The deposition of isotope, both at 1 and 72 h, was significantly greater in upper lateral compartment, where the injection was performed, than in all other compartments (all p < 0.05). CONCLUSIONS: Using the SPECT/CT hybrid method, we proved that the majority of isotope is located at the compartment adjacent to the injection. Two injections targeting different compartments might improve the clinical efficacy of the procedure.
Asunto(s)
Artritis Reumatoide/diagnóstico , Artritis Reumatoide/cirugía , Articulación de la Rodilla/cirugía , Sinovectomía , Tomografía Computarizada de Emisión de Fotón Único , Tomografía Computarizada por Rayos X , Artritis Reumatoide/diagnóstico por imagen , Femenino , Humanos , Masculino , Persona de Mediana Edad , Radioisótopos de Itrio/metabolismoRESUMEN
UNLABELLED: Somatostatin receptor targeting is a valuable method to treat somatostatin receptor-positive tumours. In peptide receptor radionuclide therapy, it is essential to determine the highest activity that can be safely administered to the patient. As (90)Y emits no gamma rays, absorbed doses for (90)Y are usually estimated using the same peptide labelled with (111)In. The aim of the study was to determine if replacement of (90/88)Y by (111)In affects the biodistribution profile of five selected somatostatin analogues in preclinical experiments. MATERIALS AND METHODS: Radiolabelled peptides were administered intravenously to male Wistar rats. RESULTS: The peptides under study labelled either with (111)In or with (88/90)Y showed similar distribution profiles in all tissues excepting the kidney. The kidney radioactivity uptake was significantly lower for (88/90)Y-labeled peptide in comparison with the one of (111)In. CONCLUSION: We conclude that a radiation-absorbed dose after (90)Y-labelled somatostatin analogues appears to be lower than that predicted by the (111)In-labelled peptide.
Asunto(s)
Radioisótopos de Indio/metabolismo , Riñón/metabolismo , Somatostatina/metabolismo , Radioisótopos de Itrio/metabolismo , Animales , Masculino , Ratas , Ratas Wistar , Somatostatina/análogos & derivadosRESUMEN
Purpose Unwanted deposition of 90Y microspheres in organs other than the liver during radioembolization of liver tumours may cause severe side effects such as duodenal ulcer. The aim of this study was to evaluate the significance of posttherapy bremsstrahlung (BS) SPECT/CT images of the liver in comparison to planar and SPECT images in the prediction of radioembolization-induced extrahepatic side effects.Methods A total of 188 radioembolization procedures were performed in 123 patients (50 women, 73 men) over a 2-year period. Planar, whole-body and BS SPECT/CT imaging were performed 24 h after treatment as a part of therapy work-up.Any focally increased extrahepatic accumulation was evaluated as suspicious. Clinical follow-up and gastroduodenoscopy served as reference standards. The studies were reviewed to evaluate whether BS SPECT/CT imaging was of benefit.Results In the light of anatomic data obtained from SPECT/CT, apparent extrahepatic BS in 43% of planar and in 52% of SPECT images proved to be in the liver and hence false positive.The results of planar scintigraphy could not be analysed further since 12 images were not assessable due to high scatter artefacts. On the basis of the gastrointestinal (GI)complications and the results of gastroduodenoscopy, true positive,true-negative, false-positive and false-negative results of BS SPECT and SPECT/CT imaging in the prediction of GI ulcers were determined. The sensitivity, specificity, positive and negative predictive values and the accuracy of SPECT and SPECT/CT in the prediction of GI ulcers were 13%, 88%, 8%,92% and 82%, and 87%, 100%, 100%, 99% and 99%,respectively.Conclusion Despite the low quality of BS images, BSSPECT/CT can be used as a reliable method to confirm the safe distribution of 90Y microspheres and in the prediction of GI side effects.
Asunto(s)
Embolización Terapéutica/efectos adversos , Imagen Multimodal , Tomografía Computarizada de Emisión de Fotón Único , Tomografía Computarizada por Rayos X , Radioisótopos de Itrio/uso terapéutico , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Microesferas , Persona de Mediana Edad , Neoplasias/diagnóstico por imagen , Neoplasias/metabolismo , Neoplasias/terapia , Radioisótopos de Itrio/efectos adversos , Radioisótopos de Itrio/metabolismoRESUMEN
The clinical application of the pure beta emitter (90)Y constitutes a fundamental advancement in non-invasive medicine. Nowadays, mainly three oncological therapies exploit the intrinsic emissive characteristic of (90)Y. Radionuclide therapies include peptide receptor radionuclide therapy (PRRT) in neuroendocrine tumour (NET) treatment, radioimmunotherapy (RIT) in non-Hodgkin's lymphoma (NHL) treatment and transarterial radioembolization therapy (TARET) in unresectable hepatocellular carcinoma (HCC) and liver metastatic colorectal cancer (mCRC) treatment. The last ten years of clinical experience from E-PubMed research have been reviewed and an efficacy correlation between (90)Y-therapies has shown a better objective response rate for RIT (ORR 80±15%; range 53-100) compared to PRRT (ORR 23.5±14%; range 9-50), and TARET (ORR for mCRC, 40±25%; range 19-91, and ORR for HCC, 42±20%; range 20-82). This review reports on the state of the art of the efficacy of (90)Y-therapies from the last decade and discusses new perspectives of therapeutic development.
Asunto(s)
Anticuerpos Monoclonales/uso terapéutico , Embolización Terapéutica , Neoplasias/terapia , Radioinmunoterapia , Receptores de Péptidos/metabolismo , Radioisótopos de Itrio/uso terapéutico , Carcinoma Hepatocelular/terapia , Ensayos Clínicos como Asunto , Humanos , Neoplasias Hepáticas/terapia , Linfoma no Hodgkin/radioterapia , Tumores Neuroendocrinos/radioterapia , Resultado del Tratamiento , Radioisótopos de Itrio/metabolismoRESUMEN
PURPOSE: An angiographic evaluation combined with (99m)Tc-macroaggregated albumin (Tc-MAA) scanning should precede the treatment of any selected candidates for radioembolization (RE) of the liver. If the tumours in one liver lobe have not been targeted in the test angiogram, it should be repeated. However, in a few cases treatment of one liver lobe or at least some segments is safe and feasible and performing a repeated test angiogram with Tc-MAA (Re-MAA) in a separate session leads to more radiation exposure and could be time consuming. Our aim was to evaluate the feasibility of concurrent RE of a part of the liver and therapy planning for another region by simultaneous injection of the Tc-MAA and (90)Y-microspheres in two different locations in the therapy session. Tc-MAA and bremsstrahlung (BS) single photon emission computed tomography (SPECT)/CT were performed separately in an effort to distinguish between the distributions of these two different radiopharmaceuticals. METHODS: RE was combined with a simultaneous second test angiogram of another lobe or segments in the same session in six patients [44-70 years; five women (83%)]. Five patients suffered from colorectal carcinoma (CRC) and one from ovarian cancer. Tc-MAA and BS SPECT/CT were performed for all cases. RESULTS: Post-therapeutic Tc-MAA SPECT/CT showed in all patients only the distribution of Tc-MAA without any detectable BS. Evaluation of (90)Y-microsphere distribution was not always possible in the post-therapeutic BS scan performed 24 h later due to remaining Tc-MAA radiation. However, scans performed at 48 h post-intervention no longer showed any Tc-MAA "contamination". CONCLUSION: Combining RE and Re-MAA is feasible in appropriately selected patients.
Asunto(s)
Embolización Terapéutica/métodos , Microesferas , Planificación de la Radioterapia Asistida por Computador/métodos , Compuestos de Sulfhidrilo/uso terapéutico , Agregado de Albúmina Marcado con Tecnecio Tc 99m/uso terapéutico , Tomografía Computarizada de Emisión de Fotón Único , Tomografía Computarizada por Rayos X , Adulto , Anciano , Femenino , Humanos , Inyecciones , Neoplasias Hepáticas/diagnóstico por imagen , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/terapia , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Compuestos de Sulfhidrilo/química , Compuestos de Sulfhidrilo/metabolismo , Agregado de Albúmina Marcado con Tecnecio Tc 99m/química , Agregado de Albúmina Marcado con Tecnecio Tc 99m/metabolismo , Factores de Tiempo , Resultado del Tratamiento , Radioisótopos de Itrio/química , Radioisótopos de Itrio/metabolismo , Radioisótopos de Itrio/uso terapéuticoRESUMEN
Yttrium-90 (Y-90) selective internal radiation therapy (SIRT) is increasingly used to treat inoperable hepatocellular carcinoma. We describe two patients where hepatic falciform ligament Technetium-99m-macroaggregated albumin (Tc-99m-MAA) activity was identified on single photon emission computed tomography with integrated low-dose CT (SPECT/CT) scan during pre-therapy planning, and the steps taken to prevent radiation dermatitis. The first patient underwent prophylactic coil embolization of the patent hepatic falciform artery; the second patient underwent super-selective infusion of Y-90 resin microspheres to avoid the patent hepatic falciform artery. The incidence of falciform ligament Tc-99m-MAA activity detected on SPECT/CT at our institution is 10%. Tc-99m-MAA SPECT/CT scan provides valuable diagnostic information for treatment planning prior to Y-90 SIRT.
Asunto(s)
Arterias/efectos de la radiación , Embolización Terapéutica/efectos adversos , Ligamentos/diagnóstico por imagen , Hígado/anomalías , Tomografía Computarizada de Emisión de Fotón Único , Tomografía Computarizada por Rayos X , Arterias/metabolismo , Humanos , Hígado/irrigación sanguínea , Hígado/diagnóstico por imagen , Masculino , Microesferas , Persona de Mediana Edad , Dosis de Radiación , Agregado de Albúmina Marcado con Tecnecio Tc 99m , Radioisótopos de Itrio/química , Radioisótopos de Itrio/metabolismo , Radioisótopos de Itrio/uso terapéuticoRESUMEN
BACKGROUND: Maximum injected activity in radioimmunotherapy (RIT) is limited by bone marrow toxicity. Many dosimetric approaches have been proposed, leading to high variability in the results and elusive absorbed dose-effect relations. This study presents the results of red marrow (RM) absorbed dose estimates performed with 3 methods. METHODS: Five patients received 2 co-infusions of (90)Y-labeled (370 MBq/m2) and (111)In- labeled (120 MBq) epratuzumab (1.5 mg/kg) 1 week apart. RM-absorbed dose was estimated by 3 methodologies. The first approach (M1) used L(2)-L(4) lumbar vertebrae imaging. M2 and M3 methods used different red marrow to blood ratios (RMBLR) to assess RM-absorbed dose. RMBLR was set to a fixed value of 0.36 in M2 or assessed according to each patient's hematocrit in M3. RESULTS: Median RM-absorbed doses were 4.1 (2.9-8.4), 2.3 (2.0-2.7), and 2.3 (1.6-2.5) mGy/MBq for M1, M2, and M3, respectively. No trend could be found between total RM-absorbed dose and toxicity for M2 and M3. Conversely, M1 seemed to provide the best absorbed dose-effect relation. The 4 patients with the highest RM-absorbed doses exhibited grade 4 toxicity. The fifth patient, with the lowest RB absorbed dose, exhibited only a mild (grade 2) toxicity. CONCLUSIONS: Image-based methodology (M1) seems to better predict hematological toxicity as compared with blood-based methods. Only this method provides for bone marrow involvement.
Asunto(s)
Médula Ósea/efectos de la radiación , Linfoma de Células B/radioterapia , Radioinmunoterapia/métodos , Radiometría/métodos , Dosificación Radioterapéutica , Radioisótopos de Itrio/metabolismo , Adolescente , Adulto , Femenino , Humanos , Masculino , Radioisótopos de Itrio/uso terapéuticoRESUMEN
UNLABELLED: Protease degradable linkers have been proposed to improve the therapeutic index (TI) (i.e., tumor to normal tissue) of molecular targeted radioisotope therapy by reducing unbound radiotargeting agent in the blood and other normal tissues. If the radioisotope is detached from the circulating targeting agent once the radioisotope level in the tumors has been maximized, the success of this system depends on the ability to anticipate a preferred intervention time that will lead to significantly improved TIs. This paper presents a method to predict preferred intervention times and TIs by using pharmacokinetic tracer studies carried out without intervention. METHODS: Pharmacokinetic data for the blood and tumors from tracer doses of 111In-labeled chimeric and mouse monoclonal antibodies in patients and in mice were used as surrogates for corresponding 90Y radioimmunoconjugates. Data were fit with simple pharmacokinetic functions. A set of formulas was then developed to estimate the improvement in therapeutic index and the preferred intervention time, using simple modeling assumptions. RESULTS: A modeled introduction of enzymatic cleavable linkers resulted in an increase in the tumor-to-blood TI by a factor of 3.2-1.6 for the systems analyzed. As expected, the preferred intervention times varied depending on the pharmacokinetic data, but could be predicted based on a priori knowledge of the actual or anticipated pharmacokinetics in the absence of intervention. CONCLUSIONS: These results highlight the potential value of cleavable linkers in substantially increasing the TI, and provide an approach for estimating a preferred intervention time, using actual or predicted pharmacokinetic data obtained without intervention.
Asunto(s)
Vasos Sanguíneos/enzimología , Radioisótopos de Indio/metabolismo , Radioisótopos de Indio/farmacocinética , Péptidos/metabolismo , Radioisótopos de Itrio/metabolismo , Radioisótopos de Itrio/farmacocinética , Animales , Línea Celular Tumoral , Humanos , Radioisótopos de Indio/química , Radioisótopos de Indio/uso terapéutico , Ratones , Modelos Animales , Modelos Biológicos , Estudios Retrospectivos , Factores de Tiempo , Radioisótopos de Itrio/química , Radioisótopos de Itrio/uso terapéuticoRESUMEN
The results of radiometric and haematological studies of striped field mice (Apodemus agrarius) sampled over the years 1995-2003 from the territory of the preserved radioactive waste burial (RWB), which is located in the Moscow recreation forest "Kuzminki", are presented and discussed in the paper. It was shown that the level of 90Sr-90Y content in mice sampled from the RWB area varies within the range of 0-1200 Bq/kg with an average of 98.7+/-21.5 Bq/kg. The content of 90Sr-90Y in the body of 80% of the mice sampled from the RWB area was below 100 Bq/kg. Only in 4% of the sampled mice, the 90Sr-90Y specific radioactivity was above 300 Bq/kg. Haematological indications of the animals sampled from the RWB area were within the range of normal physiological fluctuations. Nevertheless, a slight but statistically significant increase in the average amount of erythrocytes and the average percentage of banded neutrophils was registered in peripheral blood of the mice.
Asunto(s)
Ratones , Contaminantes Radiactivos/análisis , Radioisótopos de Estroncio/análisis , Radioisótopos de Itrio/análisis , Animales , Monitoreo del Ambiente , Recuento de Eritrocitos , Recuento de Leucocitos , Moscú , Plantas/química , Dosis de Radiación , Contaminantes Radiactivos/metabolismo , Residuos Radiactivos , Recreación , Radioisótopos de Estroncio/metabolismo , Árboles , Radioisótopos de Itrio/metabolismoRESUMEN
90Y-TA138 is a (90)Y-labeled nonpeptide integrin alpha(v)beta(3) receptor antagonist that binds with high affinity and specificity to integrin alpha(v)beta(3) receptors overexpressed on both endothelial and tumor cells. (90)Y-TA138 has demonstrated significant therapeutic effects in several preclinical tumor-bearing animal models. Since (90)Y is a pure beta-emitter, (111)In-TA138 has been chosen as the imaging surrogate for dosimetry determination of (90)Y-TA138. This report describes the synthesis of (111)In-TA138 and biological evaluations of both (111)In-TA138 and (90)Y-TA138 in the c-neu Oncomouse model. The HPLC data shows that (111)In-TA138 is more hydrophilic with the retention time approximately 4.5 min shorter than that of (90)Y-TA138 under identical chromatographic conditions. Since the only difference between (111)In-TA138 and (90)Y-TA138 is the metal ion, the HPLC retention time difference strongly suggests that indium and yttrium chelates do not share the same coordination sphere in solution even though they are coordinated by the same DOTA conjugate. Despite their differences in lipophilicity and solution structure, biodistribution data in the c-neu Oncomouse model clearly showed that (111)In-TA138 and (90)Y-TA138 are biologically equivalent with respect to their uptake in tumors and other major organs. Therefore, (111)In-TA138 is useful as an imaging surrogate for (90)Y-TA138 and should be able to predict the radiation dosimetry of (90)Y-TA138, a therapeutic radiopharmaceutical for treatment of rapidly growing tumors.