Recommendations for the management of yttrium-90 radioembolization in the treatment of patients with colorectal cancer liver metastases: a multidisciplinary review.

PURPOSE: Strategies for the treatment of liver metastases from colon cancer (lmCRC) are constantly evolving. Radioembolization with yttrium 90 (Y-90 TARE) has made significant advancements in treating liver tumors and is now considered a potential option allowing for future resection. This study reviewed the scientific evidence and developed recommendations for using Y-90 TARE as a treatment strategy for patients with unresectable lmCRC. METHODS: A multidisciplinary scientific committee, consisting of experts in medical oncology, hepatobiliary surgery, radiology, and nuclear medicine, all with extensive experience in treating patients with ImCRC with Y-90 TARE, led this project. The committee established the criteria for conducting a comprehensive literature review on Y-90 TARE in the treatment of lmCRC. The data extraction process involved addressing initial preliminary inquiries, which were consolidated into a final set of questions. RESULTS: This review offers recommendations for treating patients with lmCRC using Y-90 TARE, addressing four areas covering ten common questions: 1) General issues (multidisciplinary tumor committee, indications for treatment, contraindications); 2) Previous process (predictive biomarkers for patient selection, preintervention tests, published evidence); 3) Procedure (standard procedure); and 4) Post-intervention follow-up (potential toxicity and its management, parameters for evaluation, quality of life). CONCLUSIONS: Based on the insights of the multidisciplinary committee, this document offers a comprehensive overview of the technical aspects involved in the management of Y-90 TARE. It synthesizes recommendations for applying Y-90 TARE across various phases of the treatment process.

The American Brachytherapy Society consensus statement for permanent implant brachytherapy using Yttrium-90 microsphere radioembolization for liver tumors.

PURPOSE: To develop a multidisciplinary consensus for high quality multidisciplinary implementation of brachytherapy using Yttrium-90 (90Y) microspheres transarterial radioembolization (90Y TARE) for primary and metastatic cancers in the liver. METHODS AND MATERIALS: Members of the American Brachytherapy Society (ABS) and colleagues with multidisciplinary expertise in liver tumor therapy formulated guidelines for 90Y TARE for unresectable primary liver malignancies and unresectable metastatic cancer to the liver. The consensus is provided on the most recent literature and clinical experience. RESULTS: The ABS strongly recommends the use of 90Y microsphere brachytherapy for the definitive/palliative treatment of unresectable liver cancer when recommended by the multidisciplinary team. A quality management program must be implemented at the start of 90Y TARE program development and follow-up data should be tracked for efficacy and toxicity. Patient-specific dosimetry optimized for treatment intent is recommended when conducting 90Y TARE. Implementation in patients on systemic therapy should account for factors that may enhance treatment related toxicity without delaying treatment inappropriately. Further management and salvage therapy options including retreatment with 90Y TARE should be carefully considered. CONCLUSIONS: ABS consensus for implementing a safe 90Y TARE program for liver cancer in the multidisciplinary setting is presented. It builds on previous guidelines to include recommendations for appropriate implementation based on current literature and practices in experienced centers. Practitioners and cooperative groups are encouraged to use this document as a guide to formulate their clinical practices and to adopt the most recent dose reporting policies that are critical for a unified outcome analysis of future effectiveness studies.

Ytrrium-90 transarterial radioembolization in patients with gastrointestinal malignancies.

Transarterial radioembolization (TARE) with yttrium-90 (Y90) is a promising alternative strategy to treat liver tumors and liver metastasis from colorectal cancer (CRC), as it selectively delivers radioactive isotopes to the tumor via the hepatic artery, sparring surrounding liver tissue. The landscape of TARE indications is constantly evolving. This strategy is considered for patients with hepatocellular carcinoma (HCC) with liver-confined disease and preserved liver function in whom neither TACE nor systemic therapy is possible. In patients with liver metastases from CRC, TARE is advised when other chemotherapeutic options have failed. Recent phase III trials have not succeeded to prove benefit in overall survival; however, it has helped to better understand the patients that may benefit from TARE based on subgroup analysis. New strategies and treatment combinations are being investigated in ongoing clinical trials. The aim of this review is to summarize the clinical applications of TARE in patients with gastrointestinal malignancies.

A cost-effective way to reduce the equivalent eye lens dose fromYttrium-90 radiopharmaceuticals.

PURPOSE: We analyzed the effect of the use of Eye Protective Equipment (EPE) and the best position to use individual dosimeters to estimate the eye lens radiation dose to a medical staff that works with yttrium-90. METHODS: Three Alderson-Head-Phantoms were exposed to 58MBq of 90Y for 24h, in two different experiments: (1) at different dosimeter placements and (2) with and without the use of EPE. The measurements were carried on by thermoluminescent technique. RESULTS: Doses received by dosimeters on both lenses were more closely represented by the ones placed between the eyes than those on the temples, which underestimated the doses by a factor of 3. Also, the transmission factors showed that the EPE was able to reduce the Hp(3) values from about 78% to 92%. CONCLUSIONS: This study demonstrated that the use of EPE can optimize the 90Y eye lens dose. An individual dosimeter should be worn between the eyes for an appropriate estimate of this equivalent dose.

25 años de CENTIS. Pandemia y Radiofármacos / 25 years of CENTIS. Pandemic and Radiopharmaceuticals

Resumen Próximo a su 25 aniversario CENTIS reflexiona sobre su quehacer en el contexto de los trastornos que causa la COVID-19. Con ese propósito se examinan el estado de la medicina nuclear y la radiofarmacia antes y durante la epidemia y sus perspectivas de desarrollo. La producción global de radiofármacos continúa siendo una industria consolidada y aunque la pandemia afecta a esta esfera, la presencia de otras enfermedades no cesa, por lo que los servicios de medicina nuclear esenciales y críticos siguen siendo necesarios. Se espera su paulatina reapertura y que se retome con más fuerza la investigación, dado que la COVID-19 es tan compleja y se asocia a tantos factores que constituye, en perspectiva, terreno virgen para las técnicas diagnósticas en medicina nuclear. Ha de permanecer asimismo el papel de los radiofármacos terapéuticos en un grupo importante de enfermedades, en cáncer sobre todo. El Centro de Isótopos pone por ello énfasis tanto en la consolidación, bajo buenas prácticas, de la producción y el suministro de radiofármacos, como en el desarrollo de nuevos productos. Ambos aspectos se basan principalmente en dos radionúclidos: Tc-99m e Y-90.

Abstract Close to its 25th anniversary, CENTIS evaluates its work in the context of the disorders triggered by COVID-19. For this purpose, the situation of nuclear medicine and radiopharmacy, before and during the epidemic and their current development prospects is examined. The production of radiopharmaceuticals continues to be a consolidated global industry and although the pandemic affects this area, the presence of other diseases does not cease, so essential and critical nuclear medicine services are still needed, therefore its gradual reopening is expected. In addition, research will be taken with more strength, given that COVID-19 is so complex and associated with so many factors that it constitutes virgin terrain in perspective for diagnostic techniques in nuclear medicine. The role of therapeutic radiopharmaceuticals in an important set of diseases, especially cancer, will also remain. As a result, the Isotope Center focus its attention under good management practices, on the consolidation of the production and distribution of radiopharmaceuticals and in the development of new products. Both aspects are mainly based on two radionuclides: Tc-99m and Y-90.

Criterios de calidad de dispersiones radiactivas en radiosinovectomía / Quality criteria of the radiopharmaceutical suspensions used in radiosynoviorthesis

En el trabajo se examinan los criterios de calidad de dispersiones radiactivas utilizadas en radiosinovectomía a partir de los requisitos recogidos en la farmacopea para el Fosfato Crómico- de la firma Mallinkrodt, las recomendaciones de uso de radiofármacos registrados de la Asociación Europea de Medicina Nuclear y datos aportados por las firmas comercializadoras. Tomando como base el estudio de dos formulaciones propias de Fosfato Crómico, una marcada con y la otra, con , en las que se estudia la consistencia (reproducibilidad) tanto de la pureza radioquímica como de la distribución de tamaños de partículas, se prueba que el tenor de 5 % de fosfato libre admitido en la formulación de la firma Mallinkrodt y que se extendiera a formas iónicas de otros radiofármacos de matrices diferentes, se debe probablemente al efecto inevitable de la esterilización a vapor sobre la suspensión y de que tanto al momento de decidir sobre el empleo de un lote, como en los requisitos de las farmacopeas, debiera prestarse más atención a la distribución de tamaños por estar más vinculada a la eficacia y seguridad de los radiofármacos

The quality criteria of radioactive dispersions used in radiosynovectomy are examined, taking into account the requirements of the Pharmacopoeia for the Chromic Phosphate P-32 of Mallinckrodt, recommendations for the use of approved radiopharmaceuticals of the European Association of Nuclear Medicine and data provided by others marketing firms. The behavior of two formulations of chromic phosphate, one -labeled and the second -labeled, from the point of view of the consistency (reproducibility) of both the radiochemical purity and the particle size distribution was assayed. It is proven that the presence of 5% of free phosphate admitted in the Mallinckrodt formulation, and extended to the presence of ionic forms of other radiopharmaceuticals of different matrices, is probably due to the inevitable effect of steam sterilization on the suspension. Based on these results and the accumulated clinical experience, it is considered that to establish the quality requirements of the radioactive suspensions for radiosynovectomy, more attention should be paid to the particle size distribution than to the percentage of free ionic forms. The first one is more related to the efficacy and safety of this kind of radiopharmaceuticals

Fósforo-32 e itrio-90 como opciones en el tratamiento del dolor óseo metastásico / Phosphorous-32 and Yttrium-90 as options in the treatment of metastatic bone pain

En el trabajo se estima la prevalencia del dolor óseo metastásico en nuestro país en no menos de 3 750 pacientes. Se examina, asimismo, el papel del Fosfato de sodio-[], de eficacia comparable y menor costo que el de otros radiofármacos, lo que hace posible el renacer de su uso. Aunque más radiotóxico, ello no lo invalida como opción, lo que se evidencia también en la experiencia cubana. El Centro de Isótopos (Centis) puso en marcha una línea de producción con posibilidad de obtener hasta 37 GBq (1 Ci) de de alta calidad cada semana. El hecho de que se produzca por separación electroquímica mediante un generador de radionúclidos, a partir del 90Sr, hace que no se requiera importación de materia prima radiactiva, prácticamente, por tiempo indefinido, es decir, que el radionúclido estaría disponible de manera sostenible. Al tener el una energía de emisión β- mayor, pudiera pensarse que debiera ser más radiotóxico que el . Sin embargo, se dan evidencias de que el en forma de fosfato es más radiotóxico que el 90Y en forma de citrato. En Europa un radiofármaco basado en un liofilizado de EDTMP y Cloruro de itrio-[] ha tenido buen efecto para el alivio del dolor en 191 pacientes. (Centis) tiene registrado el Cloruro de itrio-[] para marcaje y se trata de introducir en el mercado un radiofármaco con este precursor radioactivo y el liofilizado importado, a los efectos de dar adecuada atención al importante número de pacientes que se beneficiarían

In this paper the prevalence of metastatic bone pain is estimated in our country in no less than 3 750 patients. Moreover, the role of -phosphate, which effectiveness is comparable to other radiopharmaceuticals, and the possible return to its previous general use, as it is cheaper, is examined. The fact that is considered more radiotoxic doesn’t invalidate it as a treatment option, which is also evidenced by the Cuban experience. The Center of Isotopes (Centis) has established a production line of up to 37 GBq (1 Ci) per week of high quality . The fact of its being obtained through a radionuclide generator by electrochemical separation from makes the import of radioactive raw material practically not required for indefinite time. This implies that the radionuclide could be available in a sustainable way. By having the greater β- emission energy, it might be more radiotoxic than . Nevertheless, some evidences show that in the form of orthophosphate is more radiotoxic than 90Y citrate. In Europe, a radiopharmaceutical consisting of a lyophilized kit of EDTMP and Chloride solution was able to relief pain in 191 patients. Centis has registered the chloride solution for labeling. Then the task is to introduce in the market a radiopharmaceutical with this radioactive precursor and the imported lyophilized kit in order to increase the treatment to an important number of patients that, as a result, could be benefitted

Itrio 90 como radionúclido para terapia / Ytrium 90 as a radionuclide for therapy

El 90Y es un emisor beta puro con período de semidesintegración de 64.1 horas y 2.28 MeV de energía, características apropiadas para su uso como radionúclido terapéutico. Radiofármacos de 90Y han sido efectivos en el tratamiento de diferentes enfermedades como sinovitis crónica, cáncer de hígado, dolor por metástasis óseas y tumores de origen neuroendocrino. Mención aparte merecen los resultados en el tratamiento de los linfomas no-Hodgkin, que combinan la especificidad de un anticuerpo monoclonal por el antígeno CD20 y la energía beta pura del 90Y. Aunque el período de semidesintegración del 90Y permite su transportación, se comercializa a precios elevados para una utilización sistemática o a gran escala. El hecho de que se pueda obtener a través de un generador radisotópico, basado en el equilibrio secular que se establece con el 90Sr, hace que su producción local sea atractiva, pues reduciría significativamente los costos y facilitaría su disponibilidad. En este trabajo se exponen las vías para obtener 90Y, aspectos relacionados con la calidad del producto final, sus principales aplicaciones y los resultados obtenidos en el Centro de Isótopos.

90Y is a pure beta emitter with a half-life of 64.1h and 2.28 MeV of energy, suitable properties for its use as a therapeutic radionuclide. Radiopharmaceuticals based on 90Y have been effectively used in the treatment of different diseases such as chronic synovitis, liver cancer, pain caused by bone metastases and neuroendocrine tumors. The results in the treatment of no-Hodgkin lymphoma, that combine the specificity of a monoclonal antibody for CD20 antigen and the pure beta energy of 90Y, deserve a particular distinction. Although the half-life of 90Y makes possible its transportation, it is sold at high prices for a systematic or large-scale use. The fact that 90Y can be produced through a radionuclide generator system, based on the secular equilibrium of 90Sr decaying to 90Y, is very attractive for developing a local production because the cost could be significantly reduced and 90Y availability could be guaranteed. The present work shows the ways to obtain 90Y, the aspects related to the quality of final product, the main applications and the results achieved by the Isotope Centre in this area.

Modificación del hR3 con DOTA-NHS. Marcaje con 90Y y biodistribución / hR3 modification with DOTA-NHS. 90Y labeling and biodistribution

RESUMEN En el trabajo se reporta la conjugación y biodistribución del radioinmunoconjugado -DOTAhR3. Se empleó el ácido 1, 4, 7, 10 tetraazaciclododecano N, N’, N’’, N’’’ tetraacético (DOTA) como agente quelatante bifuncional (AQB) y se estudiaron las relaciones molares 320:1, 160:1 y 88:1 DOTA/anticuerpo monoclonal (hR3), evaluándose su influencia en la integridad del conjugado y la eficiencia de marcaje. La estabilidad in vivo de los radioinmunoconjugados -DOTAhR3 se determinó en ratas Wistar sanas a las 4, 24 y 48 horas. Los estudios de estabilidad realizados mediante reto versus ácido dietilentriaminopentaacético (DTPA) demostraron que el compuesto es estable en un amplio intervalo de tiempo (hasta 216 h). Los estudios de estabilidad in vivo basados en la captación en hueso del radioinmunoconjugado demostraron que no es apreciable la pérdida del radiometal en el radioinmunoconjugado hasta las 48 horas.

ABSTRACT The conjugation, characterization and biodistribution of -DOTA-hR3 radioimmunoconjugate are reported in this work. DOTA was used as bifunctional chelating agent. Molar ratios 320:1, 160:1 and 88:1 DOTA/monoclonal antibody hR3 were studied in order to evaluate their influence on the integrity of conjugate and labeling efficiency. In vivo stability of -DOTA-hR3 radioimmunoconjugates was determined in healthy Wistar rats at 4, 24 and 48 h after the injection. Stability studies performed by means of DTPA challenge showed that the compound is stable in a wide period of time (up to 216 h). In vivo stability studies, based on the bone uptake, showed that the radiometal release from the radioimmunoconjugate is not significant in the first 48 hours.

Experimental and Monte Carlo determination of mass absorption coefficients for / beta particles in organic compounds / Determinación experimental y por Monte Carlo de coeficientes de absorción másicos para partículas beta de / en compuestos orgánicos

ABSTRACT In order to investigate the bparticles absorption in organic compounds, an experimental arrangement was designed. A Monte Carlo transport code was also used to simulate this process. This allowed reporting for the first time m () values in several organic compounds for / isotopic sources. The obtained experimental and calculated values showed a good concordance. Methodological aspects of the µ () determination concerning the range of the absorber’s superficial density are discussed.

RESUMEN Se estudia la absorción de partículas beta en compuestos orgánicos en una instalación diseñada al efecto. El proceso de absorción es además simulado mediante el código de Monte Carlo. Se reportan, por primera vez, los coeficientes de absorción másicos para partículas beta de / en varios compuestos orgánicos. Se obtiene una buena correspondencia entre los resultados experimentales y los simulados. Se discuten aspectos metodológicos de la determinación del coeficiente de absorción másico, relacionado con el intervalo de densidad de absorción superficial.

Nuevo radioinmunoconjugado -dota-h-r3: Sintesis y radiomarcaje / New radioimmunoconjugate -dota-h-r3: synthesis and radiolabeling

El marcaje de anticuerpos monoclonales con metales radiactivos para diagnóstico y terapia generalmente involucra el uso de agentes quelatantes bifuncionales que contienen una función reactiva para conjugarse con las proteínas y un grupo capaz de enlazar fuertemente al metal formando complejos fisiológicamente estables. El objetivo del trabajo fue modificar el anticuerpo monoclonal humanizado (h-R3) con el ácido 1,4,7,10-tetraazaciclododecano-N,N´,N´´,N´´´-tetraacético (DOTA) en solución acuosa, realizar el marcaje de los conjugados obtenidos con y estudiar algunas de las variables que influyen en la reacción, así como la estabilidad del radioinmunoconjugado en presencia de otros agentes quelatantes.

Labelling of monoclonal antibodies with radioactive metals for cancer diagnosis and therapy has usually been accomplished by the use of bifunctional chelating agents, which contain both a reactive functionality for covalent attachment to proteins and a strong metal-binding group capable of forming a physiologically stable complex with the radionuclide. The objective of the present work was to modify the humanized monoclonal antibody (h-R3) with the 1,4,7,10-tetraaza-cyclododecane N,N´,N´´,N´´´-tetraacetic acid (DOTA) in aqueous solution, achieve the labelling of the obtained conjugates with and study some of the variables that influence in the labelling reaction, as well as the stability of the radioimmunoconjugate in presence of other chelating agents.