Eficacia de lutecio-177 DOTATATE/TOC en pacientes con tumores neuroendocrinos bien diferenciados en estado avanzado. Ensayo clínico fase II / Efficacy of Lutetium-177 DOTATATE/TOC in Advanced Neuroendocrine Tumors

Resumen Introducción: En 2009, el Instituto Nacional de Cancerología (INC) elaboró el 177Lu-DOTATATE/TOC. El propósito del estudio fue demostrar la eficacia de estos radiopéptidos en el tratamiento paliativo de pacientes con tumores neuroendocrinos (TNE) avanzados inoperables (metastásicos o localmente avanzados) y en progresión. Métodos: Ensayo clínico abierto fase II de un solo brazo en 13 pacientes adultos con TNE grado 1 o 2, con expresión de receptores de somatostatina en lesiones blanco demostrada por captación Krenning 3 o 4 en 99mTc-HYNIC TOC. Los pacientes fueron tratados con 177Lu-DOTATATE o 177Lu-DOTATOC (según disponibilidad) a una actividad acumulativa proyectada de 600-800 mCi dividida en 3-4 dosis cada 6-9 semanas comenzando siempre con una actividad fija de 200 mCi y dosimetría con la primera dosis. El desenlace primario fue la respuesta objetiva calculada 6 y 12 meses después de la última dosis del tratamiento. Resultados: Se incluyeron 13 pacientes (7 mujeres) de 63 ± 11,6 años con TNE avanzado inoperable y en progresión. La actividad final administrada fue de 800 mCi, 600 mCi, 400 mCi y 200 mCi en 4, 7, 1 y 1 pacientes, respectivamente. La tasa de control de enfermedad a 6 y 12 meses fue de 69,2% y 45,5%, respectivamente, logrando únicamente enfermedad estable. Fallecieron 7 pacientes, 2 de ellos en los primeros 6 meses. La mediana de supervivencia global a partir de la última dosis del radiopéptido fue de 15,7 meses. Conclusiones: Se corroboró la eficacia y la seguridad del tratamiento con los radiopéptidos en NETs avanzados.

Abstract Objectives: The National Cancer Institute first elaborated 177Lu-DOTATATE/TOC in 2009. The purpose of this study was to prove the efficacy of these radiopeptides in the palliative treatment of patients with progressive advanced inoperable neuroendocrine tumors (NETs). Methods: A single-phase phase II open clinical trial was conducted in 13 adult patients with grade 1 y 2 NETs, with expression of somatostatin receptors in target lesions proven by Krenning Score 3 or 4 uptake in 99mTc-HYNIC TOC. Patients were treated with 177Lu-DOTATATE or 177Lu-DOTATOC (depending upon availability) at a projected acumulative activitiy of 600-800 mCi divided into 3-4 doses every 6-9 weeks always beginning with a fixed activity of 200 mCi and dosimetry during the first dose. The primary outcome was objective response to therapy. Results: 13 patients (7 women) aged 63 ± 11.6 years with inoperable advanced NETs were included. The final therapeutic administered activity was 800 mCi, 600 mCi, 400 mCi and 200 mCi in 4, 7, 1 and 1 patients, respectively. The disease control rate at 6 and 12 months was 69.2% and 45.5%, respectively, only obtaining stable disease. Six patients died, 2 of them in the first 6 months. Median overall survival was 15.7 months from the last treatment dose. Conclusions: The efficacy of the treatment with 177Lu-DOTATATE or 177Lu-DOTATOC radiopeptides elaborated in-house was confirmed, becoming a management alternative for patients with advanced NETs.

Dawn of Theranostics in Myanmar (Dream, Reality, and Constraint) / 대한핵의학회잡지

Prostate cancer is third common malignancy in men of old age (average 65 years) in Myanmar. Currently, serum PSA and bone scan are the markers of choice. Because of the evidence-based, promising success of ⁶⁸Ga-PSMA PET-CT and 177Lu-PSMA theranostics in prostate cancer worldwide, (99m)Tc-PSMA SPECT-CT imaging and ¹⁷⁷Lu-PSMA therapy has launched as a stepping-stone of theranostics in Myanmar with the available facilities. Twelve cases of prostate cancer patients were imaged with 600 MBq of (99m)Tc-PSMA I+S SPECT-CT. Four metastatic castration resistant prostate cancer (MCRPC) patients with abnormal result were treated with ¹⁷⁷Lu-PSMA. The protocol consists of 6–8 GBq of ¹⁷⁷Lu-PSMA, three successive doses at interval of 4–6 weeks. Post-therapy SPECT-CT imaging was done. All treated patients were improved by free of bone pain, and fall/rise in serum PSA level. Two patients with extensive skeletal metastases succumbed to complications. The results are well documented and present at the multidisciplinary conferences for clinical awareness. Theranostics in prostate cancer with available facilities is an additional boon to our health care professionals to upgrade cancer management in Myanmar. This paper provides the technology with cost effectiveness and benefit to prostate cancer patients of Myanmar.

Production, quality control, biodistribution assessment and preliminary dose evaluation of [177Lu]-tetra phenyl porphyrin complex as a possible therapeutic agent / Produção, controle de qualidade, avaliação de biodistribuição e avaliação da dose preliminar de [177Lu] -tetra complexo fenil porfirina como um possível agente terapêutico

Due to interesting therapeutic properties of ¹⁷⁷Lu and tumor avidity of tetraphenyl porphyrins (TPPs), ¹⁷⁷Lu-tetraphenyl porphyrin was developed as a possible therapeutic compound. ¹⁷⁷Lu of 2.6-3 GBq/mg specific activity was obtained by irradiation of natural Lu₂O₃sample with thermal neutron flux of 4 × 10¹³ n.cm^-2.s^-1. Tetraphenyl porphyrin was synthetized and labeled with ¹⁷⁷Lu. Radiochemical purity of the complex was studied using Instant thin layer chromatography (ITLC) method. Stability of the complex was checked in final formulation and human serum for 48 h. The biodistribution of the labeled compound in vital organs of wild-type rats was studied up to 7 d. The absorbed dose of each human organ was calculated by medical internal radiation dose (MIRD) method. A detailed comparative pharmacokinetic study was performed for ¹⁷⁷Lu cation and [¹⁷⁷Lu]-TPP. The complex was prepared with a radiochemical purity: >97±1% and specific activity: 970-1000 MBq/mmol. Biodistribution data and dosimetric results showed that all tissues receive approximately an insignificant absorbed dose due to rapid excretion of the complex through the urinary tract. [¹⁷⁷Lu]-TPP can be an interesting tumor targeting agent due to low liver uptake and very low absorbed dose of approximately 0.036 to the total body of human...

Devido às propriedades interessantes do ¹⁷⁷Lu e da avidez tumoral das tetrafenil porfirinas (TPP), desenvolveu-se a ¹⁷⁷Lu-tetrafenil porfirina como composto terapêutico potencial. ¹⁷⁷Lu de atividade específica de 2,6-3 GBq/mg foi obtido por irradiação de amostra de Lu₂O₃ com fluxo térmico de nêutrons de 4 × 10¹³ n.cm^-2.s^-1. Sintetizou-se a tetrafenil porfirina e marcou-se com ¹⁷⁷Lu. A pureza radioquímica do complexo foi estudada usando método de Cromatografia Instantânea de Camada Delgada ( ITLC). A estabilidade do complexo foi checada na formulação final e no ser humano por 48 h. A biodistribuição do composto marcado em órgãos vitais de ratos do tipo selvagem foi estudada por mais de 7 dias. A dose absorvida para cada órgão humano foi calculada pelo método da Dose Médica de Radiação Interna (MIRD). Estudo farmacocinético comparativo detalhado foi efetuado para o cátion ¹⁷⁷Lu e para o [¹⁷⁷Lu]-TPP. O complexo foi preparado com pureza radioquímica >97±1% e atividade específica de 970-1000 MBq/mmol. Os dados de biodistribuição e os resultados dosimétricos mostraram que todos os tecidos receberam uma dose absorvida aproximadamente insignificante devido à rápida excreção do complexo pelo trato urinário. O [¹⁷⁷Lu]-TPP pode ser um agente interessante de direcionamento do tumor devido à baixa captação pelo fígado e pela dose bem baixa absorvida, de, aproximadamente, 0,036 do corpo humano total...

Tratamento de tumores neuroendócrinos por medicina nuclear: revisão sistemática da eficácia e segurança do radiofármaco Dotatate-177Lu / Treatment of neuroendocrine tumors by nuclear medicine: a systematic review of efficacy and safety of the radiopharmaceutical 177Lu-Dotatate

O DOTATATE-177Lu é um análogo de somatostatina radiomarcado que guia a radioatividade para tumores neuroendócrinos (NETs) que superexpressam receptores de somatostatina (SSTRs), promovendo o seu tratamento por terapia radionuclídica receptor-específica (PRRT). O objetivo deste trabalho foi avaliar a eficácia e a segurança da PRRT dos NETs com o DOTATATE-177Lu, através de uma revisão sistemática da literatura. A PRRT com o DOTATATE-177Lu foi eficaz no tratamento de NETs metastáticos ou inoperáveis que expressam SSTR tipo 2. Observou-se estabilização ou até regressão da doença em 20 a 50 % dos casos. Já a prevalência de remissão total da doença, apesar de numericamente baixa, foi satisfatória, principalmente levando-se em conta o estágio avançado dos tumores. Os efeitos adversos mais comuns da PRRT foram toxicidade renal e hematológica. Apesar dos estudos evidenciarem a eficácia e a segurança da PRRT com o radiofármaco, essa terapia ainda é considerada em desenvolvimento.

The DOTATATE-177Lu is a radiolabeled somatostatin analogue that guides the radioactivity to neuroendocrine tumors (NETs) that overexpress somatostatin receptors (SSTRs), allowing their treatment by receptor- specific radionuclide therapy (PRRT). The aim of this study was to evaluate the efficacy and safety of PRRT of NETs with DOTATATE-177Lu through a systematic literature review. PRRT with 177Lu - DOTATATE was effective in the treatment of inoperable or metastatic NETs that express SSTR type 2. Stabilization or regression of the disease was observed in 20 to 50% of the cases . The prevalence of total remission, although numerically low, was satisfactory, especially taking into account the advanced tumor stage. The most common adverse events in the PRRT were hematological toxicity and renal failure. Despite studies demonstrate the efficacy and safety of PRRT with the radiotracer , this treatment modality is still considered under development.

An approach for conjugation of 177Lu- DOTA-SCN- Rituximab (BioSim) & its evaluation for radioimmunotherapy of relapsed & refractory B-cell non Hodgkins lymphoma patients.

Background & objectives: The prerequisite of radioimmunotherapy is stable binding of a radionuclide to monoclonal antibodies, which are specific to the tumour-associated antigen. Most B-cell lymphomas express CD20 antigen on the surface of the tumour cells, making it a suitable target for therapeutic radioactive monoclonal antibodies. In the present study, the immunoconjugate of biosimilar Rituximab (Reditux™) and macrocyclic chelator, p-SCN-Bz-DOTA, was prepared and radiolabelled with Lutetium-177 followed by quality control procedures. Methods: Rituximab(BioSim) was desalted with sodium bicarbonate (0.1M, pH 9.0) and incubated with DOTA-SCN (1:50). The effectiveness of the conjugation was evaluated by determining the number of chelators per antibody molecule. This conjugate was radiolabelled with Lutetium-177 and purified using PD10 column. The quality control parameters like pH, clarity, radiochemical purity, in vitro stability and sterility were studied. Immunoreactivity of 177Lu-DOTA-Rituximab (BioSim) was assessed using RAMOS cells. The radioimmunoconjugate (RIC) after stringent quality assurance was injected in three patients and the biodistribution profile was analysed. Results: An average of 4.25 ± 1.04 p-SCN-Bz-DOTA molecules could be randomly conjugated to a single molecule of Rituximab (BioSim).The radiochemical purity of the labelled antibody was >95 per cent with preserved affinity for CD20 antigen. The final preparation was stable up to about 120 h when tested under different conditions. A favourable biodistribution profile was observed with liver showing the maximum uptake of the RIC. Interpretation & conclusions: A favourable radiochemical purity, stability and biodistribution of the radiolabelled immunoconjugate indicate that clinical trials for evaluation of toxicity and efficacy of 177Lu-DOTA-antiCD20 antibody-Rituximab (BioSim) in patients of relapsed and refractory non Hodgkin’s lymphoma can be considered.