Prognostic factors in patients with advanced differentiated thyroid cancer treated with multikinase inhibitors - a single Brazilian center experience

ABSTRACT Objective: The aim of this study was to describe the real-world experience multikinase inhibitors (MKI) in the treatment advanced differentiated thyroid carcinoma (DTC) refractory to radioactive iodine (RAIR) therapy. Subjects and methods: We reviewed the records of all patients with MKI-treated DTC from 2010 to 2018. Progression free survival (PFS), response rates (RR) and adverse events (AE) profiles were assessed. Clinical parameters were compared between groups with different outcomes (disease progression and death) to identify possible prognostic factors and benefit from treatment. Results: Forty-four patients received MKI for progressive RAIR DTC. Median PFS was 24 months (10.2-37.7) and median overall survival (OS) was 31 months. Best overall response was complete response in one patient (4.5%), partial response in nine (20.4%), stable disease in twenty-two (50%), and progressive disease (PD) in twelve (27.3%). Seventy-two point 7 percent patients had clinical benefit and AE were mild in most cases (82.7%). Progressive patients were more likely to have FDG positive target lesion than those who did not progress (p = 0.033) and higher maximum SUV on target lesions (p = 0.042). Presence of lung-only metastasis and lower thyroglobulin (Tg) during treatment was associated with stable disease (p = 0.015 and 0,049, respectively). Patients with shorter survival had larger primary tumor size (p = 0.015) and higher maximum SUV on target lesions (p = 0.023). Conclusion: Our findings demonstrate safety and effectiveness of MKI in patients with advanced RAIR DTC. We were able to identify as possible prognostic markers of better outcomes: absence of FDG uptake on target lesions, lower maximum SUV on PET-CT, presence of lung-only metastasis and lower Tg during treatment.

Dramatic clinical response to dabrafenib plus trametinib in anaplastic thyroid carcinoma and the challenges faced during the COVID-19 pandemic

SUMMARY Anaplastic thyroid carcinoma is the rarest tumor of the thyroid gland, representing less than 2% of clinically recognized thyroid cancers. Typically, it has an extremely rapid onset, fatal outcomes in most cases, and a median overall survival of 3 to 10 months despite aggressive multidisciplinary management. The presence of targetable mutations in anaplastic thyroid carcinoma patients is an opportunity for treatment when conventional therapeutics approaches are not effective, a frequent situation in the majority of patients. We present our experience in the management of a patient with unresectable anaplastic thyroid cancer who had a remarkable and rapid response to treatment with dabrafenib and trametinib during the COVID-19 pandemic. After four weeks of dabrafenib 150 mg twice daily plus trametinib 2 mg daily, he showed a dramatic reduction of the cervical mass around 90%. Nearly eight weeks under treatment with dabrafenib plus trametinib, the patient remains with minimal locoregional disease without distant metastases.

La respuesta excelente al tratamiento en pacientes con cáncer diferenciado de tiroides se mantiene a lo largo del seguimiento independientemente del riesgo de recurrencia inicial / Excellent response to treatment in patients with differentiated thyroid cancer is maintained throughout follow-up regardless of the risk of initial recurrence

Resumen Introducción: El riesgo de recurrencia en cáncer diferenciado de tiroides (CDT) se utiliza para determinar la frecuencia de las respuestas estructurales incompletas o excelentes con un valor predictivo positivo cercano al 30%. El riesgo dinámico, que evalúa la respuesta inicial al tratamiento demostró tener una proporción de varianza explicada de hasta el 80%. Por otro lado, en nuestro medio es fácil establecer la respuesta inicial, pero muchas veces es dificultoso determinar el riesgo de recurrencia desde donde partió el paciente. A esto hemos denominado "la silla rota" en pacientes con CDT. Materiales y métodos: Se realizó el análisis retrospectivo incluyendo 340 pacientes con los siguientes criterios:1) edad ≥18 años al momento del diagnóstico, 2) tratamiento inicial con tiroidectomía total y ablación con radioyodo, 3) seguimiento mínimo ≥3 años (excepto si ocurrió metástasis a distancia o muerte antes de ese tiempo), 4) datos anatomopatológicos y estudios complementarios suficientes para poder determinar tanto el riesgo de recurrencia como la respuesta inicial (evaluada en los primeros 6 meses a 2 años de seguimiento) y el estado al final del seguimiento (al momento de la última consulta). Objetivos: Describir la evolución de la respuesta inicial al final del seguimiento para demostrar que esta es la definición más importante, independientemente del riesgo de recurrencia al diagnóstico en pacientes con CDT. Resultados: El 36% de los pacientes presentó una respuesta excelente al tratamiento inicial (n=122) y de ellos, ninguno presentó evidencia estructural de enfermedad al final del seguimiento, independientemente del RR inicial. Conclusiones: La denominada "silla rota" parecería "repararse" correctamente cuando el paciente presenta una respuesta excelente al tratamiento, ya que esta se mantiene al final del seguimiento independientemente del RR inicial. La carencia de un correcto RR inicial no parecería ser imprescindible en pacientes con respuestas excelentes al tratamiento.

ABSTRACT Background: The risk of recurrence (RR) stratification system has been proposed as a useful tool for stablishing the frequency of the structural incomplete and excellent response-to-treatment in patients with differentiated thyroid cancer (DTC). However, the available information at diagnosis could be insufficient to accurately determine the initial RR. We called this situation "the broken chair". Although many studies have shown that the initial response to treatment usually predicts the final outcome, it is not clear if the final outcome could be different in the distinctive responses to treatment, if we analyze it together with the initial RR. Purpose: To investigate the outcomes of patients by comparing both situations: the initial RR and the initial response to treatment with the final outcome to establish if there was a different frequency of structural incomplete response at the end of follow-up. Methods: Retrospective review of 340 DTC patients followed up for at least 3 years after initial total thyroidectomy and radioactive iodine ablation (RAI). We assessed the initial response as the best response to therapy during the first 2 years, and the final response to therapy as the status at the end of follow-up, according to the definitions of the 2015 ATA guidelines. Conclusions: An excellent response to treatment during the first two years of follow-up can fix the "broken chair" in patients treated with DTC who received remnant ablation and it is independent of the initial RR. Results: None of the patients that achieved an initial excellent response to treatment (n=122, 36%), showed structural evidence of disease in the entire follow-up despite their initial RR.

Rare complications of multikinase inhibitor treatment

ABSTRACT Objective: The advent of multikinase inhibitor (MKI) therapy has led to a radical change in the treatment of patients with advanced thyroid carcinoma. The aim of this manuscript is to communicate rare adverse events that occurred in less than 5% of patients in clinical trials in a subset of patients treated in our hospital. Subjects and methods: Out of 760 patients with thyroid cancer followed up with in our Division of Endocrinology, 29 (3.8%) received treatment with MKIs. The median age at diagnosis of these patients was 53 years (range 20-70), and 75.9% of them were women. Sorafenib was prescribed as first-line treatment to 23 patients with differentiated thyroid cancer and as second-line treatment to one patient with advanced medullary thyroid cancer (MTC). Vandetanib was indicated as first-line treatment in 6 patients with MTC and lenvatinib as second-line treatment in two patients with progressive disease under sorafenib treatment. Results: During the follow-up of treatment (mean 13.7 ± 7 months, median 12 months, range 6-32), 5/29 (17.2%) patients presented rare adverse events. These rare adverse effects were: heart failure, thrombocytopenia, and squamous cell carcinoma during sorafenib therapy and squamous cell carcinoma and oophoritis with intestinal perforation during vandetanib treatment. Conclusions: About 3 to 5 years after the approval of MKI therapy, we learned that MKIs usually lead to adverse effects in the majority of patients. Although most of them are manageable, we still need to be aware of potentially serious and rare or unreported adverse effects that can be life-threatening.

Tratamiento con radioyodo endovenoso y estimulación con TSH recombinante humana en paciente con cáncer de tiroides extenso: caso clínico / Intravenous radioiodine and recombinant human TSH in a patient with extensive thyroid cáncer: report of one case

Abstract: We report a 72-years-old male patient with extensive differentiated thyroid cancer (DTC), who required a tracheostomy and gastrostomy. Considering his clinical condition, risk of aspiration and management of the ostomies, radioiodine (131I) was administered intravenously, using recombinant human thyrotropin (rhTSH) and levothyroxine. The procedure was successful, both clinically and in terms of radioprotection.

Respuesta parcial a lenvatinib como segunda línea de tratamiento en cáncer diferenciado avanzado de tiroides / Partial response to lenvatinib as a second line of treatment in advanced differentiated cancer of thyroid

RESUMEN Las metástasis a distancia ocurren en alrededor del 10% de los pacientes con cáncer diferenciado de tiroides (CDT), y cerca de la mitad de estos casos serán refractarios al radioyodo (RAIR). Sorafenib fue el primer inhibidor multicinasa (IMK) aprobado por la FDA para su uso en cáncer diferenciado de tiroides RAIR avanzado y progresivo, y hasta el momento es el único aprobado por la ANMAT en nuestro país para esta indicación. Lenvatinib es el segundo IMK aprobado por la FDA para este grupo de pacientes, y es una alternativa terapéutica que debe ser considerada, debido a su disponibilidad como fármaco de uso compasivo en nuestro país. Presentamos nuestra experiencia con el uso de lenvatinib como segunda línea de tratamiento en una paciente con CDT progresivo previamente tratado con sorafenib.

ABSTRACT Distant metastases occur in around 10% of patients with differentiated thyroid cancer (DTC), and half of these cases will become refractory to radioiodine therapy (RAIR). Sorafenib was the first multikinase inhibitor (MKI) approved by the FDA for patients with differentiated advanced and progressive RAIR thyroid cancer, and it is the only one approved by ANMAT in our country for this indication. Lenvatinib is the second MKI approved by the FDA for this group of patients, and is a therapeutic alternative that should be considered, due to its availability as a compassive use drug in our country. We present our experience with the use of lenvatinib as a second line of treatment in a patient with DTC with advanced and progressive disease under treatment with sorafenib.

Riesgo de recurrencia en cáncer diferenciado de tiroides: escala MINSAL / Risk of recurrence in differentiated thyroid cancer

Background: Differentiated thyroid cancer (DTC) is generally associated with a favorable prognosis. Its treatment requires surgery, selective use of radioiodine and levothyroxine, and its intensity must be adjusted to the initial risks of mortality and recurrence. Aim: To validate the risk of recurrence classification developed by the Chilean Ministry of Health in 2013 (MINSAL 2013), and compare it with the American Thyroid Association (ATA) 2009 and 2015 classifications. Material and Methods: Retrospective study of 362 patients with DTC aged 44.3 ± 13.4 years (84% women), treated with total thyroidectomy, selective radioiodine ablation and levothyroxine and followed for a median of 4.2 years (range 2.0-7.8). Risk of recurrence was estimated with MINSAL 2013, ATA 2009 and ATA 2015 classifications, and risk of mortality with 7th and 8th American Joint Committee on Cancer (AJCC)/TNM systems. Clinical data obtained during follow-up were used to detect structural and biochemical persistence/recurrence. Results: A mean dose of 104 ± 48 mCi radioiodine was received by 91% of patients. MINSAL 2013 classified 148 (41%), 144 (40%), 67 (19%) and 3 (1%) patients as very low, low, intermediate and high risk of recurrence, respectively. Forty-five (12.4%) patients had persistence or recurrence during follow-up: 33 structural and 12 biochemical. Rates of persistence/recurrence on each category of MINSAL 2013 were 4.1%, 7.6%, 37.3% and 100%, respectively (p < 0.01). Areas under Receiver Operating Characteristic curves for persistence or recurrence of MINSAL 2013, ATA 2009 and ATA 2015 were 0.77 vs 0.73 vs 0.72, respectively. Conclusions: MINSAL 2013 classifies appropriately DTC patients and estimates correctly their risk of persistence or recurrence.

Medullary thyroid carcinoma - Adverse events during systemic treatment: risk-benefit ratio

ABSTRACT Medullary thyroid carcinoma (MTC) is a rare neuroendocrine tumor originating from parafollicular C cells of the thyroid and associated with mutations in the proto-oncogene REarranged during Transfection (RET). The prognosis of MTC depends on clinical stage, with a 95.6% 10-year survival rate among patients with localized disease and 40% among patients with advanced disease. Standard chemotherapy and radiotherapy have no significant impact on the overall survival of these patients and two tyrosine kinase receptor inhibitors (TKIs), vandetanib and cabozantinib, have been recently approved for the systemic treatment of locally advanced or metastatic MTC. However, since patients with MTC and residual or recurrent disease may have an indolent course with no need for systemic treatment, and since these drugs are highly toxic, it is extremely important to select the patients who will receive these drugs in a correct manner. It is also essential to carefully monitor patients using TKI regarding possible adverse effects, which should be properly managed when occurring.

Guía práctica para el manejo de efectos adversos por inhibidores multicinasas (sorafenib y vandetanib) en pacientes con cáncer de tiroides avanzado / Practice guidelines for the management of adverse effects due to multikinase inhibitors (sorafenib and vandetanib) in patients with advanced thyroid cancer

El advenimiento de la terapia con inhibidores multicinasas (IMK) representó un cambio radical en el tratamiento de pacientes con carcinoma avanzado de tiroides. Hasta la fecha, 2 fármacos se encuentran aprobados por la Asociación Nacional de Medicamentos, Alimentos y Tecnología Médica (ANMAT) en Argentina: sorafenib, para pacientes con carcinoma diferenciado de tiroides radiorresistente, y vandetanib, para aquellos con carcinoma medular de tiroides (enfermedad progresiva y/o sintomática). Los estudios de fase III han demostrado que estos fármacos aumentan significativamente la supervivencia libre de progresión en este grupo de pacientes. Si bien tienen una indicación precisa, su manejo requiere de un equipo multidisciplinario en contacto estrecho con un paciente involucrado en su tratamiento. Los efectos adversos de sorafenib y vandetanib son frecuentes, sin embargo, muchos de ellos disminuyen con el tiempo y la mayoría puede manejarse a menudo sin disminuir la dosis ni suspender el fármaco. El conocimiento del correcto manejo de los efectos adversos por parte del equipo tratante constituye una herramienta fundamental para poder educar al paciente y, consecuentemente, poder prevenirlos o minimizarlos, y de esta manera evitar complicaciones severas. El objetivo de esta publicación es brindar una guía para el diagnóstico y tratamiento de los efectos adversos de estos IMK y, por otro lado, presentar la iniciativa del Hospital de Clínicas de la Universidad de Buenos Aires en cuanto a la implementación de la misma.

The advent of multikinase inhibitors therapy has led to a radical change in the treatment of patients with advanced thyroid carcinoma. The ANMAT (the Argentinian regulatory health agency) has currently approved sorafenib for patients with radioiodine resistant differentiated thyroid carcinoma, and vandetanib for patients with medullary thyroid carcinoma (progressive and/or symptomatic disease). It has been demonstrated by phase III clinical trials that these drugs improve progression free survival in this group of patients. Although they have a precise indication, an interdisciplinary team in close contact with a committed patient, are required for their effective management. The adverse events of these drugs are common, but many of them may ameliorate over time, and most of them are manageable, even without the need for dose reduction or drug withdrawal. Knowledge of the correct management of the adverse events is a fundamental tool for the medical team and for the patient to prevent or minimise them, to avoid serious complications and to obtain better patient compliance. The primary objective of this article is to provide a guideline for the diagnosis and treatment of the adverse events produced by the multikinase inhibitors, and to present the initiative of the Hospital de Clinicas in order to implement these guidelines.

Radioactive iodine-refractory differentiated thyroid cancer: an uncommon but challenging situation

ABSTRACT Radioiodine (RAI)-refractory thyroid cancer is an uncommon entity, occurring with an estimated incidence of 4-5 cases/year/million people. RAI refractoriness is more frequent in older patients, in those with large metastases, in poorly differentiated thyroid cancer, and in those tumors with high 18-fluordeoxyglucose uptake on PET/CT. These patients have a 10-year survival rate of less than 10%. In recent years, new therapeutic agents with molecular targets have become available, with multikinase inhibitors (MKIs) being the most investigated drugs. Two of these compounds, sorafenib and lenvatinib, have shown significant objective response rates and have significantly improved the progression-free survival in the two largest published prospective trials on MKI use. However, no overall survival benefit has been achieved yet. This is probably related to the crossover that occurs in most patients who progress on placebo treatment to the open treatment of these studies. In consequence, the challenge is to correctly identify which patients will benefit from these treatments. It is also crucial to understand the appropriate timing to initiate MKI treatment and when to stop it. The purpose of this article is to define RAI refractoriness, to summarize which therapies are available for this condition, and to review how to select patients who are suitable for them.

Iodine-131 treatment of thyroid cancer cells leads to suppression of cell proliferation followed by induction of cell apoptosis and cell cycle arrest by regulation of B-cell translocation gene 2-mediated JNK/NF-kappaB pathways

Iodine-131 (131I) is widely used for the treatment of thyroid-related diseases. This study aimed to investigate the expression of p53 and BTG2 genes following 131I therapy in thyroid cancer cell line SW579 and the possible underlying mechanism. SW579 human thyroid squamous carcinoma cells were cultured and treated with 131I. They were then assessed for 131I uptake, cell viability, apoptosis, cell cycle arrest, p53 expression, and BTG2 gene expression. SW579 cells were transfected with BTG2 siRNA, p53 siRNA and siNC and were then examined for the same aforementioned parameters. When treated with a JNK inhibitor of SP600125 and 131I or with a NF-κB inhibitor of BMS-345541 and 131I, non-transfected SW579 cells were assessed in JNK/NFκB pathways. It was observed that 131I significantly inhibited cell proliferation, promoted cell apoptosis and cell cycle arrest. Both BTG2 and p53 expression were enhanced in a dose-dependent manner. An increase in cell viability by up-regulation in Bcl2 gene, a decrease in apoptosis by enhanced CDK2 gene expression and a decrease in cell cycle arrest at G0/G1 phase were also observed in SW579 cell lines transfected with silenced BTG2 gene. When treated with SP600125 and 131I, the non-transfected SW579 cell lines significantly inhibited JNK pathway, NF-κB pathway and the expression of BTG2. However, when treated with BMS-345541 and 131I, only the NF-κB pathway was suppressed. 131I suppressed cell proliferation, induced cell apoptosis, and promoted cell cycle arrest of thyroid cancer cells by up-regulating B-cell translocation gene 2-mediated activation of JNK/NF-κB pathways.

Eficacia y seguridad de sorafenib en el tratamiento de pacientes con diagnóstico de carcinoma de tiroides diferenciado, metastásico, irresecable, refractario a tratamiento con yodo radioactivo / Efficacy and safety of sorafenib in the treatment of patients with differentiated, metastatic, unresectable thyroid carcinoma refractory to treatment with radioactive iodine

INTRODUCCIÓN: Antecedentes: El Instituto de Evaluación de Tecnologías en Salud e Investigación (IETSI) ha recibido la solicitud de evaluar el uso e la seguridad y eficacia de sorafenib en el tratamiento de pacientes con diagnóstico de carcinoma de tiroides, metastásico, irresecable, refractario a tratamiento con yodo radioactivo detnro del sistema de EsSalud, indicación actualmente no contempla en el petitorio de medicamentos.Generalidades: El cáncer de tiroides es la neoplasia endocrin más frecuente, representando más del 90% de todas las neoplasias endocrinas. Se estima que a nível mundial la incidencia de cáncer de tiroides es mayor en los países desarrollados que en los países en desarrrollo, específicamente 11.1 casos por cada 100 000 habitantes y 4.7 casos por cada 100 000 habitantes, respectivamente. Sin embargo, la mortalidad por cáncer de tiroides es menos en los países desarrollados que en los países en desarrollo, específicamente 0.4 muertes por cada 100 000 habitantes y en 0.7 muertes por cada 100 000 habitantes, respectivamente. Tecnología Sanitaria de Interés: Sorafenib: Sorafenib es un compuesto sintético, inhibidor de quinasas múltiple con capacidad de inhibir tanto los VEGFR-1, VEGFR-2, VEGFR-3 y el receptor beta del factor de crecimiento derivado de las plaquetas, así como la expresión de los genes RET (incluyendo la translocación RET/PTC), RAF (incluyendo la mutación BRAFV600E, C-RAF y B-RAF), c-kit y Flt-3 (25,26).Desde el punto de vista farmacológico, sorafenib alcanza concentraciones séricas máximas a las 2.5-12-5 horas post administración oral, pero se asocia con una biodisponibilidad del 38%-49% que disminuye significativamente con la ingesta de grasas. METOLOGÍA: Estrategia de Búsqueda: La presente evaluación de tecnología fue preparada y revisada por el equipo técnico del IETSI. Las siguientes fuentes ha sido revisadas y consultadas con la intención de buscar la mejor evidencia disponible que directamente responda a la pregunta PICO de esta evaluación. American Thyroid Association (ATA) de los Estados Unidos, British Thyroid Association (ETA) del Reino Unido, Canadian Agency for Drugs and Technologies in Health (CADTH), Cochrane Library, Canadian Agency for Drugs and Technologies in Helath (CADTH), Cochrane Library, Cumulative Index to Nursing and Allied Health Literatura (CINAHL), Embase, European Society of Medical Oncology (ESMO) de Europa, European Thyroid Association (ETA) de Europa, Institute for Health Technology Assessment Ludwing Boltzmann Gelsellschaft (LBIHTA) de Austria, Medline/Pubmed, National Guideline Clearinghouse (NGC) de los Estados Unidos, National Institute for Health Research (NIHR) del Reino Unido, Scopus, Scopus, Scottihs Medicines Consortium (SMC), Translating Research into Practice (TRIP Database)Web of Science. RESULTADOS: Luego de revisar un total de 853 referencias resultados de nuestra búsqueda bibliográfica, logramos filtrar 166 referencias relevantes para nuestra pregunta PICO de interés, de los cuales sólo 21 referencias fueron finalmente selecionadas para nuestro análisis, toda vez que constituían referencias que respondían a la pregunta PICO de interés de este dictamen, incluyendo tres guias de práctica clínica, tres meta-análisis, una evaluación de tecnología y 14 referencias todas procedentes de un ensayo clínico de fase III. CONCLUSIONES: A la fecha no se dispone de evidencia que sustente de maera consistente un beneficio neto de sorafenib como alternativa de tratamiento más eficaz, segura en el manejo de pacientes con diagnóstico carcinoma de tiroides, metastásico, irresecable, refractario a tratamiento con yodo radioactivo. La evidencia disponible, sugiere que sorafenit tiene una ventaja relativa sobre el placebo solo en términos de desenlaces intermedios como la sobrevida libre de progresión y tasa de respuesta parcial, pero no se tiene evidencia que éstas se traduzcan en un beneficio en cuanto a desenlaces clínicos finales de alta relevancia desde la perspectiva del paciente, como la sobrevida global y la calidad de vida; es más, existe evidencia consistente que sorafenib conctituye un riesgo mayor eventos adversos serios y evidencia que sugiere que este medicamento puede incrementar el riesgo muerte por cualquier causa durante el lapso de seguridad del tratamiento. El hecho que la evidencia al momento existente establece que las ganancias atribuibles al sorafenib se da solo en desenlaces clínicos intermedios de relativo significado clínico desde la perspectiva del paciente (como la sobrevida livre de progresión y tasa de respuesta), que no se traducen en otros desenlaces de alta relevancia para el paciente (como la sobrevida global y la calidad de vida), y que ocurre a costa de un mayor riesgo (con evidencia bastante consistente incluso proveniente de meta-análisis) de muerte por culquier causa y de eventos adversos serios, limita seriamente la posibilidad de recomendar el uso de este medicamento algún beneficio neto para estos pacientes.El Instituto de Evaluación de Tecnologías en Salud e Investigación-IETSI, no aprueba el uso de sorafenib en Pacientes adultos con carcinoma de tiroides diferenciado, metastásico, irresecable, refractario a tratamiento con yodo radioactivo.

Uso de tirotropina recombinante humana (rhTSH) en rastreo corporal total con radioyodo (131 I), en pacientes con cáncer diferenciado de tiroides intolerante a la suspención de levotiroxina y con sospecha de recurrencia / Use of recombinant human thyrotropin (rhTSH) in total body tracing with radioiodine (131 I) in patients with differentiated thyroid cancer intolerant to levothyroxine suspension and with suspected recurrence

INTRODUCCIÓN: Antecedentes: El presente dictamen expone la evaluación de tecnología del uso de la tirotropina alfa o tirotropina recombinante humana (rhTSH, por su nombre en inglés) como preparación para realizar un rastreo corporal total (RCT) con radioyodo. Esta evaluación específica para pacientes con sospecha de recidiva de cáncer de tiroides diferenciado, en los que el retiro del tratamiento con levotiroxina no es tolerado. Aspectos Generales: El cáncer de tiroides es el tipo más común de cáncer endocrino y representa menos del 1% de todos los tumores humanos. La incidencia anula de este cáncer varia considerablemente por área geográfica, edad y sexo. Tecnología Sanitaria de Interés: En pacientes en seguimiento posterior al tratamiento de cáncer diferenciado de tiroides y en los que se sospecha recidiva del mismo se sugiere la realización pruebas diagnósticas como el RCT con radioyodo. Para realizar esta prueba en los pacientes mencionados es necesario lograr una elevación de la TSH sérica y promover la captación del marcador en el tejido facilitando su identificación. La tirotropina alfa o rhTSH es una glicoproteína heterodimérica con propriedades bioquíimicas comparables al TSH pituiario humano. La unión de esta sustancia con receptores de TSH en las células epiteliales tiroideas o en tejido tiroideo canceroso diferenciado estimula en éstas la captación de yodo y organización, así como la síntesis y secreción de Tg. METODOLOGÍA: Estrategia de Búsqueda: Se realizó una estrategia de búsqueda sistemática de la evidencia científica con respecto al uso del rhTSH para realizar un rastreo corporal total (RCT) con radioyodo para la detección de cáncer diferenciado de tiroides, intolerante la suspensión de levotiroxina, con sospecha de recurrencia. Se ralizó una búsqueda de estudios en humanos que mostraron evidencia científica en relación a los puntos desarrollados en la pregunta PICO. Se dio preferencia a estudios de tipo meta-análisis, revisiones sistemáticas de ensayos clínicos aleatorizados y ensayos clínicos aleatorizados; así como a guías de práctica clínica de grupos o instituciones relevantes al tema analizado. la bibliografia usada en los artículos seleccionados, así como la inforamación disponible por entes reguladores y normativos como la Food and Drug Administration ( Administración de Drogas y Alimentos, o FDA por sus siglas en inglés) de los Estados Unidos y, a nivel nacional, la DIGEMID. RESULTADOS: Sinopsis de la Evidencia: Se realizó la búsqueda y revisión de la evidencia científica actual para la evaluación del rhTSH para realizar un rastreo corporal total (RCT) con radioyodo para la detección de cáncer diferenciado de tiroides, itolerante la suspensión de levotiroxina, con sospecha de recurrencia. Se presenta la información encontrada de acuerdo al tipo de evidencia revisada. CONCLUSIONES: La evidencia encontrada a la fecha (mayo 2016) indica que el rhTSH puede ser utilizado como una opción alternativa a la suspensión de tratamiento reemplazo hormonal tiroideo como preparación para un RCT con radioyodo en los pacientes descritos. Esta opción no ha demostrado un benefício en la precisión diagnóstica del RCT, presentado solo un benefício de corto plazo al disminuir los efectos adversos asociados a la realización de la prueba. Así, si bien la evidencia no es contundente con respecto al uso la rhTSH como una primera opción para la preparación para un rastreo corporal total con radioyodo en los pacientes descritos, esta es útil y corresponde a la única alternativa disponible actualmente como prueba diagnóstica en el caso de los pacientes que no puedan suspender el tratamiento hormonal por falta de tolerancia, definida por el médico tratante, u obras causas médicas que contraindioquen el estado hipotiroideo. El Instituto de Evaluación de Tecnologías en Salud e Investigación, aprueba el uso de la tirotropina recombinante humana (rhTSH) como preparación para un rastreo corporal total con radioyodo en pacientes con cáncer diferenciado de tiroides posterior al tratamiento, en los que se sospecha recurrencia y que no puedan suspender el tratamiento hormonal por falta de tolerancia, definida por el médico tratante, u otras causas médicas que contraindiquen el estado hipotiroideo.

Electrochemotherapy as palliative treatment in patients with thyroid papillary carcinoma / Eletroquimioterapia como tratamento paliativo em pacientes com carcinoma papilar da tireoide

ABSTRACT INTRODUCTION: Local progression of papillary thyroid carcinoma (PTC) after failure of standard therapies may cause pain, ulceration, and bleeding. As patients are fully aware of the tumor growth, they might suffer high grade anxiety. Electrochemotherapy (ECT) is a new local palliative treatment for skin metastases of malignant melanoma or other tumors, including squamous head e neck cancer patients. OBJECTIVE: To evaluate the impact of ECT in patients with local progression of PTC. METHODS: Four patients with local progression of PTC were treated with ECT based on Bleomycin, and evaluated according to tumor response, local pain and side effects. RESULTS: In all cases, some grade of tumor response was observed, lasting 6, 7, 12 and 8 months, respectively. Also, reduction of local pain and anxiety was registered in all patients. Tumor infiltrated skin necrosis was the only collateral effect of the treatment. ECT induced a tumor response in all PTC patients with improvement of symptoms. CONCLUSIONS: ECT may be an option for local palliative treatment in PTC patients with local tumor progression.

Resumo Introdução: A progressão local do carcinoma papilífero de tireoide (CPT) após a falha da terapia de rotina pode causar dor, ulceração e sangramento. Considerando que os pacientes estão perfeitamente cientes do crescimento tumoral, podem apresentar um alto grau de ansiedade. A eletroquimioterapia (EQT) é um novo tratamento paliativo para metástases de pele de melanoma maligno ou de outros tumores, inclusive em pacientes com carcinoma escamoso de cabeça e pescoço. Objetivo: Avaliar o impacto da EQT em pacientes com progressão local de CPT. Método: Quatro pacientes com progressão local de CPT foram tratados com EQT com base em bleomicina, e avaliados em relação ao grau de resposta tumoral, dor local, efeitos colaterais. Resultados: Em todos os casos, foi observado algum grau de resposta tumoral, que perdurou por 6, 7, 12 e 8 meses, respectivamente. Da mesma forma, foi registrada diminuição da dor local e da ansiedade em todos os pacientes. Necrose cutânea na infiltração tumoral foi o único efeito colateral do tratamento. EQT induziu resposta tumoral em todos os pacientes com CPT, com melhora dos sintomas. Conclusões: EQT pode ser uma opção para o tratamento paliativo tópico em pacientes com CPT com progressão tumoral local.

Drug-induced liver injury caused by iodine-131

Iodine-131 is a radioisotope that is routinely used for the treatment of differentiated thyroid cancer after total or near-total thyroidectomy. However, there is some evidence that iodine-131 can induce liver injury . Here we report a rare case of drug-induced liver injury (DILI) caused by iodine-131 in a patient with regional lymph node metastasis after total thyroidectomy. A 47-year-old woman was admitted with elevated liver enzymes and symptoms of general weakness and nausea. Ten weeks earlier she had undergone a total thyroidectomy for papillary thyroid carcinoma and had subsequently been prescribed levothyroxine to reduce the level of thyroid-stimulating hormone. Eight weeks after surgery she underwent iodine-131 ablative therapy at a dose of 100 millicuries, and subsequently presented with acute hepatitis after 10 days. To rule out all possible causative factors, abdominal ultrasonography, endoscopic ultrasonography (on the biliary tree and gall bladder), and a liver biopsy were performed. DILI caused by iodine-131 was suspected. Oral prednisolone was started at 30 mg/day, to which the patient responded well.

Rapid response of hypercortisolism to vandetanib treatment in a patient with advanced medullary thyroid cancer and ectopic Cushing syndrome

Medullary thyroid carcinoma (MTC) may rarely present with paraneoplastic syndromes. Among the most frequent ones are the appearance of diarrhea and ectopic Cushing syndrome (ECS). The ECS in the context of MTC is usually present in patients with distant metastatic disease. The use of drugs such as ketoconazole, metyrapone, somatostatin analogs and etomidate have been ineffective alternatives to control hypercortisolism in these patients. Bilateral adrenalectomy is often required to manage this situation. Recently, the use of tyrosine kinase inhibitors has been shown to be a useful tool to achieve eucortisolism in patients with metastatic MTC and ECS. We present a patient with sporadic advanced persistent and progressive MTC with lymph node and liver metastases, which after 16 years of follow-up developed an ECS. After one month of 300 mg/day vandetanib treatment, a biochemical and clinical response of the ECS was achieved but it did not result in significant reduction of tumor burden. However the patient reached criteria for stable disease according to response evaluation criteria in solid tumors (RECIST 1.1) after 8 months of follow-up.

Exercise is associated with better quality of life in patients on TSH-suppressive therapy with levothyroxine for differentiated thyroid carcinoma / O exercício está associado com melhor qualidade de vida em pacientes em terapia de supressão de TSH com levotiroxina para o carcinoma diferenciado de tireoide

Objective : To evaluate if a supervised exercise training program improves the quality of life (QoL) of differentiated thyroid carcinoma (DTC) patients on TSH-suppressive therapy with levothyroxine (L-T4).Subjects and methods : Initially, a cross-sectional study was performed to compare the QoL and the health-related quality of life (HRQoL) between subclinical hyperthyroidism (SCH) patients (n = 33) and euthyroid subjects (EU; n = 49). In the prospective phase of the study, SCH patients were randomized in a non-blinded fashion to either participate (SCH-Tr = trained patients; n = 16) or not (SCH-Sed = untrained patients; n = 17) in a supervised exercise training program. The exercise program consisted of 60 minutes of aerobic and stretching exercises, twice a week, during twelve weeks. The QoL was assessed by the application of the WHOQOL-Bref, and the SF-36 was used to assess the HRQoL.Results : SCH patients had statistically lower scores than EU on the “physical” domain of WHOQOL-Bref, besides “physical function”, “role-physical”, “bodily pain”, “general health”, “vitality”, “role-emotional”, and “mental-health” domains of SF-36. After three months, SCH-Tr patients showed improvement in the “physical” and “psychological” domains of WHOQOL-Bref (p < 0.05), and in the “physical function”, “role-physical”, “bodily pain”, “vitality” and “mental health” domains of SF-36.Conclusion : Patients on TSH-suppressive therapy with L-T4 for DTC had impaired QoL and HRQoL compared to EU, but it was improved after 3-months of an exercise training program. Exercise seems to play an important role in the follow-up of DTC patients, since it seems to minimize the adverse effects of the treatment on QoL and HRQoL. Arq Bras Endocrinol Metab. 2014;58(3):274-81.

Objetivo : Avaliar se um programa de exercícios supervisionado melhora a qualidade de vida (QV) de pacientes com carcinoma diferenciado de tireoide (CDT) em tratamento de supressão de TSH com levotirotoxina (L-T4).Sujeitos e métodos : Inicialmente, foi feito um estudo cruzado para se comparar a QV e a qualidade de vida relacionada à saúde (QVRS) em pacientes com hipertireoidismo subclínico (HSC, n = 33) e indivíduos eutiroides (EU; n = 49). Na fase prospectiva do estudo, os pacientes com HSC foram randomizados de forma não cega para participar (HSC-Tr = pacientes treinados; n = 16) ou não (HSC-Sed = pacientes não treinados; n = 17) de um programa de exercícios supervisionado. O programa de exercícios consistiu de 60 minutos de atividade aeróbica e alongamento, duas vezes por semana, por 12 semanas. A qualidade de vida foi avaliada pelos questionários WHOQOL-Bref, e a QVRS pelo SF-36.Resultados : Os pacientes com HSC apresentaram escores estatisticamente mais baixos do que os EU no domínio “físico” do WHOQOL-Bref, além dos domínios “função física”, “papel físico”, “dor corporal”, “saúde geral”, “vitalidade”, “papel emocional” e “saúde mental” do SF-36. Após três meses, os pacientes HSC-Tr mostraram melhora nos domínios “físico” e “psicológico” do WHOQOL-Bref (p < 0,05) e nos domínios “função física”, “papel físico”, “dor corporal”, “vitalidade” e “saúde mental” do SF-36.Conclusão : Os pacientes em terapia de supressão de TSH com L-T4 para CDT apresentaram QV e QVRS afetados negativamente quando comparados com sujeitos EU, mas essas avaliações melhoraram após ...

Response to sorafenib treatment in advanced metastatic thyroid cancer / Resposta ao tratamento com sorafenibe em pacientes com carcinoma metastático de tireoide

Objective: To investigate the efficacy of sorafenib in progressive radioiodine resistant metastatic thyroid carcinoma.Subjects and methods: Off-label observational study. Sorafenib 400 mg twice daily was evaluated. Therapy duration was 12 ± 3 months (range 6-16 months).Results: Eight patients were included (seven papillary, one insular variant). The eight patients meeting study criteria received sorafenib 400 mg orally twice a day until disease progression or unacceptable toxicity developed. One patient showed a partial response with tumor regression of -35%, six months after the beginning of the treatment; five patients exhibited stable disease and two patients had progressive disease and died. Thyroglobulin decreased within 4 weeks in all patients by 50% ± 23%.Adverse events: one patient had heart failure, and recovered after sorafenib withdrawal. However, she died five months later of sudden death.Conclusion: These data suggest a possible role for sorafenib in the treatment of progressive metastatic DTC. Adverse event are usually manageable, but severe ones may appear and these patients should be strictly controlled.

Objetivo: Investigar a eficácia do sorafenibe no carcinoma de tireoide metastático progressivo e refratário à iodoterapia.Sujeitos e métodos: Estudo observacional do efeito do sorafenibe off-label administrado 400 mg duas vezes ao dia. A duração da terapia foi de 12 ± 3 meses (variação de 6-16 meses).Resultados: Oito pacientes foram incluídos (sete com variante papilífera e um com variante insular). Os oito pacientes que preencheram os critérios do estudo receberam o sorafenibe 400 mg por via oral duas vezes por dia até progressão da doença ou toxicidade inaceitável. Um paciente apresentou uma resposta parcial com regressão tumoral da lesão alvo de 35% seis meses após o início do tratamento; cinco pacientes apresentaram doença estável e dois pacientes progrediram e morreram. A tireoglobulina diminuiu 50% ± 23% em 4 semanas em todos os pacientes.Eventos adversos: um paciente teve insuficiência cardíaca e morreu por morte súbita cinco meses após a retirada do sorafenibe.Conclusão: Esses dados sugerem um possível papel para sorafenibe para o tratamento do CDT metastático progressivo.

The Effectiveness of Recombinant Human Thyroid-Stimulating Hormone versus Thyroid Hormone Withdrawal Prior to Radioiodine Remnant Ablation in Thyroid Cancer: A Meta-Analysis of Randomized Controlled Trials

We evaluated the efficacy of recombinant human thyroid-stimulating hormone (rhTSH) versus thyroid hormone withdrawal (THW) prior to radioiodine remnant ablation (RRA) in thyroid cancer. A systematic search of MEDLINE, EMBASE, the Cochrane Library, and SCOPUS was performed. Randomized controlled trials that compared ablation success between rhTSH and THW at 6 to 12 months following RRA were included in this study. Six trials with a total of 1,660 patients were included. When ablation success was defined as a thyroglobulin (Tg) cutoff of 1 ng/mL (risk ratio, 0.99; 95% confidence interval, 0.96-1.03) or a Tg cutoff of 1 ng/mL plus imaging modality (RR 0.97; 0.90-1.05), the results of rhTSH and THW were similar. There were no significant differences when ablation success was defined as a Tg cutoff of 2 ng/mL (RR 1.03; 0.95-1.11) or a Tg cutoff of 2 ng/mL plus imaging modality (RR 1.02; 0.95-1.09). When a negative 131I-whole body scan was used solely as the definition of ablation success, the effects of rhTSH and THW were not significantly different (RR 0.97; 0.93-1.02). Therefore, ablation success rates are comparable when RRA is prepared by either rhTSH or THW.