Dynamic risk allows us to adequately select patients with differentiated thyroid cancer who do not require radioiodine treatment

ABSTRACT Objective: The treatment of patients with differentiated thyroid cancer (DTC) was modified in the last decade towards a more individualized approach according to the risk of recurrence (RR). We compared the outcomes of patients with low and intermediate RR (LRR and IRR) who received or did not receive radioiodine remnant ablation (RRA) after assessing the dynamic risk. Materials and methods: We included 307 DTC patients with LRR and IRR submitted to total thyroidectomy. All patients were reclassified according to the dynamic risk stratification (low or high). Patients with high dynamic risk received RRA (141 patients). Results: LRR patients who received RRA presented a frequency of structural incomplete response (SIR) of 5% at the end of the follow-up, compared to 2% in those who did not receive it (p=0.353). IRR patients treated with RRA had a frequency of SIR of 22%, compared to 5% in patients without RRA (p=0.008). Conclusions: This study demonstrates the usefulness of dynamic risk assessment to decide RRA in a cohort with a long-term follow-up. The lower prevalence of SIR at the end of the follow-up in patients who did not receive RRA highlights the adequate selection of those who would not benefit from RRA, even with an intermediate risk of recurrence.

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.

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.

Riesgo dinámico en pacientes con cáncer diferenciado de tiroides no ablacionados / Dynamic risk assessment in patients with differentiated thyroid cancer without remnant ablation

En la actualidad, el enfoque terapéutico y el seguimiento de los pacientes con carcinoma diferenciado de tiroides (CDT) es individualizado de acuerdo con el riesgo de recurrencia de la enfermedad, con una menor tendencia a ablacionar a pacientes de bajo riesgo de recurrencia. Por otro lado, la evaluación de las respuestas al tratamiento se validó en pacientes tratados con tiroidectomía total (TT) y ablación con radioyodo (RAI), pero son escasos los estudios en pacientes no ablacionados. Los objetivos de este estudio fueron describir las características de una población de pacientes con CDT no ablacionados y validar las respuestas al tratamiento durante el seguimiento. Se incluyó a 88 pacientes con un seguimiento mínimo de 12 meses. El 87,6% eran mujeres y la edad promedio en el momento del diagnóstico fue de 47,5 años. Basados en el Consenso Intersocietario Argentino, el 97,7% de la cohorte fue clasificada como de bajo riesgo y el 2,3% como de riesgo intermedio de recurrencia. Los pacientes presentaron una respuesta inicial excelente en el 73% de los casos, con un estado sin evidencia de enfermedad al final del seguimiento en el 85,5%. Una minoría de los pacientes (1%) presentó una respuesta inicial estructural incompleta, la cual fue similar al final del seguimiento (1%). Por otro lado, el 26% de los pacientes presentó una respuesta inicial indeterminada, aunque solo el 13,5% permaneció con esta respuesta al final del seguimiento. Nuestros datos validan las respuestas al tratamiento en pacientes con CDT que recibieron TT no ablacionados como una herramienta efectiva para la estratificación del riesgo dinámico. Los pacientes apropiadamente seleccionados tratados sin RAI tienen un excelente pronóstico, con una baja frecuencia de respuesta estructural incompleta en el seguimiento, inclusive menor que la de los pacientes de bajo riesgo ablacionados.

The therapeutic approach and the follow-up of patients with differentiated thyroid cancer (DTC) is currently individualised according to the risk of recurrence, with a lower tendency to perform remnant ablation (RA) in patients with low risk of recurrence. While response to therapy assessment has been validated for DTC patients treated by total thyroidectomy (TT) and RA, it has not been widely confirmed in patients treated with TT without RA. The aims of this study were to describe the characteristics of the population of patients treated with TT without RA, and to validate the response to therapy. The study included 88 patients followed-up for at least 12 months after surgery. In the entire cohort, 87.9% were female and the mean age was 47.5 years old. Based on the Argentine Intersociety Consensus, 97.7% and 2.3% were classified as low risk and intermediate risk of recurrence, respectively. Patients had an initial excellent response to treatment in 73% of cases, with a disease-free status at the end of follow-up of 85.5%. A minority of patients (1%) presented with an initial structural incomplete response, which was similar at the end of follow-up (1%). On the other hand, 26% of the patients had an initial indeterminate response, although only 13.5% remained with this response at the end of follow-up. These results validate the responses to treatment in DTC patients treated with TT without RA as an effective tool for the dynamic risk stratification. Patients appropriately selected who did not receive RA have an excellent outcome, with a low frequency of structural incomplete response, even lower than that observed in low risk ablated patients.

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.

Prevalencia de enfermedades tiroideas en una población del área metropolitana de Buenos Aires / Prevalence of thyroid diseases in a population of the metropolitan area of Buenos Aires

La prevalencia de alteraciones morfológicas palpables tiroideas no supera el 8% en la población adulta. En el Hospital de Clínicas de la Universidad de Buenos Aires se llevó a cabo un programa gratuito para la detección de enfermedades tiroideas, convocándose a sujetos que desconocieran antecedentes tiroideos. Nuestro objetivo fue establecer la frecuencia de patología morfológica palpable tiroidea, en una población seleccionada de pacientes, y comparar dichos resultados con los hallazgos de un programa de detección similar, realizado en el año 2001¹. Adicionalmente, evaluar la prevalencia de alteraciones funcionales y de autoinmunidad tiroidea. Los individuos que concurrieron se dividieron en 3 grupos: Grupo 1 (n = 186) pacientes con antecedentes personales de enfermedad tiroidea conocida (excluidos del análisis); Grupo 2 (n = 184) sujetos con antecedentes familiares, otras enfermedades autoinmunes, o sintomatología que pudiera atribuirse a alteración de la función tiroidea (grupo inducido), y Grupo 3 (n = 288) sujetos que consultaron por mera curiosidad (grupo random). La función y autoinmunidad tiroidea se evaluó en 144 participantes del Grupo 3, citados al azar. En el grupo random, la prevalencia de alteraciones morfológicas tiroideas, detectadas por palpación, fue del 11,09%. Al comparar estos resultados con los obtenidos 12 años atrás en un estudio similar, realizado en nuestro hospital, no se encontraron diferencias estadísticamente significativas (8,7 vs. 11,09%; p = 0,25). En cuanto a la función tiroidea, se halló hipotiroidismo subclínico en el 6,25%, hipertiroidismo subclínico en el 0,7% y autoinmunidad en el 11% de los sujetos evaluados. En conclusión, la prevalencia de alteraciones palpables de la glándula tiroides no cambió en laúltima década. Esta investigación realizada en una población correctamente seleccionada constituye una herramienta útil para referencias futuras como población control en Argentina.

The prevalence of palpable thyroid morphological abnormalities does not exceed 8% in the adult population. A free program was conducted in the Hospital de Clínicas (University of Buenos Aires) for the detection of thyroid diseases, inviting subjects who were unaware of a history of these diseases. The aim was to establish the frequency of goitre in the selected population, as well as to evaluate the prevalence of functional disorders and thyroid autoimmunity, and to compare these results with the findings of a similar study performed in 2001¹. The subjects were divided into three groups: Group 1 (n = 186) patients with a history of previously known thyroid disorders (excluded subjects); Group 2 (n = 184) subjects with a family history of thyroid disease, other autoimmune diseases, or symptoms that could be attributed to changes in thyroid function (Induced Group), and Group 3 (n = 288) subjects who participated in this program due to mere curiosity (Random Group). Autoimmunity and thyroid function was assessed in 144 randomly selected participants in Group 3. In Group 3, the prevalence of morphological alterations of the thyroid gland was 11.09%. Comparing these results with those obtained 12 years ago in a similar study performed in our hospital, no statistically significant differences were found when the prevalence of morphological thyroid alterations were compared (8.7% vs 11.09%, p=.25). As for thyroid function, subclinical hypothyroidism was found in 6.25%, subclinical hyperthyroidism in 0.7%, and autoimmunity in 11% of subjects evaluated. It was concluded that the prevalence of palpable thyroid abnormalities had not change in the last decade. This study, made in a correctly selected population, is a useful tool for future reference as a control population in Argentina.

Partial response to sorafenib treatment associated with transient grade 3 thrombocytopenia in a patient with locally advanced thyroid cancer

Advanced radioactive refractory and progressive or symptomatic differentiated thyroid carcinoma (DTC) is a rare condition. Sorafenib was recently approved for the treatment of these patients. We present the case of a 67 year old woman diagnosed with DTC who underwent a total thyroidectomy with central, lateral-compartment neck dissection and shaving of the trachea and esophagus due to tumor infiltration. A local recurrence was detected 14 months later requiring, additionally, two tracheal rings resection. The patient received a cumulative 131I dose of 650 mCi and developed dysphagia and dyspnea 63 months after initial surgery. A 18FGD-PET/CT showed progression of the local mass associated to hypermetabolic pulmonary nodules. Sorafenib 800 mg/day was then prescribed. A dose reduction to 400 mg/day was necessary due to grade 3 thrombocytopenia that appeared four months after drug prescription. Platelet count went to normal after this dose reduction. Five months after initiation of sorafenib, a partial response of the local mass with significant intra-tumoral necrosis was observed. We conclude that sorafenib is a valid option for locally advanced DTC and that the platelet count should be evaluated regularly because it seems that thrombocytopenia might be more frequently observed in DTC than in other types of tumors.

Disfunción tiroidea en adultos infectados por el virus de inmunodeficiencia humana

Los pacientes con infección por el virus de inmunodeficiencia humana (HIV) tienen una mayor prevalencia de disfunción tiroidea cuando se los compara con la población general. Las manifestaciones más frecuentemente observadas son: el síndrome del eutiroideo enfermo, la enfermedad de Graves y el hipotiroidismo subclínico. La relación entre el uso de la terapia antirretroviral y el incremento en la prevalencia de alteraciones tiroideas fue demostrada en varias series de pacientes. La enfermedad de Graves se reconoce claramente como una consecuencia del síndrome de restitución inmune. Además, existen estudios que sugieren una relación entre hipotiroidismo y el uso de inhibidores nucleósidos de la transcriptasa reversa, en particular estavudina y el inhibidor no nucleósido de la transcriptasa reversa efavirenz. Nuevos estudios podrán aportar evidencia adicional sobre la necesidad de evaluaciones rutinarias de la función tiroidea en pacientes infectados por HIV.

Patients infected with human immunodeficiency virus (HIV) have a higher prevalence of thyroid dysfunction when compared with the general population. The most frequently observed manifestations are euthyroid sick syndrome, Graves´ disease and subclinical hypothyroidism. The relationship between the use of highly active antiretroviral therapy and the increased prevalence of thyroid dysfunction has been demonstrated in several series of patients. Grave’s disease is recognized as a consequence of immune restitution syndrome. Besides, several studies have suggested an association between hypothyroidism and the use of nucleoside reverse transcriptase inhibitors, particularly stavudine and non-nucleoside reverse transcriptase inhibitors such as efavirenz. Further studies could provide additional evidence of the need for routine assessment of thyroid function in HIV-infected patients.

Undetectable pre-ablation thyroglobulin levels in patients with differentiated thyroid cancer: it is not always what it seems / Níveis indetectáveis de tireoglobulina pré-ablação em pacientes com câncer de tireoide: nem sempre é o que parece

OBJECTIVE: To establish the frequency of U Tg (undetectable pre-ablation thyroglobulin) in TgAb- negative patients and to evaluate the outcome in the follow-up. SUBJECTS AND METHODS: We retrospectively reviewed 335 patients' records. Twenty eight patients (9%) had U Tg. Mean follow-up was 42 ± 38 months. All subjects had undergone total thyroidectomy, and lymph nodes were positive in 13 (46%) patients. Tg and TgAb levels were measured 4 weeks after surgery by IMA technology in hypothyroid state. No evidence of disease (NED) status was defined as undetectable (< 1 ng/mL) stimulated Tg and negative Tg-Ab and/or negative WBS, together with normal imaging studies. RESULTS: Seventeen patients (61%) were considered with NED. Four patients (14%) had persistent disease (mediastinum, n = 1, lung n = 2, unknown n = 1), and 7 (25%) had detectable TgAb by other method during their follow-up. CONCLUSIONS: U Tg levels usually is associated to a complete surgery. However, in a low percentage of patients, this may be related to false negative Tg or TgAb measurement.

OBJETIVO: Estabelecer a frequência de U Tg (tireoglobulina indetectável pré-ablação) em pacientes com TgAb negativo e avaliar o prognóstico no seguimento. SUJEITOS E MÉTODOS: Foram analisados retrospectivamente 335 registros de pacientes. Vinte e oito pacientes (9%) tiveram U Tg. O acompanhamento médio foi de 42 ± 38 meses. Todos os participantes receberam uma tireoidectomia total, e os linfonodos foram positivos em 13 (46%) pacientes. Tg e TgAb foram medidos quatro semanas após a cirurgia pelo método IMA em estado de hipotireoidismo. A não evidência de doença (NED) foi definida como níveis indetectáveis (<1 ng/mL) de Tg estimulada com anticorpos anti-Tg negativos e/ou PCI negativo, com estudos de imagem normais. RESULTADOS: Dezessete pacientes (61%) foram considerados com NED. Quatro pacientes (14%) tiveram doença persistente (mediastino, n = 1, pulmão n = 2, n = desconhecido 1), e 7 (25%) apresentavam anticorpos anti-Tg detectáveis por outro método durante acompanhamento. CONCLUSÕES: U Tg geralmente indica uma cirurgia completa. No entanto, em uma pequena porcentagem de pacientes, pode estar relacionada com uma medida de Tg ou de anticorpos anti-Tg falsamente negativos.

Patients with familial non-medullary thyroid cancer have an outcome similar to that of patients with sporadic papillary thyroid tumors / Pacientes com câncer não medular familiar da tiroide têm evolução similar aos portadores de câncer papilífero esporádico

OBJECTIVE:The purpose of this study was to determine whether familial non-medullary thyroid cancer (FNMTC) is more aggressive than sporadic thyroid cancer. SUBJECTS AND METHODS: We compared the clinical behavior and outcome of 16 subjects with FNMTC from 7 unrelated kindred with those observed in 160 subjects with sporadic PTC (SPTC) from our database. RESULTS: The only different baseline characteristics observed between both groups were: bilateral malignancy, 38 percent vs. 24 percent, respectively (p = 0.03), and lymph node metastasis, 56.2 percent vs. 39 percent, respectively (p = 0.01). Considering the outcome, in the FNMTC, 9 (56.2 percent) patients were rendered free of disease, one patient died from thyroid cancer (6 percent), and 6/16 (37.5 percent) had persistent disease. In the SPTC Group, 87 (54 percent) patients were considered free of disease, 11 (7 percent) died due to PTC, and 62 (38 percent) had persistent disease (p = ns). CONCLUSIONS: Despite the higher incidence of lymph node metastasis in FNMTC patients this situation seemed not to alter the compared outcome.

OBJETIVO: O objetivo deste estudo foi determinar se o câncer de tiroide não medular (CNMF) é mais agressivo do que o câncer esporádico de tiroide. SUJEITOS E MÉTODOS: Comparamos o comportamento clínico e a evolução de 16 portadores de CNMF de sete famílias não relacionadas com 160 CP (câncer papilífero) esporádicos de nosso serviço. RESULTADOS: As únicas diferenças nas características basais dos grupos eram: malignidade bilateral 38 por cento vs. 24 por cento, respectivamente (p = 0,03), e metástases linfonodais, 57,1 por cento vs. 39 por cento, respectivamente (p = 0,01). Em relação à evolução, 9 (56,2 por cento) pacientes com CNMF ficaram livres de doença, um paciente faleceu devido ao CP (6 por cento) e 6/16 (37,5 por cento) apresentavam persistência da doença. No grupo de CP esporádicos, 87 (54 por cento) foram considerados livres de doença, 11 (7 por cento) morreram em decorrência do CP e 62 (38 por cento) apresentavam persistência da doença (p = ns). CONCLUSÃO: Apesar da elevada incidência de metástases linfonodais nos pacientes com CNMF, essa situação não parece alterar a evolução dos dois grupos em longo prazo.