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.

Metástasis a distancia en cáncer diferenciado de tiroides: diagnóstico y tratamiento / Distant metastases in differentiated thyroid carcinoma: Diagnosis and treatment

La presencia de metástasis a distancia en el cáncer diferenciado de tiroides es un hecho infrecuente que ocurre en menos del 10% de los pacientes. Cuando sucede, la supervivencia a 10 años disminuye significativamente. La curación es el objetivo primario, pero dado que 2 tercios de los tumores metastásicos se volverán radiorrefractarios en su evolución, la finalidad terapéutica es estabilizar la enfermedad y tratar sus síntomas. En la última década, el manejo de estos pacientes cambió radicalmente con el advenimiento de las terapias con blancos moleculares. El objetivo de esta revisión es describir las características de los pacientes con cáncer diferenciado de tiroides que presenten metástasis a distancia, la supervivencia global, los métodos diagnósticos utilizados, y los tratamientos locales y sistémicos disponibles.

Distant metastases occur in less than 10% of patients with differentiated thyroid carcinoma. In these patients, overall survival at 10 years is considerably reduced. Whereas cure is the initial goal of treatment, stabilisation of the disease and management of symptoms have become the primary objective in many patients with persistent radio-iodine refractory progressive disease. In the last decade, several targeted therapies have shown encouraging results in patients with advanced disease. The objective of this review is to describe the characteristics, diagnosis, overall survival, and the local and systemic available treatments for patients with distant metastases from differentiated thyroid cancer.

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.

Radiation exposure and thyroid cancer: a review

ABSTRACT The association between radiation exposure and the occurrence of thyroid cancer has been well documented, and the two main risk factors for the development of a thyroid cancer are the radiation dose delivered to the thyroid gland and the age at exposure. The risk increases after exposure to a mean dose of more than 0.05-0.1 Gy (50-100mGy). The risk is more important during childhood and decreases with increased age at exposure, being low in adults. After exposure, the minimum latency period before the appearance of thyroid cancers is 5 to 10 years. Papillary carcinoma (PTC) is the most frequent form of thyroid carcinoma diagnosed after radiation exposure, with a higher prevalence of the solid subtype in young children with a short latency period and of the classical subtype in cases with a longer latency period after exposure. Molecular alterations, including intra-chromosomal rearrangements, are frequently found. Among them, RET/PTC rearrangements are the most frequent. Current research is directed on the mechanism of genetic alterations induced by radiation and on a molecular signature that can identify the origin of thyroid carcinoma after a known or suspected exposure to radiation.

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.

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.

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.