Advances in the management of anaplastic thyroid carcinoma: transforming a life-threatening condition into a potentially treatable disease.

Anaplastic thyroid cancer (ATC) is an infrequent thyroid tumor that usually occurs in elderly patients. There is often a history of previous differentiated thyroid cancer suggesting a biological progression. It is clinically characterized by a locally invasive cervical mass of rapid onset. Metastases are found at diagnosis in 50% of patients. Due to its adverse prognosis, a prompt diagnosis is crucial. In patients with unresectable or metastatic disease, multimodal therapy (chemotherapy and external beam radiotherapy) has yielded poor outcomes with 12-month overall survival of less than 20%. Recently, significant progress has been made in understanding the oncogenic pathways of ATC, leading to the identification of BRAF V600E mutations as the driver oncogene in nearly 40% of cases. The combination of the BRAF inhibitor dabrafenib (D) and MEK inhibitor trametinib (T) showed outstanding response rates in BRAF-mutated ATC and is now considered the standard of care in this setting. Recently, it was shown that neoadjuvant use of DT followed by surgery achieved 24-month overall survival rates of 80%. Although these approaches have changed the management of ATC, effective therapies are still needed for patients with BRAF wild-type ATC, and high-quality evidence is lacking for most aspects of this neoplasia. Additionally, in real-world settings, timely access to multidisciplinary care, molecular testing, and targeted therapies continues to be a challenge. Health policies are warranted to ensure specialized treatment for ATC.The expanding knowledge of ATC´s molecular biology, in addition to the ongoing clinical trials provides hope for the development of further therapeutic options.

Thirty years of active surveillance for low-risk thyroid cancer, lessons learned and future directions.

Active Surveillance is a non-invasive strategy designed to identify a minority of patients with low-risk papillary thyroid carcinoma who might experience clinical progression and benefit from additional definitive treatments. Global experience suggests that these tumors typically show minimal changes in size during active surveillance, often demonstrating very slow growth or even size reduction. Moreover, the rate of lymph node metastases is low and can be effectively managed through rescue surgery, without impacting cancer-related mortality. However, despite 30 years of experience demonstrating the safety and feasibility of active surveillance for appropriately selected patients, this approach seems to have limited adoption in specific contexts. This limitation can be attributed to various barriers, including disparities in access to accurate information about the indolent nature of this disease and the prevalence of a maximalist mindset among certain patients and medical settings. This review aims to revisit the experience from the last three decades, provide current insights into the clinical outcomes of active surveillance trials, and propose a systematic approach for its implementation. Furthermore, it intends to emphasize the importance of precise patient selection and provides new perspectives in the field.

Conservative management of low-risk papillary thyroid carcinoma: a review of the active surveillance experience.

The detection of low-risk thyroid carcinoma has increased in recent decades, although disease-specific mortality remained without changes. The high prevalence of occult carcinomas in autopsy studies, and hence the underlying indolent course of this entity, prompted the emergence of active surveillance as an alternative approach to these tumors. This strategy aims to recognize the minority group of patients who will develop clinical progression and probably benefit from deferred surgery. Experience around the world has shown that during active surveillance these tumors are mostly unchanged in size, with very-slow growth and even a decrease in diameter. Moreover, the rates of lymph node metastases were low and easily handled by rescue surgery, and distant metastases have not been reported. Given the high prevalence of small thyroid carcinomas and the excellent outcomes for observation, active surveillance provides a safe and feasible alternative in properly selected patients with low-risk thyroid cancer.

Dabrafenib plus trametinib treatment in patients with anaplastic thyroid carcinoma: an Argentinian experience.

PURPOSE: To present our real-life experience with dabrafenib and trametinib (D-T) treatment in patients with BRAF V600E-mutated ATC in Argentina. PATIENTS Y METHODS: We included five patients from four different hospitals. The median age was 70 years, and 60% were male. The performance status at diagnosis was grade 0 in 60% and grade 2 in 40% of patients. Four patients could undergo total thyroidectomy; in one of them, surgical treatment was amenable due to the indication of D-T as neoadjuvant therapy. From the total cohort, the best response to treatment was complete response in 40%, partial response in 20%, and stable disease in 20%. The median duration of response was 20 weeks, ranging from 16 to 92 weeks. All patients experienced at least one adverse event (AE). Grade ≥3 AEs were observed in two (40%) patients. They were upper gastrointestinal bleeding and subclavian vein thrombosis. The median follow-up was 20 weeks (range: 16 to 92). CONCLUSION: This report contributes to illustrate the feasibility and effectiveness of D-T treatment in five patients with loco-regionally advanced and metastatic BRAF V600E-mutated ATC in a real-life setting. A multidisciplinary approach and rapid molecular-tailored testing are essential to begin this therapeutic option.

New approaches for patients with advanced radioiodine-refractory thyroid cancer.

The cumulative evidence over the past decades has shown that the incidence of differentiated thyroid carcinoma (DTC) has exponentially increased. Approximately 10% of patients with DTC exhibit recurrent or metastatic disease, and about two-thirds of the latter will be defined as refractory to radioactive iodine (RAIR) treatment. Since this condition implies 10-year survival rates less than 10% after detection, using available treatments, such as systemic and targeted therapies, have become increasingly relevant. The initiation of these treatments aims to reach stabilization, tumor volume reduction, and/or symptom improvement and it should be decided by highly specialized endocrinologists/oncologists on the basis of patient's features. Considering that despite enlarged progression-free survival was proven, multikinase inhibitors remain non-curative, their benefits last for a limited time and the side effects potentially cause harm and quality of life reduction. In this context, molecular testing of cancer cells provides a promising spectrum of targeted therapies that offer increased compatibility with individual patient needs by improving efficacy, progression free survival, overall survival and adverse events profile. This review article aims to provide a summary of the current therapeutic strategies in advanced RAIR-DTC, including approved target therapies as well as those for off-label use, RAI resensitization agents, and immunotherapy.

Active surveillance in small cytological indeterminate thyroid nodules: a call to common sense?

PURPOSE: To describe the clinical characteristics and outcomes of patients with cytologically Bethesda IV category (B IV) thyroid nodules who opted for active surveillance. MATERIALS AND METHODS: We prospectively evaluated 155 patients with a single thyroid nodule classified as B IV. Immediate molecular testing and/or thyroid surgery was offered, except when the patient (i) could not afford molecular testing/rejected the surgery, (ii) had a high surgical risk, (iii) had other disorders/comorbidities which needed to be addressed with higher priority, and (iv) had undetectable serum calcitonin levels, in whom active surveillance (AS) was performed. RESULTS: From 155 patients, only two patients could afford molecular testing; 84% (n = 130) underwent immediate thyroid surgery: lobectomy was performed in only 8% (n = 10). AS was the initial management for 15% (n = 23) of the patients. The frequency of tumor enlargement was 14% (n = 3), after a median of 42 months (range, 7-72) of follow-up, without any evidence of lymph node or clinical distant metastases development. Deferred surgery was performed in 4 patients (17%) after a median of 24 months (range, 12-48) of AS. Follicular adenoma was diagnosed in three and a follicular variant of papillary thyroid carcinoma in one patient, all of them without evidence of disease after 12 months of follow-up. CONCLUSIONS: Despite current guidelines does not support AS for indeterminate Bethesda IV nodules, our findings showed that most of these patients had excellent outcomes, in a setting where lobectomy was not the preference and the access to molecular testing was limited. Probably AS could be a valid alternative in these low-risk tumors in selected patients.

Active surveillance in low risk papillary thyroid carcinoma.

In recent decades, while the incidence of thyroid cancer has increased exponentially around the world, mortality has remained stable. The vast majority of this increase is attributable to the identification of intrathyroidal papillary microcarcinomas, which exhibit slow growth rates with indolent courses. A diagnosis of thyroid cancer based upon the presence of these small tumors could be considered as an overdiagnosis, as the majority of these tumors would not likely result in death if left untreated. Although surgical resection was the classical standard therapy for papillary microcarcinomas, active surveillance (AS) has emerged over the last three decades as an alternative approach that is aimed to recognize a minority group of patients who will clinically progress and would likely benefit from rescue surgery. Despite the encouraging results of AS, its implementation in clinical practice is strongly influenced by psychosocial factors. The aim of this review is to describe the epidemiology, clinical evolution, prognostic factors, and mortality of papillary thyroid microcarcinomas. We also summarize the AS strategy according to published evidence, characterize the criteria for selecting patients for AS according to risk factors and environmental characteristics, as well as analyze the current limitations for AS implementation.

Thyroid cancer in the Era of COVID-19.

The recent coronavirus infectious disease (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is placing health systems in serious challenges worldwide. Shocking statistics each day has prompted the World Health Organization to officially declare the COVID-19 outbreak as a pandemic in March 2020. Preliminary studies have shown increased mortality in patients with solid cancers and infection by SARS-CoV-2. Until now, the evidence on the behavior of COVID-19 in patients with a history of thyroid cancer remains scarce, and most of the recommendations given are based on common sense. Therefore, in this viewpoint, we present a brief review of several challenges we are frequently facing during this pandemic and a series of recommendations based on what we have implemented in our clinical practice at a university hospital currently mostly dedicated to COVID-19.

High rate incidence of post-surgical adverse events in patients with low-risk papillary thyroid cancer who did not accept active surveillance.

PURPOSE: To describe the outcomes and the incidence of adverse events following active surveillance (AS) versus immediate surgery in patients with low-risk papillary thyroid carcinoma (PTC). METHODS: We prospectively evaluated 286 patients who attended the Hospital de Clínicas, with a single thyroid nodule <1.5 cm classified as Bethesda category V or VI (PTC). Those patients with no aggressive features were considered as harboring a low-risk PTC and were offered AS or immediate surgery. For patients who opted for AS, surgery was recommended if tumor progression was observed. Post-operative adverse events were recorded for those patients treated with surgery (after AS or immediate surgery). RESULTS: From 286 eligible patients, 164 harbored a low-risk PTC. Among these, 75% (n = 123) underwent immediate surgery and 25% (n = 41) opted for AS. Within the last group, increase in tumor size more than 3 mm was observed in 14.6 and 4.8% was diagnosed with lymph-node metastases after a median of 37.5 months (range, 12-65) of follow-up. One hundred and thirty five patients underwent surgery: in 123, it was immediate after diagnosis and in 12 after a median of 35 months (range, 12-65) of AS. Both groups had excellent oncological outcomes. The frequency of postoperative adverse events was 24.4%, which was permanent in 9.6% of cases. The immediate-surgery group presented higher incidence of permanent vocal cord paralysis (2.4 vs. 0%); permanent hypoparathyroidism (5.7 vs. 0%) and local complications (4 vs. 2.4%) compared with the AS group, all non-statistically significant. CONCLUSIONS: The high incidence of postoperative complications observed in our media could be avoided if AS was performed as the initial approach in patients with low-risk PTCs. The frequency of tumor growth and LN metastases during AS was similar to other series.

Active surveillance in papillary thyroid carcinoma: not easily accepted but possible in Latin America

ABSTRACT Objectives To determine the percentage of patients with papillary thyroid carcinoma (PTC) who accepted active surveillance as an alternative to surgery in our clinical practice and to describe the clinical characteristics and outcomes of patients with Bethesda category V and VI thyroid nodules who chose active surveillance. Subjects and methods We included 136 PTC patients from the Hospital de Clínicas, University of Buenos Aires without (i) US extrathyroidal extension, (ii) tumors adjacent to the recurrent laryngeal nerve or trachea, and/or (iii) US regional lymph-node metastasis or clinical distant metastasis. PTC progression was defined as the presence of i) a tumor larger than ≥ 3 mm, ii) novel appearance of lymph-node metastasis, and iii) serum thyroglobulin doubling time in less than one year. For patients with these features, surgery was recommended. Results Only 34 (25%) of 136 patients eligible for active surveillance accepted this approach, and around 10% of those who accepted abandoned it due to anxiety. The frequency of patients with tumor enlargement was 17% after a median of 4.6 years of follow-up without any evidence of nodal or distant metastases. Ten patients who underwent surgical treatment after a median time of 4 years of active surveillance (AS) had no evidence of disease after a median of 3.8 years of follow-up after surgery. Conclusion Although not easily accepted in our cohort of patients, AS would be safe and easily applicable in experienced centers.

Active surveillance in papillary thyroid carcinoma: not easily accepted but possible in Latin America.

OBJECTIVES: To determine the percentage of patients with papillary thyroid carcinoma (PTC) who accepted active surveillance as an alternative to surgery in our clinical practice and to describe the clinical characteristics and outcomes of patients with Bethesda category V and VI thyroid nodules who chose active surveillance. SUBJECTS AND METHODS: We included 136 PTC patients from the Hospital de Clínicas, University of Buenos Aires without (i) US extrathyroidal extension, (ii) tumors adjacent to the recurrent laryngeal nerve or trachea, and/or (iii) US regional lymph-node metastasis or clinical distant metastasis. PTC progression was defined as the presence of i) a tumor larger than ≥ 3 mm, ii) novel appearance of lymph-node metastasis, and iii) serum thyroglobulin doubling time in less than one year. For patients with these features, surgery was recommended. RESULTS: Only 34 (25%) of 136 patients eligible for active surveillance accepted this approach, and around 10% of those who accepted abandoned it due to anxiety. The frequency of patients with tumor enlargement was 17% after a median of 4.6 years of follow-up without any evidence of nodal or distant metastases. Ten patients who underwent surgical treatment after a median time of 4 years of active surveillance (AS) had no evidence of disease after a median of 3.8 years of follow-up after surgery. CONCLUSION: Although not easily accepted in our cohort of patients, AS would be safe and easily applicable in experienced centers.

Should Age at Diagnosis Be Included as an Additional Variable in the Risk of Recurrence Classification System in Patients with Differentiated Thyroid Cancer.

OBJECTIVE: To evaluate the influence of age at diagnosis on the frequency of structural incomplete response (SIR) according to the modified risk of recurrence (RR) staging system from the American Thyroid Association guidelines. PATIENTS AND METHODS: We performed a retrospective analysis of 268 patients with differentiated thyroid cancer (DTC) followed up for at least 3 years after initial treatment (total thyroidectomy and remnant ablation). The median follow-up in the whole cohort was 74.3 months (range: 36.1-317.9) and the median age at diagnosis was 45.9 years (range: 18-87). The association between age at diagnosis and the initial and final response to treatment was assessed with analysis of variance (ANOVA). Patients were also divided into several groups considering age younger and older than 40, 50, and 60 years. RESULTS: Age at diagnosis was not associated with either an initial or final statistically significant different SIR to treatment (p = 0.14 and p = 0.58, respectively). Additionally, we did not find any statistically significant differences when the percentages of SIR considering the classification of RR were compared between different groups of patients by using several age cutoffs. CONCLUSIONS: When patients are correctly risk stratified, it seems that age at diagnosis is not involved in the frequency of having a SIR at the initial evaluation or at the final follow-up, so it should not be included as an additional variable to be considered in the RR classifications.

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.