Search Results (10)

Thyroid cancer (TC) remains a prevalent malignancy, with over 820,000 global cases diagnosed in 2022. Differentiated thyroid carcinoma (DTC), primarily papillary and follicular types, accounts for most cases and has a favorable prognosis with total thyroidectomy and radioiodine (RAI) ablation. However, 5–15% of patients develop RAI-refractory (RAI-R) disease, leading to a significantly poorer outcome. For RAI-R patients, treatment decisions depend on disease progression. Active surveillance is suitable for indolent cases, while symptomatic or progressive disease requires systemic therapy. Multikinase inhibitors (MKIs) such as lenvatinib and sorafenib serve as first-line options, with cabozantinib recently approved for resistant cases. Additionally, novel targeted therapies, including RET and NTRK inhibitors, and immune checkpoint inhibitors, are under investigation, offering a personalized approach. A key challenge is determining the optimal timing for systemic therapy, balancing progression-free survival (PFS) benefits against MKI-related toxicities, which significantly impact quality of life (QoL). Molecular testing can identify actionable mutations, guiding therapy selection. Clinical guidelines (ATA, ESMO) recommend initiating treatment based on disease progression and patient condition, integrating strategies such as active surveillance, surgery, and radiotherapy when appropriate. Despite advances, systemic therapies carry significant adverse events (e.g., hypertension, fatigue, gastrointestinal toxicity), necessitating careful monitoring to prevent dose reductions or interruptions. A multidisciplinary approach is essential to optimize patient outcomes and maintain QoL. As targeted therapies continue to evolve, further research is needed to refine treatment sequencing and improve outcomes for RAI-R TC. This review synthesizes current evidence to guide clinical decision-making. Full article

Background and Objectives: Anlotinib, a novel multi-kinase inhibitor targeting angiogenesis and tumor proliferation pathways, has shown promising efficacy in various cancers. Its role in treating thyroid cancer, particularly radioactive iodine-refractory differentiated thyroid cancer (RAIR-DTC), medullary thyroid carcinoma (MTC), and anaplastic thyroid carcinoma (ATC), is of significant clinical interest. This systematic review aims to evaluate the efficacy and safety of Anlotinib in patients with thyroid cancer, analyzing outcomes such as progression-free survival (PFS), overall survival (OS), response rates, and adverse events. Methods: A comprehensive literature search was conducted using PubMed, Scopus, and Web of Science databases up to October 2023. The review included randomized controlled trials and prospective studies assessing Anlotinib in thyroid cancer patients. Data extraction and quality assessment were performed independently by two reviewers following PRISMA guidelines. Results: Six studies involving a total of 277 patients were included. In patients with RAIR-DTC, Anlotinib demonstrated significant improvement in median PFS and objective response rates. In advanced or metastatic MTC, Anlotinib significantly prolonged median PFS compared to placebo, with high objective response rates. Subgroup analyses showed that older patients and those with bone metastases benefited significantly from Anlotinib treatment. In patients with ATC, Anlotinib-based chemotherapy yielded a 60% objective response rate. Anlotinib was also effective as neoadjuvant therapy in locally advanced thyroid cancer, achieving an objective response rate of 76.9%. Common adverse events included hypertension, proteinuria, and palmar–plantar erythrodysesthesia syndrome, which were generally manageable. Conclusions: Anlotinib appears to be an effective and well-tolerated treatment option for patients with various types of thyroid cancer, providing significant improvements in PFS and objective response rates. Further large-scale randomized studies are warranted to confirm these findings and to explore long-term outcomes. Full article

Thyroid cancer (TC) remains the most common cancer in endocrinology. Differentiated thyroid cancer (DTC), the most common type of TC, generally has a favorable outlook with conventional treatment, which typically includes surgery along with radioiodine (RAI) therapy and thyroid-stimulating hormone (TSH) suppression through thyroid hormone therapy. However, a small subset of patients (less than 5%) develop resistance to RAI. This resistance occurs due to the loss of Na/I symporter (NIS) activity, which is crucial for iodine absorption in thyroid cells. The decline in NIS activity appears to be due to gene modifications, reconfigurations with irregular stimulation of signaling pathways such as MAPK and PI3K/Akt pathways. These molecular changes lead to a diminished ability of DTC cells to concentrate iodine, which makes RAI therapy ineffective. As a consequence, patients with radioiodine-refractory DTC require alternative treatments. Therapy with tyrosine kinase inhibitors (TKIs) has emerged as the primary treatment option to inhibit proliferation and growth of RAIR-DTC, targeting the pathways responsible for tumor progression. In this article, we analyze molecular processes responsible for RAI resistance and explore both conventional and emerging therapeutic strategies for managing RAIR-DTC, aiming to improve patient outcomes. Full article

Since the 1940s, 131-I radioiodine therapy (RIT) has been the primary treatment for metastatic differentiated thyroid cancer (DTC). Approximately half of these patients respond favorably to RIT, achieving partial or complete remission or maintaining long-term stable disease, while the other half develop radioiodine-refractory DTC (RAI-R DTC). The main genomic alteration involved in radioiodine resistance is the activated mitogen-activated protein kinase (MAPK) pathway, which results in the loss of sodium iodide symporters (NIS). Therefore, RAI-R DTC requires alternative treatment options such as tyrosine kinase inhibitors. Over the past decade, several studies have investigated pharmacological induction or enhancement of NIS expression through “redifferentiation” therapies, mainly targeting the MAPK pathway. These novel approaches can restore radioiodine sensitivity in previously refractory patients and, therefore, potentially reestablish the efficacy of RIT. This review discusses various redifferentiation strategies, including their molecular mechanisms and clinical implications. Full article

Background: Differentiated thyroid cancer (DTC) patients have an outstanding overall long-term survival rate, and certain subsets of DTC patients have a very high likelihood of disease recurrence. Radioactive iodine (RAI) therapy is a cornerstone in DTC management, but cancer cells can eventually develop resistance to RAI. Radioactive iodine-refractory DTC (RAIR-DTC) is a condition defined by ATA 2015 guidelines when DTC cannot concentrate RAI ab initio or loses RAI uptake ability after the initial therapy. The RAIR condition implies that RAI cannot reveal new met-astatic foci, so RAIR-DTC metabolic imaging needs new tracers. ¹⁸F-FDG PET/CT has been widely used and has demonstrated prognostic value, but ¹⁸F-FDG DTC avidity may remain low. Fibroblast activation protein inhibitors (FA-Pi)s, prostatic-specific membrane antigen (PSMA), and somatostatin receptor (SSTR) tracers have been proposed as theragnostic agents in experimental settings and Arg-Gly-Asp (RGD) peptides in the diagnostic trial field. Multi-targeted tyrosine kinase inhibitors are relatively new drugs approved in RAIR-DTC therapy. Despite the promising targeted setting, they relate to frequent adverse-event onset. Sorafenib and trametinib have been included in re-differentiation protocols aimed at re-inducing RAI accumulation in DTC cells. Results appear promising, but not excellent. Conclusions: RAIR-DTC remains a challenging nosological entity. There are still controversies on RAIR-DTC definition and post-RAI therapy evaluation, with post-therapy whole-body scan (PT-WBS) the only validated criterion of response. The recent introduction of multiple diagnostic and therapeutic agents obliges physicians to pursue a multidisciplinary approach aiming to correct drug introduction and timing choice. Full article

Differentiated thyroid cancer (DTC) is the most common subtype of thyroid cancer and has an excellent overall prognosis. However, metastatic DTC in certain cases may have a poor prognosis as it becomes radioiodine-refractory. Molecular imaging is essential for disease evaluation and further management. The most commonly used tracers are [¹⁸F]FDG and isotopes of radioiodine. Several other radiopharmaceuticals may be used as well, with different diagnostic performances. This review article aims to summarize radiopharmaceuticals used in patients with radioiodine-refractory DTC (RAI-R DTC), focusing on their different molecular pathways. Additionally, it will demonstrate possible applications of the theranostics approach to this subgroup of metastatic DTC. Full article

Radio-iodine refractory (RAI-R) differentiated thyroid cancer (DTC) is a rare disease with a poor prognosis and limited therapeutic resources. Therefore, identifying prognostic factors is essential in order to select patients who could benefit from an early start of treatment. The aim of this study is to identify positron emission tomography with 18F-fluorodeoxyglucose with integrated computed tomography (18F-FDG-PET/CT) parameters to predict overall survival (OS) in patients with RAI-R DTC. In this single-center retrospective study, we analyze the 18F-FDG-PET/CT parameters of 34 patients with RAI-R DTC between April 2007 and December 2019. The parameters collected are MTV, SUVmax and progression for each site of metastasis (neck, mediastinum, lungs, liver, bone) and total sites. ROC curves, Kaplan–Meier survival analysis curves, univariate and multivariate Cox analyses determine prognostic factors for 1-year and 5-year OS. The parameters for mediastinum, liver and total sites are significantly associated with worse 1-year and 5-year OS by both ROC curve analysis and Kaplan–Meier survival analysis. Univariate Cox analysis confirms significance of mediastinum SUVmax (HR 1.08; 95% CI [1.02–1.15]; p = 0.014) and total SUVmax (HR 1.06; 95% CI [1–1.12]; p = 0.042) for worse 1-year OS; of mediastinum SUVmax (HR 1.06; 95% CI [1.02–1.10]; p = 0.003), liver SUVmax (HR 1.04; 95% CI [1.01–1.08]; p = 0.02), liver MTV (HR 2.56; 95% CI [1.13–5.82]; p = 0.025), overall SUVmax (HR 1.05; 95% CI [1.02–1.08]; p = 0.001) and total MTV (HR 1.41; 95% CI [1.07–1.86]; p = 0.016) for worse 5-year OS. Multivariate Cox analysis confirms a significant association between liver MTV (HR 1.02; 95% CI [1–1.04]; p = 0.042) and decrease 1-year OS. In this study, we demonstrate that in RAI-R DTC, 18F-FDG-PET/CT parameters of the mediastinum, liver and overall tumor burden were prognostic factors of poor 1-year and 5-year OS. Identifying these criteria could allow early therapeutic intervention in order to improve patients’ survival. Full article

Two-thirds of differentiated thyroid cancer (DTC) patients with distant metastases would be classified as radioactive iodine-refractory (RAIR-DTC), evolving into a poor outcome. Recent advances underlying DTC molecular mechanisms have shifted the therapy focus from the standard approach to targeting specific genetic dysregulations. Lenvatinib and sorafenib are first-line, multitargeted tyrosine kinase inhibitors (TKIs) approved to treat advanced, progressive RAIR-DTC. However, other anti-angiogenic drugs, including single targeted TKIs, are currently being evaluated as alternative or salvage therapy after the failure of first-line TKIs. Combinatorial therapy of mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K) signalling cascade inhibitors has become a highly advocated strategy to improve the low efficiency of the single agent treatment. Recent studies pointed out targetable alternative pathways to overcome the resistance to MAPK and PI3K pathways’ inhibitors. Because radioiodine resistance originates in DTC loss of differentiation, redifferentiation therapies are currently being explored for efficacy. The present review will summarize the conventional management of DTC, the first-line and alternative TKIs in RAIR-DTC, and the approaches that seek to overcome the resistance to MAPK and PI3K pathways’ inhibitors. We also aim to emphasize the latest achievements in the research of redifferentiation therapy, immunotherapy, and agents targeting gene rearrangements in advanced DTC. Full article

Background: As reported in the literature, [18F]-fluorodeoxyglucose positron emission tomography/computed tomography ([18F]-FDG PET/CT) provides useful qualitative and semi-quantitative data for the prognosis of advanced differentiated thyroid cancer. Instead, there is a lack of data about the real clinical impact of 18F-FDG PET/CT on the choice of the more effective therapeutic approach for advanced differentiated thyroid cancer (DTC) that starts to lose iodine avidity. The primary aim of this retrospective study was to assess how 18F-FDG PET/CT can guide the choice of the best therapeutic approach to RAI-refractory DTC (RAI-R-DTC) in patients with a doubtful iodine uptake/negative 18F-FDG PET/CT I whole-body scan after several radioactive iodine therapies (RAIT). The secondary aim was to assess the prognostic role of clinical and semi-quantitative metabolic 18F-FDG PET/CT parameters in comparison to published data. Materials and methods: A monocentric retrospective observational study was performed, reviewing the medical records of 53 patients recruited from a database of 208 patients treated at our Institution between 2011 and 2019, with advanced DTC that underwent FDG PET/CT scan for a suspected RAI-R-DTC. Selected patients had to perform a 18F-FDG PET/CT scan after the second RAIT based on a doubtful iodine uptake/negative 131 I whole-body scan and/or persistent elevated thyroglobulin levels. Metabolic response was defined according to positron emission tomography response criteria in solid tumors (PERCIST) guidelines. Standardized uptake value (SUV)max, SUVmean, metabolic tumor volume (MTV), and total lesion glycolysis (TLG) were calculated. The association between metabolic features, clinical parameters and progression free survival (PFS) was assessed applying Kruskal–Wallis, chi-square-Pearson correlation tests, and Cox regression analyses when appropriate. Results: Among our sample of 53 patients (mean age 52.0 ± 19.9 years; 31 women and 22 men), 27 (51.0%) presented a positive 18F-FDG PET/CT scan: 16 (59.0%) underwent watchful waiting, 4 (15.0%) received external-beam radiation therapy (EBRT), 4 (15.0%) underwent surgery, 2 (7.4%) received another course of RAI therapy, and 1 underwent surgery + EBRT. PERCIST response was evaluated in 14/27 patients. Median follow-up was 5.8 ± 3.9 years and median PFS was 38.0 ± 21.8 months. At the last follow-up assessment, 14/53 (26.4%) demonstrated disease progression, 13/53 (24.5) persistence of structural disease, 25/53 (47%) persistence of biochemical disease, and 15/53 (28%) had an excellent response. A significant association was found between therapeutic approach, metabolic response, and final disease response evaluation, as well as a linear correlation between MTV and TLG with thyroglobulin level. Conclusions: Our Institutional experience confirmed the role of 18F-FDG PET/CT as a useful guide in the clinical management of RAI-R-DTC and obviated further unnecessary RAIT. Full article

Differentiated thyroid cancer (DTC) represents the most common thyroid cancer histotype. Generally, it exhibits a good prognosis after conventional treatments; nevertheless, about 20% of patients can develop a local recurrence and/or distant metastasis. In one-third of advanced DTC, the metastatic lesions lose the ability to take up iodine and become radioactive iodine-refractory (RAI-R) DTC. In this set of patients, the possibility to perform localized treatments should always be taken into consideration before the initiation of systemic therapy. In the last decade, some multi-tyrosine kinase inhibitor (MKI) drugs were approved for advanced DTC, impacting on patient’s survival rate, but at the same time, these therapies have been associated with several adverse events. In this clinical context, the role of 2-deoxy-2-[¹⁸F]fluoro-D-glucose positron emission tomography/computed tomography ([¹⁸F]FDG PET/CT) in the early treatment response to these innovative therapies was investigated, in order to assess the potentiality of this diagnostic tool in the early recognition of non-responders, avoiding unnecessary therapy. Herein, we aimed to present a critical overview about the reliability of [¹⁸F]FDG PET/CT in the early predictive response to MKIs in advanced differentiated thyroid cancer. Full article