Metastatic Differentiated Thyroid Cancer Research Articles

The role of external-beam radiotherapy for differentiated thyroid cancer.

The treatment options for differentiated thyroid cancer (DTC) are surgery, thyroid stimulating hormone suppression, radioactive iodine, and multitargeted tyrosine kinase inhibitors. The role of external-beam radiotherapy (EBRT) for DTC is controversial because of the lack of randomized controlled trials, but prospective single-arm studies and propensity score matching analyses have shown its efficacy and safety. This review discusses the role of EBRT after resection of gross disease, when there is a high risk of locoregional failure, as well as its role for locoregionally gross recurrent and unresectable disease. As in other tumor sites, EBRT has an important role in the palliative management and local control of patients with metastatic DTC, especially with bone and brain metastases.

Oldie but Goldie: The Fundamental Role of Radioiodine in the Management of Thyroid Cancer.

Background/Objectives: The management of differentiated thyroid cancer (DTC) patients has undergone a major paradigm shift in past years, especially regarding the role of a careful postoperative disease assessment both in deciding for or against the use of iodine-131 therapy (i.e., patients' selection) and in selecting the correct goal of the treatment: ablative, adjuvant or therapeutic. Furthermore, diagnostic and risk-oriented uses of iodine isotopes (i.e., 123/124/131I) should always be considered during both postoperative assessment and follow-up of DTC patients to improve early staging and response assessment to initial treatments, respectively. The present review summarizes current (and real-life-related) evidence and the emerging perspectives on the therapeutic, diagnostic, and theragnostic use of radioiodine isotopes. Methods: A review of the pertinent literature was performed in PubMed, Web of Science, and Scopus without language restrictions or time limits and using one or more fitting search criteria and terms. Results: According to the literature evidence and real-life clinical practice, a risk-oriented postoperative iodine-131 therapy remains pivotal for most DTC patients and improves early disease staging through post-therapy functional imaging (i.e., theragnostic aim). Accordingly, the goal of iodine-131 therapy, the optimal strategy (empiric vs. dosimetric approach), the appropriate stimulation method [i.e., levothyroxine (L-T4) withdrawal vs. recombinant human thyrotropin (rhTSH) administration] and, finally, the suggested radioiodine activity to deliver for iodine-131 therapy (RIT) should be personalized, especially in metastatic DTC patients. Conclusions: The evidence related to the diagnostic and theragnostic use of iodine isotopes leads to a significant improvement in the postoperative risk stratification and staging of DTC patients in addition to a more accurate assessment of the response to initial treatments. In conclusion, radioiodine is really an oldie but goldie radiotracer. It has both a current fundamental role and a future perspective for the more careful management of DTC patients.

68Ga]Ga-LNC1007 versus 2-[18F]FDG in the evaluation of patients with metastatic differentiated thyroid cancer: a head-to-head comparative study.

This head-to-head comparison study aimed to compare the performance of [68Ga]Ga-FAPI-RGD (LNC1007) and 2-[18F]FDG PET/CT in the evaluation of patients with metastatic differentiated thyroid cancer (mDTC). Ten unexplained hyperthyroglobulinemia (UHTg) patients and 20 patients with definite metastatic lesions of thyroid cancer (DmDTC) were enrolled in the study. All patients underwent both [68Ga]Ga-LNC1007 and 2-[18F]FDG PET/CT within 1week. The final diagnosis was based on histopathological results and a comprehensive evaluation of laboratory tests and multimodal imaging characteristics. In patients with UHTg, [68Ga]Ga-LNC1007 PET/CT detected more metastatic lymph nodes (LNs) (17 vs. 15, P = 0.317) and lung lesions (2 vs. 0) than 2-[18F]FDG. In patients with DmDTC, [68Ga]Ga-LNC1007 PET/CT also detected more true positive lesions than 2-[18F]FDG (Total: 133 vs. 103, LN: 20 vs. 15, lung: 18 vs. 10, bone: 87 vs.73). [68Ga]Ga-LNC1007 PET/CT demonstrated significantly higher SUVmax (Total: 6.30 vs. 3.84, LN: 8.28 vs. 4.82, Lung: 3.31 vs. 1.49, Bone: 5.73 vs. 3.87, all P < 0.05) and TBR (Total: 6.92 vs. 4.93, LN: 6.48 vs. 4.16, Lung: 5.16 vs. 2.57, Bone: 7.22 vs. 5.41, all P < 0.05) in true positive lesions compared to 2-[18F]FDG. Specifically, the sensitivity of [68Ga]Ga-LNC1007 PET/CT was higher than that of 2-[18F]FDG in detecting lung and bone metastases (94.7% vs. 52.6% and 100% vs. 83.9%, all P < 0.05). [68Ga]Ga-LNC1007 PET/CT exhibited better specificity and accuracy in diagnosing LNs (96.9% vs. 66.7% and 96.3% vs. 68.5%, all P < 0.05). However, the specificity of [68Ga]Ga-LNC1007 for bone metastasis was inferior to 2-[18F]FDG (15.4% vs. 88.5%, P < 0.05). Compared with 2-[18F]FDG, [68Ga]Ga-LNC1007 PET/CT could detect more metastatic lesions, with higher SUVmax and TBR, in patients with mDTC. [68Ga]Ga-LNC1007 had better accuracy in the diagnosis of LN and lung metastasis. Trial registration ClinicalTrials.gov NCT05515783. Registered 01 May 2022. URL of registry https://classic. gov/ct2/show/NCT05515783.

7911 High Dose Serial Radioactive Iodine Therapies Facilitated byAutologous Stem Cell Cryopreservation in a Patient with Exceptionally Avid Metastatic FTC

Abstract Disclosure: S. Paknikar: None. D. Toro Tobon: None. J. Durski: None. H. Alkhateeb: None. M.M. Ryder: None. Introduction: Radioactive iodine (RAI) therapy-induced myelosuppression is a dose-limiting toxicity for RAI avid metastatic differentiated thyroid cancers. We describe a patient with exceptionally RAI avid metastatic follicular thyroid cancer (FTC) who underwent autologous stem cell cryopreservation (ASCC) to enable high dose I-131 treatments. Case: A 60-year-old woman with T1bN0M0 FTC underwent two-stage thyroidectomy and three doses of I-131 between 2002-2007 (434 mCi cumulative activity) due to incomplete biochemical response. She presented to our institution in 2015 with rising thyroglobulin (Tg) levels and lung nodules that were intensely RAI avid. She enrolled in a clinical trial of selumetinib versus placebo (for 1 month) followed by 150 mci I-131. She had a profound response with an 80% reduction in Tg and 50% tumor shrinkage. The following year her Tg rose to 8381 ng/mL and she developed biopsy proven, well differentiated metastatic FTC in the hip and liver. Lenvatinib treatment resulted in partial tumor and Tg response but was halted due to grade 3/4 toxicities. Tumor genomic interrogation revealed NRAS, PIK3CA, and TSH-R activating mutations, providing a causal explanation of her intensely RAI avid and responsive disease. Repeat I-131 therapy was facilitated by GM-CSF stimulated ASCC (8.57 x10(6) CD34+ cells/kg for two cycles) as a tool to help mitigate future potential RAI-induced myelosuppression. The patient received 295 mci I-131 followed by a 98% decrease in Tg and 20-25% shrinkage of liver metastases. Transient pancytopenia ensued but did not require autologous stem cell transplantation (ASCT). Due to insurance issues, the patient was lost to follow-up for two years. She returned with cachexia from severe, untreated thyrotoxicosis due to widespread functional, thyroxine producing metastatic disease. Anti-thyroid drug therapy (ATD) restored euthyroid status with significant clinical improvement. A non-stimulated I-123 whole body scan showed diffuse RAI avid disease with 88% whole body radioiodine retention at 48h. She received 125 mci I-131 with initial tumor response but with progression of bone marrow, calvaria, and retinal metastases. Six months later, a final dose of 253 mCi I-131 (cumulative activity 1,370 mCi) resulted in mixed tumor responses. Unfortunately, resection of a RAI refractory calvaria lesion postoperatively resulted in serious complications. ASCT and salvage treatments could not be pursued due to her impaired functional status. The patient pursued hospice care and passed away 20 years after her diagnosis. Conclusion: We characterize a patient with NRAS, PIK3CA and TSH-R mutant metastatic, thyroxine-producing FTC whose recurrences over 20 years retained intense RAI avidity and response to I-131 therapy. In cases with potential benefit from multiple high dose RAI therapies, ASCT may be a tool to mitigate I-131-induced myelosuppression. Presentation: 6/1/2024

Use of liquid biopsy in metastatic differentiated thyroid cancer: paving the way of precision management

Use of liquid biopsy in metastatic differentiated thyroid cancer: paving the way of precision management

Observation and treatment of patients with progressive metastatic differentiated thyroid cancer after establishment of radioiodine refractoriness

Differentiated thyroid cancer is one of the most common malignant diseases of the endocrine system. Usually, it responds well to the standard treatment (surgery + radioiodine therapy), especially at early stages. During both treatment and dynamic observation, distant metastases are detected in 10–15 % of patients. In these cases, the patients continue treatment with radioactive iodine. If tumor cells have insufficient ability to capture and retain 131I or completely lose this ability, the effect of radioiodine therapy becomes limited and the disease progresses during therapy which leads to 5–10 % decrease in 10-year survival. The main problem in treatment of differentiated thyroid cancer is communication between radiologists in centers performing radioiodine therapy and clinical oncologists performing surgeries and observation at patient’s place of residence. For both specialists, the main goal is to identify clinical situations where early and effective treatment intervention can be beneficial without the risk of overdiagnosis and excessive treatment.The article considers common questions arising during multidisciplinary interactions with radiologists of radioiodine centers and presents concise guidelines on the observation and treatment procedures for patients with differentiated thyroid cancer.

Challenges in treating radioiodine-refractory thyroid cancer: a global perspective with a focus on developing nations in Latin America.

This article aims to comprehensively analyze the unique challenges in managing patients with metastatic Differentiated Thyroid Cancer (DTC) that develop radioiodine-refractory disease, especially in developing countries in Latin America. We discuss key contentious aspects of their treatment, such as the optimal timing for initiating systemic therapy, the choice of first-line medications, the appropriate timing for requesting molecular interrogation, and the challenges associated with accessing these drugs and molecular panels. To illustrate these challenges and enhance understanding, we present five real clinical cases from the authors' experiences. Patients with Differentiated Thyroid Cancer (DTC) generally have an excellent prognosis, with an overall 10-year survival rate exceeding 97%. However, approximately 5% of DTC patients, especially those with distant metastases, may develop radioiodine-refractory disease, reducing survival rates. Access to medications remains difficult and time-consuming, particularly for patients within the public healthcare system. Urgent discussions on drug pricing involving all stakeholders are imperative. To break free from complacency, stakeholders must prioritize patient well-being by advocating for evidence-based drug pricing, increased participation in clinical trials, and streamlined regulatory processes. Beyond the recognized need for prospective randomized clinical trials to determine the optimal first-line drug and the timing of molecular testing, this type of manuscript plays a pivotal role in stimulating discussions and disseminating comprehensive knowledge about the challenges associated with treating and monitoring patients with radioiodine-refractory thyroid carcinoma, especially in developing countries.

Comparative Uptake Patterns of Radioactive Iodine and [18F]-Fluorodeoxyglucose (FDG) in Metastatic Differentiated Thyroid Cancers.

Background: Metastatic differentiated thyroid cancer (DTC) represents a molecularly heterogeneous group of cancers with varying radioactive iodine (RAI) and [18F]-fluorodeoxyglucose (FDG) uptake patterns potentially correlated with the degree of de-differentiation through the so-called "flip-flop" phenomenon. However, it is unknown if RAI and FDG uptake patterns correlate with molecular status or metastatic site. Materials and Methods: A retrospective analysis of metastatic DTC patients (n = 46) with radioactive 131-iodine whole body scan (WBS) and FDG-PET imaging between 2008 and 2022 was performed. The inclusion criteria included accessible FDG-PET and WBS studies within 1 year of each other. Studies were interpreted by two blinded radiologists for iodine or FDG uptake in extrathyroidal sites including lungs, lymph nodes, and bone. Cases were stratified by BRAF V600E mutation status, histology, and a combination of tumor genotype and histology. The data were analyzed by McNemar's Chi-square test. Results: Lung metastasis FDG uptake was significantly more common than iodine uptake (WBS: 52%, FDG: 84%, p = 0.04), but no significant differences were found for lymph or bone metastases. Lung metastasis FDG uptake was significantly more prevalent in the papillary pattern sub-cohort (WBS: 37%, FDG: 89%, p = 0.02) than the follicular pattern sub-cohort (WBS: 75%, FDG: 75%, p = 1.00). Similarly, BRAF V600E+ tumors with lung metastases also demonstrated a preponderance of FDG uptake (WBS: 29%, FDG: 93%, p = 0.02) than BRAF V600E- tumors (WBS: 83%, FDG: 83%, p = 1.00) with lung metastases. Papillary histology featured higher FDG uptake in lung metastasis (WBS: 39%, FDG: 89%, p = 0.03) compared with follicular histology (WBS: 69%, FDG: 77%, p = 1.00). Patients with papillary pattern disease, BRAF V600E+ mutation, or papillary histology had reduced agreement between both modalities in uptake at all metastatic sites compared with those with follicular pattern disease, BRAF V600E- mutation, or follicular histology. Low agreement in lymph node uptake was observed in all patients irrespective of molecular status or histology. Conclusions: The pattern of FDG-PET and radioiodine uptake is dependent on molecular status and metastatic site, with those with papillary histology or BRAF V600E+ mutation featuring increased FDG uptake in distant metastasis. Further study with an expanded cohort may identify which patients may benefit from specific imaging modalities to recognize and surveil metastases.

Characterization of Immune Infiltrate Along the Leading Edge of Differentiated Thyroid Cancer.

Background: Although the impact of tumor-immune infiltrate has been reported on differentiated thyroid cancer (DTC) behavior, the expression of immune checkpoints [programmed cell death protein 1 (PD-1) and its ligand (PD-L1)] alone has not been able to predict response to immunotherapies. We aimed to identify tumor-infiltrating immune cells and checkpoints associated with DTC. Methods: We performed multiplex immunofluorescence on deparaffinized thyroid tissue collected at thyroidectomy from 17 adults with DTC to characterize the tumor immune microenvironment for leukocytes (CD45+), T cells (CD3+), T regulatory cells (Tregs) (CD3+FOXP3+), CD4+ T cells (CD3+CD4+), CD8+ T cells (CD3+CD8+), macrophages (CD68+), M2 macrophages (CD68+CD163+), M1 Macrophages (CD68+ inducible nitric oxide synthase [iNOS]+), and immune checkpoints PD-1 and PD-L1. We compared the mean percentage expression of immune markers between tumor and adjacent thyroid tissue from the same patient by paired t-test and performed spatial analysis along the tumor's leading edge. Results: Immune checkpoints PD-1 and PD-L1 showed a significant increase in expression intratumorally as compared to adjacent thyroid tissue (p < 0.05). A higher trend for M2 macrophages was observed intratumorally compared to adjacent tissue. Along the leading edge, PD-L1 expression correlated negatively with CD45 and positively with CD163 intratumorally. On exploratory analysis, there was a nonsignificant trend for higher FOXP3 but less CD8 and iNOS expression in tumor from DTC with (n = 3) versus without distant metastases (n = 14). There was a nonsignificant trend for higher CD58 and iNOS expression in DTC with (n = 7) than without thyroiditis (n = 10). Conclusions: Higher tumoral PD-1 and PD-L1 expression indicate their role in DTC occurrence. A trend for more Tregs and M2 macrophages but less M1 macrophages intratumorally in patients with distant metastatic DTC, suggests their potential role as prognostic biomarkers. Future studies with larger sample sizes are needed to compare various clinicopathologic severities to harness tumor microenvironment for cancer prognostication and therapy.

Vandetanib in locally advanced or metastatic differentiated thyroid cancer refractory to radioiodine therapy.

The VERIFY study aimed to determine the efficacy of vandetanib in patients with differentiated thyroid cancer (DTC) that is either locally advanced or metastatic and refractory to radioiodine (RAI) therapy. Specifically, VERIFY is a randomized, double-blind, multicenter phase III trial aimed to determine the efficacy and safety of vandetanib in tyrosine kinase inhibitor-naive patients with locally advanced or metastatic RAI-refractory DTC with documented progression (NCT01876784). Patients were randomized 1:1 to vandetanib or placebo. The primary endpoint was progression-free survival (PFS). Secondary endpoints included best objective response rate, overall survival (OS), safety, and tolerability. Patients continued to receive randomized treatment until disease progression or for as long as they were receiving clinical benefit unless criteria for treatment discontinuation were met. Following randomization, 117 patients received vandetanib, and 118 patients received a placebo. Median PFS was 10.0 months in the vandetanib group and 5.7 months in the placebo group (hazard ratio: 0.75; 95% CI: 0.55-1.03; P = 0.080). OS was not significantly different between treatment arms. Common Terminology Criteria for Adverse Events (CTCAE) of grade ≥3 were reported in 55.6% of patients in the vandetanib arm and 25.4% in the placebo arm. Thirty-three deaths (28.2%; one related to study treatment) occurred in the vandetanib arm compared with 16 deaths (13.6%; two related to treatment) in the placebo arm. No statistically significant improvement was observed in PFS in treatment versus placebo in patients with locally advanced or metastatic, RAI-refractory DTC. Moreover, active treatment was associated with more adverse events and more deaths than placebo, though the difference in OS was not statistically significant.

Projecting long-term clinical outcomes with larotrectinib compared with immune checkpoint inhibitors in metastatic nonsmall cell lung cancer and differentiated thyroid cancer.

Larotrectinib is approved for patients with advanced NTRK gene fusion-positive solid tumors. Prior studies demonstrated promising results with larotrectinib compared with other systemic therapy. However, comparisons to checkpoint inhibitors, such as nivolumab or pembrolizumab, have not been done. To estimate and compare expected life-years (LYs) and quality-adjusted LYs (QALYs) for patients with nonsmall cell lung cancer (NSCLC) eligible for larotrectinib vs patients with unknown NTRK gene fusion status on nivolumab or pembrolizumab. We also assessed patients with metastatic differentiated thyroid cancer (DTC), as pembrolizumab may be considered in certain circumstances. We developed partitioned survival models to project long-term comparative effectiveness of larotrectinib vs nivolumab or pembrolizumab. Larotrectinib survival data were derived from an updated July 2021 analysis of 21 adult patients (≥18 years of age) with metastatic NTRK gene fusion-positive NSCLC and 21 with DTC. Survival inputs for nivolumab and pembrolizumab were obtained from published articles. Progression-free and overall survival were estimated using survival distributions (Exponential, Weibull, Log-logistic, and Log-normal). Exponential fits were chosen based on goodness-of-fit and clinical plausibility. In NSCLC, larotrectinib resulted in gains of 5.87 and 5.91 LYs compared to nivolumab and pembrolizumab, respectively, which translated to gains of 3.53 and 3.56 QALYs. In DTC, larotrectinib resulted in a gain of 5.23 LYs and 4.24 QALYs compared to pembrolizumab. In metastatic NSCLC and DTC, larotrectinib may produce substantial life expectancy and QALY gains compared to immune checkpoint inhibitors. Additional data with longer follow-up will further inform this comparison.

Impact of molecular therapy on radioactive iodine uptake in patients with oncogene-driven metastatic differentiated thyroid cancer.

TPS10078 Background: Targetable kinase fusions and mutations are common in pediatric and young adult patients with papillary thyroid cancer (TC) and are associated with metastatic disease and lack of response to radioactive iodine therapy (RAI). While survival outcomes are excellent, less than 20% of children with metastatic TC achieve a complete response to standard treatment with surgery and radioactive iodine (RAI). Thus, repeated RAI therapy is common, increasing the risk of pulmonary fibrosis and secondary malignancies. Targeted kinase inhibitors are highly effective at shrinking oncogene-driven TC. Preliminary data suggest that these targeted therapies can improve tumor differentiation and RAI sensitivity. However, optimal integration of targeted therapy with standard of care RAI for TC remains uncertain. The objective of this study is to evaluate if targeted inhibitors in patients with metastatic, oncogene-driven differentiated TC will improve or restore tumor RAI uptake and ultimately induce durable clinical responses in patients with metastatic differentiated TC. Methods: Patients with TC lung metastases, both RAI naïve and refractory, with an identified targetable molecular driver (Table) and intent to start oncogene-specific targeted therapy are eligible for this study. Patients who received a prior oncogene-specific targeted therapy are excluded. A RAI-whole body scan (WBS) is performed at baseline and after 4 weeks of targeted therapy. Patients will be followed for up to 5 years to monitor clinical response. Response parameters include structural (CT, WBS, and/or neck US) and biochemical (thyroglobulin, thyroglobulin antibodies) evaluation. The primary endpoint is the change in RAI avidity between baseline and 4 weeks of treatment. This will be calculated as the ratio of RAI uptake in the lungs/disease sites versus the whole body for each subject at each time point. Secondary endpoints include progression free survival and the proportion of patients who achieve a complete response to the combination of targeted therapy and RAI. Five of 32 patients have been enrolled. Clinical trial information: NCT05024929 . [Table: see text]

The relationship between differentially expressed thyroid cancer genes and clinical characteristics in metastatic children and adolescents

Objective: To investigate the relationship between genes and clinical characteristics in children and adolescents with metastatic differentiated thyroid cancer (caDTC). Methods: A cross sectional study. A total of 67 caDTC patients with lymph node metastasis or distant metastasis in Peking Union Medical College Hospital from December 2020 to December 2022 were included, according to the inclusion and exclusion criteria. Then the differences in clinicopathologic features and iodine intake were compared among different genomes, and the age subgroups divided by the age of 12 were further analyzed. Results: Among the 67 cases of caDTC, the diagnosed age [M(Q1, Q3)]was 13.2 (9.7, 16.9) years old, with 23 males and 44 females. There were 68.7% (46/67) of patients have distant metastasis (M1 stage). Pathogenic or potentially pathogenic gene variants were detected in 68.7% (46/67) of the patients, with RET or NTRK fusion (RET/NTRK) being the most common [43.3%(29/67)], BRAF V600E mutation followed [19.4%(13/67)].There was only 1 caDTC with NRAS Q61R mutation. The patients were divided into RET/NTRK fusion group (n=29), BRAF mutation group (n=12), other mutation group (n=4), and non-mutation group (n=21) (1 patient was not included in the gene mutation subgroup comparison due to the presence of NRAS Q61R mutation and BRAF V600E mutation). The comparison of gene feature groups showed that compared to the BRAF mutation group, caDTC with RET/NTRK fusion tended to have a lower age at diagnosis [12.6(9.3, 15.9) vs 17.2(15.5, 18.1) years old, P<0.001], the proportion of mutation load≥2 was higher (10.4% vs 8.3%, P=0.027), with statistically significant difference. Among 46 M1 stage patients, 71.7% (33/46) had initial iodine intake, and 30.4% (14/46) developed radioiodine-refractory (RAIR). In age group comparison, the<12 year old group had a higher proportion of male patients (51.9% vs 22.5%, P=0.013) and a lower incidence of BRAF V600E mutations (0 vs 32.5%, P<0.001) compared to the≥12 year old group, and the differences were statistically significant. Conclusions: The incidence of RET/NTRK fusion ranks first in metastatic caDTC, featured with younger age at diagnosis and higher rate of distant metastasis. Although most metastatic lesions initially consume iodine, they are prone to RAIR. Attention should be paid to the potential role of RET/NTRK fusion in the invasion and iodine resistance of young caDTC patients.

Optimizing the indication of initial radioiodine oncolytic treatment for metastatic differentiated thyroid cancer by diagnostic 131I scan

As a classic theranostic radiopharmaceutical, radioiodine (131I) has been utilized in the management of differentiated thyroid cancer (DTC) for more than 8 decades, and the refinement of its clinical practice has been raised recently. This study was conducted to evaluate the efficiency of a diagnostic (Dx) 131I scan in optimizing the indication of initial radioiodine oncolytic treatment (ROT) for metastatic DTC by predicting therapeutic outcomes. A total of 100 patients (Dx positive, n=29; Dx negative, n=71) were eligible for patient-based analysis. The matching rate was 83.0% between the Dx and the post-therapeutic scans (kappa=0.648, P<0.001). The biochemical remission rate and structural shrinkage rate induced by the initial ROT in the Dx-positive group were, respectively, greater than those in the Dx-negative group (83.3% vs. 17.4%, P<0.001; 37.9% vs. 4.2%, P<0.001). Notably, the predictive values of positive Dx scans for ROT responsiveness and negative Dx scans for ROT nonresponsiveness reached up to 89.7% and 84.5%, respectively. This Dx scan approach seems viable in characterizing the 131I-avidity of metastatic DTC and plays a pivotal role in optimizing the indication of initial ROT for metastatic DTC.

Tyrosine kinase inhibitors for radioiodine refractory differentiated thyroid cancer: A systematic review and meta-analysis.

The poor overall prognosis of radioiodine refractory thyroid cancer is an inevitable challenge in managing this disease. A series of trials have demonstrated the antitumor activity of tyrosine kinase inhibitors (TKIs)in radioiodine refractory differentiated thyroid cancer (RAIR-DTC).However, the available evidence cannot determine the optimal choice of TKI in RAIR-DTC. This study searched PubMed, EMBASE, Cochrane databases, and the ClinicalTrials website. The Cochrane bias risk tool was used to assess the risk of bias, and to evaluate randomized clinical trials (RCT)of RAIR-DTCpatients treated with the TKI system. Outcomes, including progression-free survival (PFS),overall survival (OS),and adverse events (AEs)were reported. Seven studies involving 1310 patients with RAIR-DTCwas conducted to compare the PFS and OS of various TKImonotherapies with placebo. The results showed that all TKI monotherapies had a statistically significant benefit in terms of PFS compared with placebo, with lenvatinib demonstrating the greatest benefit (hazard ratio [HR]0.19, 95% credible interval [CrI] 0.14-0.25). In terms of OS, only apatinib (HR 0.42, 95% CrI 0.18-0.97) and anlotinib (HR0.36, 95% CrI 0.18-0.73) showed statistically significant benefits compared with placebo. TKIs also had a higher incidence of AEs of grade 3 or higher compared with placebo. The findings suggest that lenvatinib may be the preferred TKI for the treatment of RAIR-DTC,although its high incidence of AEs should be considered. The results also indicate that TKI treatment may be similarly effective in RAIR-DTCpatients with BRAF or RAS mutations and in those with papillary or follicular subtypes of the disease, regardless of prior TKI treatment. The results of this meta-analysis suggest that targeted therapy with TKIs may be beneficial for patients with radioiodine-refractory advanced or metastatic differentiated thyroid cancer. Among the TKIs analyzed, lenvatinib appeared to be the most effective at improving PFS, although it also had the highest incidence of AEs. Further research through direct randomized controlled trials is needed to determine the optimal choice of TKI for treating patients with RAIR-DTC.This study is beneficial for formulating patients' treatment plans and guides clinicians' decision-making.

Optimal Cumulative I-131 Activity in Metastatic Differentiated Thyroid Cancer: Balancing Efficacy and Adverse Events.

The optimal cumulative activity (CA) of I-131 therapy for patients with metastatic differentiated thyroid cancer (mDTC) remains contentious. This study aimed to determine the maximum CA of I-131 that could be administered without a significant increase in adverse events (AEs) by analyzing a long-term cohort of patients. Data from mDTC patients treated with I-131 therapy and followed for at least two years from 1967 to 2019 were reviewed. Patients were categorized into three groups based on the received CA: Group-A (≤600mCi), Group-B (>600-1000mCi), and Group-C (>1000mCi). The study assessed long-term AEs and survival outcomes. The study included 671 adult mDTC patients (mean age 48 years, range: 19-81) with a median follow-up of 122 months (IQR: 82-180). Group A, Group B, and Group C comprised 269 (40.0%), 212 (31.6%), and 190 (28.4%) patients, respectively. Ten-year survival rates were 72%, 42.7%, and 29% in Groups A, B, and C, respectively. A total of 40/671 (6%) AEs were observed in 38 patients: 3 (1.1%), 12 (5.7%), and 25 (13.2%) in Groups A, B, and C, respectively. Five patients developed second primary malignancy (SPM): 3 in Group A and one each in Group B and C. However, CA >1000mCi of I-131 was associated with significant increase in bone marrow suppression, decreased pulmonary function, and xerostomia (p < 0.001). The study suggests that a maximum CA of up to 1000mCi strikes a favorable balance between keeping AEs low and benefiting a subset of patients with extensive metastases showing intense I-131 concentration.

Risk stratification for radioactive iodine refractoriness using molecular alterations in distant metastatic differentiated thyroid cancer

Risk stratification for radioactive iodine refractoriness using molecular alterations in distant metastatic differentiated thyroid cancer

Clinical and molecular characterisation of metastatic papillary thyroid cancer according to radioiodine therapy outcomes.

Radioiodine (RAI) therapy remains the gold-standard approach for distant metastatic differentiated thyroid cancer (TC). The main objective of our work was to identify the clinical and molecular markers that may help to predict RAI avidity and RAI therapy response of metastatic lesions in a cohort of papillary thyroid cancer (PTC) patients. We performed a retrospective analysis of 122 PTC patients submitted to RAI therapy due to distant metastatic disease. We also analysed, through next-generation sequencing, a custom panel of 78 genes and rearrangements, in a smaller cohort of 31 metastatic PTC, with complete follow-up, available RAI therapy data, and existing tumour sample at our centre. The most frequent outcome after RAI therapy was progression of disease in 59.0% of cases (n = 71), with median estimate progression-free survival of 30 months. RAI avidity was associated with PTC subtype, age and stimulated thyroglobulin at first RAI therapy for metastatic disease. The most frequently altered genes in the cohort of 31 PTC patients' primary tumours were RAS isoforms (54.8%) and TERT promoter (TERTp) (51.6%). The presence of BRAF p.V600E or RET/PTC alterations was associated with lower avidity (p = 0.012). TERTp mutations were not associated with avidity (p = 1.000) but portended a tendency for a higher rate of progression (p = 0.063); similar results were obtained when RAS and TERTp mutations coexisted (p = 1.000 and p = 0.073, respectively). Early identification of molecular markers in primary tumours may help to predict RAI therapy avidity, the response of metastatic lesions and to select the patients that may benefit the most from other systemic therapies.

Role of albumin Cys34 redox state in the progression of differentiated thyroid carcinoma and induction of ferroptosis

Differentiated thyroid cancer (DTC) is the most prevalent endocrine malignancy worldwide and requires effective prognostic markers and therapeutic targets to optimize patient outcomes. This study investigated the potential of human serum albumin (HSA) cysteine-34 (Cys34) redox state as a prognostic indicator and therapeutic avenue for DTC. A retrospective cohort study of 99 patients with DTC undergoing radioactive iodine therapy found that higher concentrations of HSA with the reduced form of Cys34 (i.e., human mercaptalbumin [HMA]) were associated with improved progression-free survival in metastatic DTC. In vitro experiments using a DTC cell line revealed that HMA induced cytotoxic effects by triggering ferroptosis, characterized by lipid peroxidation, intracellular ROS accumulation, and decreased cell viability. Ferroptosis inhibitors rescued cell viability, confirming their role in cytotoxicity. These results implicate the HSA-Cys34 redox state is a promising avenue for precision medicine in DTC, shedding light on the prognostic relevance and therapeutic potential of HMA-induced ferroptosis. They emphasize the opportunity for personalized treatment strategies to advance the management of patients with DTC.

Predictive risk factors for distant metastasis in pediatric differentiated thyroid cancer from Saudi Arabia.

Despite their excellent prognosis, children and young adults (CAYA) with differentiated thyroid cancer (DTC) tend to have more frequent occurrence of distant metastasis (DM) compared to adult DTC. Data about DM in CAYA from Middle Eastern ethnicity is limited. Medical records of 170 patients with DTC ≤18 years were retrospectively reviewed. Clinico-pathological factors associated with lung metastasis in CAYA, their clinical presentation and outcome were analyzed. Rick factors related to distant metastasis-free survival (DMFS) for the whole cohort were evaluated. DM was observed in 27 patients and all were lung metastasis. Lung metastasis was significantly associated with younger age (≤15 years), extrathyroidal extension (ETE), multifocal tumors, bilaterality, presence of lymph node (LN) disease and high post-operative stimulated thyroglobulin (sTg). Highest negative predictive values were seen with low post-operative sTg (97.9%), absence of LN disease (93.8%), absence of ETE (92.2%) and age older than 15 years (92.9%). Post-therapy whole body scan (WBS) identified most of the lung metastasis (21 of 27; 77.8%). Upon evaluating patients response according to ATA guidelines, excellent response was seen in only one patient, while biochemical persistence and structural persistence were seen in 11.1% (3/27) and 77.8% (21/27), respectively. Elevated post-operative sTg (>10ng/ml) was the only risk factor found to be significantly associated with both biochemical persistence (with or without structural persistence (p = 0.0143)) and structural persistence (p = 0.0433). Cox regression analysis identified age and post-operative sTg as independent risk factors related to DMFS. Based on these two risk factors for DMFS, patients were divided into 3 groups: low risk (no risk factors), intermediate risk (1 risk factor) and high risk (both risk factors). 20-year DMFS rates in the low-, intermediate- and high-risk groups were 100.0%, 81.3% and 23.7% respectively (p < 0.0001). Higher suspicion for metastatic pediatric DTC should be considered in patients who are young, have LN disease, extrathyroidal extension and elevated post-operative sTg. Persistent disease, despite therapy, is very common and it appears to be related to post-operative sTg level. Hence, risk adaptive management is desirable in CAYA with DTC.