Metastatic Differentiated Thyroid Cancer Research Articles

Active surveillance of nodal metastasis in differentiated thyroid carcinoma: a systematic review and meta-analysis.

Cervical lymph nodes (LN) represent the most common site of recurrence in differentiated thyroid cancer (DTC), frequently requiring repeated interventions that contribute to increase morbidity to a usually indolent disease. Data on active surveillance (AS) of nodal metastasis are limited. Therefore, we performed a systematic review and meta-analysis to evaluate AS in nodal metastasis of DTC patients. MEDLINE, EMBASE, and Cochrane databases were searched up to July 2023 for studies including DTC patients with metastatic LN who were followed up with AS. The primary outcome was disease progression, according to the study's definition. Additional outcomes were LN enlargement ≥3 mm, occurrence of new cervical metastasis, and conversion from AS to surgical treatment. The search identified 375 studies and seven were included, comprising 486 patients with metastatic nodal DTC. Most were female (69.5%) and had papillary thyroid cancer (99.8%). The mean AS follow-up ranged from 28-86 months. Following each study's definition of progression, the pooled incidence was 28% [95% confidence interval (CI), 20-37%]. The pooled incidence of LN growth ≥ 3 mm was 21% [95% CI, 17-25%] and the emergence of new LN sites was 19% [95% CI, 14-25%]. Combining growth of 3 mm and the emergence of new LN criteria, we found an incidence of 26% [95% CI, 20-33%]. The incidence of neck dissection during AS was 18% [95% CI, 12-26%]. AS seems to be a suitable strategy for selected DTC patients with small nodal disease, avoiding or postponing surgical reintervention. CRD42023438293.

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.

SAT520 Efficacy of Radioactive Iodine Redifferentiation Therapy in Previously Iodine Refractory Differentiated Thyroid Cancers

Abstract Disclosure: D. Toro-Tobon: None. J.C. Morris: None. C. Hilger: None. C.S. Peskey: None. D.M. Jolanta: None. M.M. Ryder: None. Objective: Patients with metastatic differentiated thyroid cancer (DTC) that are radioactive iodine (RAI) refractory (RAIR) have a poor prognosis. Redifferentiation therapy (RDT) has emerged as a potential approach to restore RAI avidity in this disease. The aim of this study was to examine the efficacy and predictors of RAI restoration in RAIR disease, as well as examine the outcomes of patients re-treated with high dose RAI following RDT. Methods: A retrospective review was conducted of 33 patients with RECIST-progressive metastatic RAIR-DTC who underwent RDT between 2017 and 2022 at the Mayo Clinic. All patients underwent genomic profiling, and either MEK inhibitor alone or combination BRAF-MEK inhibitors were prescribed for 4 weeks. At week 3, Thyrogen-stimulated I-123 whole body scans were performed. Those with increased RAI avidity in metastatic foci received high dose I-131 therapy using a previously published modified dosimetry protocol. Baseline and clinicopathologic outcomes were comprehensively reviewed. Results: Of the 33 patients, 12 of 23 (52%) with papillary thyroid cancers (PTC), 4 of 4 (100%) with follicular variant PTCs (FV-PTC), and 7 of 7 (100%) with follicular thyroid cancers (FTC) had restored RAI avidity following RDT using dabrafenib/trametinib (7 for BRAF mutant disease) or trametinib monotherapy (12 for RAS mutant disease). All 11 (100%) RAS mutant tumors (2 PTC, 3 FV-PTC, and 6 FTC) had RAI avidity restoration compared to 7 (36%) with BRAF mutant disease (6 PTC, and 1 FV-PTC). Of the 19 patients (57%) with restored RAI avidity (responders), 18 (94%) received I-131 with a median dose of 294 mCi. The median thyroglobulin (Tg) in responders was 294 mIU/L as compared to 29 mIU/L in non-responders. Following RDT-facilitated I-131 treatment, 94.7% achieved RECIST defined objective response (complete or partial response, stable disease, non-complete response/non-progressive disease) with a median progression free survival of 18 months and an overall survival of 30 months. Overall, patients with FTC (p=0.01), RAS mutation (p&amp;lt;0.001), Tg of 294 mIU/L or more (p=0.03), largest tumor diameter of 1.7 cm or less (p=0.05), bone metastasis (p=0.007), and without locoregional nodal disease (p=0.04), were more likely to demonstrate restored RAI avidity following RDT. Of the entire cohort, 2 (6%) patients experienced histologic transformation to anaplastic thyroid cancer and 5 (15%) patients died, all had had RAI restoration and received high-dose RAI following RDT. Conclusion: RDT has the potential to restore RAI avidity and induce RECIST responses following I-131 therapy in select patients with RAIR-DTC, particularly those with RAS mutations and ‘follicular’ phenotypes. Further studies are needed to better characterize the long-term survival and/or safety outcomes of high-dose RAI following RDT, particularly whether it could be associated with histologic transformation. Presentation Date: Saturday, June 17, 2023

SAT518 Real World Use of Systemic Therapy for Treatment of Advanced Thyroid Cancer

Abstract Disclosure: D. Chen: None. M. Banerjee: None. T. Xu: None. F.P. Worden: None. M.R. Haymart: None. Background. Since 2011, the United States Food and Drug Administration (FDA) has approved eight small-molecule kinase inhibitors (SMKIs) for the treatment of advanced thyroid cancer (i.e., radioiodine-refractory metastatic differentiated thyroid cancer, metastatic medullary thyroid cancer, and anaplastic thyroid cancer). The National Comprehensive Cancer Network (NCCN) clinical practice guidelines recommend use of 15 SMKIs, of which eight are FDA-approved and seven are commercially available, for the treatment of advanced thyroid cancer. However, little is known about how these medications are used in the real-world setting for treatment of patients with advanced thyroid cancer. Methods. This descriptive study used data from Optum Clinformatics Data Mart, a de-identified commercial claims database of a large national health insurance provider. We identified patients with thyroid cancer who had prescription claims for at least one of the 15 SMKIs of interest (axitinib, cabozantinib, dabrafenib, entrectinib, everolimus, larotrectinib, lenvatinib, pazopanib, pralsetinib, selpercatinib, sorafenib, sunitinib, trametinib, vandetanib, and vemurafenib). Lines of therapy were defined by the date of SMKI claims. We describe changes in usage patterns over time with a focus on the demographics of patients who were newly initiated on treatment of advanced thyroid cancer, and on the medications used for each line of therapy. Results. Between 2013-2021, 886 patients were treated for advanced thyroid cancer with at least one of the 15 SMKIs of interest. Median age was 65.1 years. Most patients were female (54.6%), non-Hispanic White (62.1%), and had supplementary Medicare insurance (60.6%). Between 2013 and 2016, there was an increase in the proportion of Hispanic patients and a corresponding decrease in the proportion of non-Hispanic White patients treated for advanced thyroid cancer. Although most patients were initiated on an FDA-approved SMKI as first line therapy, 23.1% (N=205) were initiated on a commercially available SMKI. Sorafenib was the most prescribed first-line therapy in 2013 (24.4%) and 2014 (48.3%). Lenvatinib was the most prescribed first-line therapy between 2015-2021 when prescriptions for lenvatinib constituted 38.3-55.6% of all SMKIs prescribed for the treatment of advanced thyroid cancer. Between 2017-2021, a minority of patients were treated with up to a fifth line of therapy although the majority (81.8%) were treated with only a first line agent. Conclusions. Since 2015 when lenvatinib was approved by the FDA for treatment of advanced differentiated thyroid cancer, it has become the most commonly prescribed SMKI for treatment of advanced thyroid cancer. However, variation exists in which SMKIs are used to treat patients with advanced thyroid cancer, with almost one-quarter of patients initiated on commercially available SMKIs. Presentation Date: Saturday, June 17, 2023

The role of 18 F-FDG-PET/CT in the management of differentiated thyroid cancer.

In previous literature, 18 F-FDG-PET/ CT imaging significantly impacted differentiated thyroid cancer (DTC) therapy. Low thyroglobulin (Tg) levels and negative Iodine-131 (131I) whole-body scan (WBS), along with negative 18 F-FDG-PET/ CT, suggested a lesser likelihood of active illness. Positive 18 F-FDG-PET/CT findings, however, were associated with a variety of signs of local recurrence and regional or distant metastases in patients with suspected WBS. We aim to evaluate the utility of 18 F-FDG-PET/CT in managing DTC patients with negative 131I post-therapy WBS and elevated Tg. We retrospectively reviewed 55 patients with DTC (76% papillary and 24% follicular). Patients underwent total thyroidectomy or several radioactive iodine (RAI) treatments or both. WBS was performed 5-7 days after RAI treatment. Inclusion criteria were elevated serum Tg, negative anti-Tg auto-antibodies (AbTg) during long-term follow-up, presence of 18F-FDG-PET/CT images, and negative or suspicious WBS. 54% of 18 F-FDG-PET/CTs detected at least one lesion, mainly, cervical lymph nodes (49.9%), mediastinal lymph nodes (40.4%), local recurrence (34%), and bone or tissue metastasis (36.2%). The three major sites of metastasis were lung, bone, and liver. 18 F-FDG-PET/CT identified recurrence or metastasis in 45% of patients with high serum Tg and negative WBS, modifying therapeutic management in half the patients for suitable treatment modality (surgery vs. tyrosine kinase inhibitor). The findings redemonstrate that elevated Tg with negative or suspicious WBS necessitates 18 F-FDG-PET/CT for localization of recurrence. 18 F-FDG-PET/CT is useful in managing locally recurrent or metastatic DTC with high Tg levels. It influences treatment and accurately assesses disease severity.

Tumor Microenvironment Features as Predictive Biomarkers in Metastatic Differentiated Thyroid Cancer and Their Relationship With 18F-Fluorodeoxyglucose Positron Emission Tomography/Computed Tomography (18F-FDG PET/CT) Metabolic Parameters.

The role of the tumor microenvironment in tumor progression and treatment response is being investigated for different types of cancer. This study aimed to determine the relationships between tumor microenvironment, histopathology, 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT)-based metabolic parameters, treatment response, and overall survival (OS) in metastatic differentiated thyroid cancer (DTC). Methods: Metastatic DTC patients who underwent 18F-FDG PET/CT between 2015-2019 were evaluated. Clinicopathological, histopathological features and PET/CT parameters of patients were recorded. Microenvironmental characteristics of the primary tumor, such as mitosis, intratumoral and peritumoral lymphocytosis, intratumoral and peritumoral fibrosis, were evaluated from the tissue samples. The relationships between these factors were statistically analyzed. Sixty-five patients (38 females, 27 males, age: 49±15 years) were included. Mitosis, intra/peritumoral lymphocytosis, and intra/peritumoral fibrosis were frequent; however, none of them had a statistically significant association with PET-positive metastases, treatment response, or OS. Univariate analysis showed that gender, size, thyroglobulin values, residual thyroid tissue, PET-positive metastases, and maximum standardized uptake value (SUVmax) were significant predictors of OS. At multivariate analysis, PET-positive metastases (HR=-2.65, 95%CI 0.007-0.707, p=0.024) and SUVmax (HR=-2.74, 95%CI 0.006-0.687, p=0.023) were the only independent predictors for OS. Conclusion:Our study revealed that microenvironmental characteristics of the primary tumor did not show prognostic significance in metastatic DTC. PET-positive metastases and SUVmax levels were the only significant factors that predicted overall survival in DTC. Supporting the results of our study with further studies with a larger sample size may be necessary to determine the relationship between the tumor microenvironment and prognosis in DTC.

Treatment and outcome of patients with Graves' disease and metastatic differentiated thyroid cancer.

The aim of the study was to report on the experience in a single tertiary cancer center about the treatment and outcome of patients with Graves' disease (GD) and metastatic thyroid cancer as compared with patients without GD in our country. Altogether, 28 patients (8 males, 20 females; 49-85 years of age; median 74 years) were treated because of differentiated thyroid cancer and distant metastasis at the time of diagnosis during a 10-year period (from 2010 to 2019) in the Republic of Slovenia. The subject of our retrospective study were four patients (three men, one female; 64-76 years of age, median 73 years) who had Graves' disease and metastatic thyroid cancer. The mean age of patients without GD and with GD was 74 years and 71 years, respectively (p = 0.36). There was a trend for male predominance in patients with GD (p = 0.06). There was no statistical difference in size of primary tumors, pT stage or pN stage between the group of patients without GD and with GD. The median length of follow-up was 3.33 years (range 0.04-7.83) and 5-year disease-specific survival was 51%. One of four patients with GD and 14 of 24 patients without GD died of thyroid cancer. There was no statistical difference in disease-specific survival between patients' group of without GD and with GD (p = 0.59). In our country Slovenia, 14% of patients with metastatic differentiated thyroid carcinoma at the time of diagnosis had Graves' disease. There was no difference in the treatment, outcome or survival of patients with GD in comparison to those without GD.

Molecular Theranostics in Radioiodine-Refractory Differentiated Thyroid Cancer.

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.

Fusion Oncogenes in Patients With Locally Advanced or Distant Metastatic Differentiated Thyroid Cancer.

Fusion oncogenes are involved in the underlying pathology of advanced differentiated thyroid cancer (DTC), and even the cause of radioactive iodine (RAI)-refractoriness. We aimed to investigation between fusion oncogenes and clinicopathological characteristics involving a large-scale cohort of patients with advanced DTC. We collected 278 tumor samples from patients with locally advanced (N1b or T4) or distant metastatic DTC. Targeted next-generation sequencing with a 26-gene ThyroLead panel was performed on these samples. Fusion oncogenes accounted for 29.86% of the samples (72 rearrangement during transfection (RET) fusions, 7 neurotrophic tropomyosin receptor kinase (NTRK) fusions, 4 anaplastic lymphoma kinase (ALK) fusions) and occurred more frequently in pediatric patients than in their adult counterparts (P = .003, OR 2.411, 95% CI 1.329-4.311) in our cohort. DTCs with fusion oncogenes appeared to have a more advanced American Joint Committee on Cancer (AJCC)_N and AJCC_M stage (P = .0002, OR 15.47, 95% CI 2.54-160.9, and P = .016, OR 2.35, 95% CI 1.18-4.81) than those without. DTCs with fusion oncogenes were associated with pediatric radioactive iodine (RAI) refractoriness compared with those without fusion oncogenes (P = .017, OR 4.85, 95% CI 1.29-15.19). However, in adult DTCs, those with fusion oncogenes were less likely to be associated with RAI refractoriness than those without (P = .029, OR 0.50, 95% CI 0.27-0.95), owing to a high occurrence of the TERT mutation, which was the most prominent genetic risk factor for RAI refractoriness in multivariate logistic regression analysis (P < .001, OR 7.36, 95% CI 3.14-17.27). Fusion oncogenes were more prevalent in pediatric DTCs than in their adult counterparts and were associated with pediatric RAI refractoriness, while in adult DTCs, TERT mutation was the dominant genetic contributor to RAI refractoriness rather than fusion oncogenes.

Development and validation of survival nomograms for patients with differentiated thyroid cancer with distant metastases: a SEER Program-based study.

We aimed to develop a nomogram model of overall survival (OS) and cancer-specific survival (CSS) in patients with differentiated thyroid cancer with distant metastases, and to evaluate and validate the nomogram. Also, its prognostic value was compared with that of the 8th edition of the American Joint Committee on Cancer tumor-node-metastasis staging system (AJCC8SS). Patients with distant metastatic differentiated thyroid cancer (DMDTC) from 2004 to 2015 were selected from the Surveillance, Epidemiology, and End Results (SEER) Program to extract the clinical variables used for analysis. A total of 906 patients were divided into a training set (n = 634) and validation set (n = 272). OS and CSS were selected as the primary end point and secondary end point. LASSO regression analysis and multivariate Cox regression analysis were applied to screen variables for constructing OS and CSS nomograms for survival probability at 3, 5, and 10years. Nomograms were evaluated and validated using the consistency index (C-index), time-dependent receiver operator characteristic (ROC) curves, area under the ROC curve, calibration curves, and decision curve analysis (DCA). The predictive survival of the nomogram was compared with that of AJCC8SS. Kaplan-Meier curves and log-rank tests were used to evaluate the risk-stratification ability OS and CSS nomograms. CS and CSS nomograms included six independent predictors: age, marital status, type of surgical procedure, lymphadenectomy, radiotherapy, and T stage. The C-index for the OS nomogram was 0.7474 (95% CI = 0.7199-0.775), and that for the CSS nomogram was 0.7572 (0.7281-0.7862). The nomogram showed good agreement with the "ideal" calibration curve in the training set and validation sets. DCA confirmed that the survival probability predicted by the nomogram had high clinical predictive value. The nomogram could stratify patients more accurately, and showed more robust accuracy and predictive power, than AJCC8SS. We established and validated prognostic nomograms for patients with DMDTC, which had significant clinical value compared with AJCC8SS.

The efficacy and safety of sequential use of anlotinib and 131I for locally advanced or metastatic differentiated thyroid cancer: A single-arm phase II clinical trial.

e18102 Background: Locally advanced or metastatic differentiated thyroid cancer (DTC) commonly responds poorly to radioiodine (131I) treatment alone. Tyrosine kinase inhibitors, however, have exerted promising antitumor activity in multiple advanced solid tumors. This study aimed to investigate the efficacy and safety of sequential use of anlotinib and 131I for the treatment of locally advanced or metastatic DTC. Methods: This is a single-arm phase II open-label clinical trail. The key eligibility criteria included locally advanced or metastatic 131I-avid DTC, ECOG PS of 0-1, and at least one measurable lesion. Previous tyrosine kinase inhibitor was not allowed. Patients initially received anlotinib (12 mg QD, 2 weeks on/1 week off ) for 4 cycles. At the beginning of 13th week when levothyroxine had been discontinued for 4 weeks, diagnostic 131I whole body scan (Dx-WBS) was performed, and those with 131I-avid lesions were immediately identified to undergo 131I treatment. The primary endpoint was objective response rate (ORR) . The secondary endpoints included disease control rate (DCR), biochemical response rate (BRR), time-to-response (TTR), progression-free survival (PFS), and safety. Results: From June 2021 to December 2022, a total of 16 patients with locally advanced or metastatic DTC were included. At the data cut off, 8 patients (4 males and 4 females) were withdrawn from the trial due to negative Dx-WBS, and the remaining 8 patients were subsequently treated with 131I. Six patients who had completed at least one cycle of sequential treatment were eligible for data analysis. Partial response and stable disease were found in 2 (33.33%) and 3 (50%) patients, respectively. An ORR of 33.33% [95% CI, 4.33-77.72], a DCR of 83.33% [95% CI, 35.88-99.58], a BRR of 100% [95% CI, 54.07-100.00], and a TTR of 6.34 months [95% CI, 5.85-NE] were achieved. Median PFS was not reached. Grade 3 adverse events occurred in 2 (33.33%) of the 6 subjects, including pain owing to skeletal metastasis in one patient and drug-related hypertention in the other. Conclusions: This study firstly demonstrates the favorable efficacy and safety of sequential therapy with tyrosine kinase inhibitor and 131I, suggesting anlotinib as a adjuvant option for 131I treatment of locally advanced or metastatic DTC. Randomized controlled studies on sequential therapy versus 131I treatment are warranted. Clinical trial information: ChiCTR2100045178 .

CO212 The Potential Long-Term Comparative Effectiveness of Larotrectinib Vs. Immune Checkpoint Inhibitors for Treatment of Metastatic NTRKGene Fusion-Positive Cancers

Larotrectinib is approved for patients with advanced NTRK gene fusion-positive solid tumors. Some studies have demonstrated promising results with larotrectinib compared to systemic therapy. However, a comparison to checkpoint inhibitors such as nivolumab or pembrolizumab has not been done. Our objective was to estimate and compare expected life-years (LYs) and quality-adjusted life-years (QALYs) for patients with non-small cell lung cancer (NSCLC) eligible for larotrectinib vs. patients with unknown NTRK gene fusion status on nivolumab or pembrolizumab. We also looked at patients with metastatic differentiated thyroid cancer (DTC) as pembrolizumab may be considered in certain circumstances.

The association between the interval of radioiodine treatment and treatment response, and side effects in patients with lung metastases from differentiated thyroid cancer.

Repeat radioiodine (RAI) treatment has been widely implemented for RAI-avid lung metastases and is clinically effective for lung metastatic differentiated thyroid cancer (DTC). We aim to investigate the association between the interval of RAI treatment and short-term response, and the side effects in patients with lung metastases from DTC and to identify predictors for non-effective response to the next RAI treatment. A total of 282 course pairs from 91 patients were established and categorized into two groups by the interval of neighboring RAI treatment (<12 and ≥12 months), and the characteristics and treatment response between the two groups were compared. Multivariate logistic regression was used to identify predictors associated with treatment response. The side effects in the former course and the latter course were compared while taking into account the interval. No significant difference was found between the two groups in treatment response in the latter course (p > 0.05). In the multivariate analysis, age ≥ 55 years (OR = 7.29, 95% CI = 1.66-33.35, p = 0.008), follicular thyroid cancer (OR = 5.00, 95% CI = 1.23-22.18, p = 0.027), and a second RAI treatment as the former course (OR = 4.77, 95% CI = 1.42-18.61, p = 0.016) were significantly associated with a non-effective response. There was no significant difference in the side effects in the former and latter courses between the two groups (p > 0.05). The interval of RAI treatment does not affect short-term response and side effects of DTC patients with RAI-avid lung metastases. It was feasible to defer repeat evaluation and treatment with an interval of at least 12 months to obtain an effective response and reduce the risk of side effects.

Metastatic differentiated thyroid cancer with negative serum stimulated Tg but positive post-therapeutic 131I-SPECT/CT scintigraphy: a single-center retrospective study.

This study aimed to describe the characteristics of patients with metastatic differentiated thyroid carcinoma (DTC) who had positive 131I-scintigraphy but negative stimulated thyroglobulin (sTg), and to evaluate their short-term response to radioiodine therapy (RAI). A total of 2250 consecutive postoperative DTC patients, who underwent RAI treatment from July 2019 to June 2022, were analyzed retrospectively. The target group was defined as stimulated Tg < 2 ng/mL with TgAb < 100 IU/mL but with post-therapeutic 131I-SPECT/CT metastases. The characteristics of these patients were analyzed and the metastatic profiles were compared with TgAb positive or sTg positive ones. A cross-sectional efficacy was evaluated 6-12 months after the RAI therapy and the treatment course until the end of the study was recorded. 105 (4.67%) DTC patients were post-therapeutic 131I-SPECT/CT positive and sTg negative (target group). Metastatic profiles were found significant differences between sTg negative and sTg positive ones (P < 0.001). Excellent response (ER) was achieved in 72.4% of the target group between 6-12 months of cross-sectional efficacy assessment, compared with only 12.8% in sTg positive ones (P < 0.001). The majority of the target group didn't require aggressive treatment in short-term follow-up compared with sTg positive group (P < 0.001). The percentage of DTCs with negative sTg but positive post-therapeutic 131I-SPECT/CT was relatively low, but still significant. Moreover, the majority of these patients showed an ER to RAI and may not require the next course of therapy. Long-term follow-up is still necessary to assess recurrence and adapt surveillance in these patients.