Iodine-refractory Differentiated Thyroid Cancer Research Articles

Efficacy and safety of multikinase inhibitors for patients with refractory thyroid cancer: Systematic review and network meta-analysis.

Multikinase inhibitors (MKIs) improve the treatment of refractory thyroid cancer, included radioactive iodine-refractory differentiated thyroid cancer (RAIR-DTC) and advanced medullary thyroid carcinoma (aMTC). This study aims to compare the efficacy of MKIs in improving survival outcomes and safety. Comprehensive database searches of MEDLINE via PubMed, EMBASE and Cochrane performed from inception to December 2023. Three independent authors selected these studies. Randomised-controlled trials that compared the use of a MKI to other MKIs or placebo were included. This review followed PRISMA guidelines. Risk of bias was analyzed using the Cochrane RoB 2 tool. Bayesian network meta-analysis was performed. Treatments were grouped into common nodes based on the type of MKI. Primary outcomes were progression-free survival (PFS) and overall survival (OS). Secondary outcomes included objective response rate, disease control rate, clinical benefit rate, and adverse events. Cabozantinib 60 mg/d (CAB60) was associated with the highest prolonged PFS in RAIR-DTC patients, followed by lentivatinib 18 or 24 mg/d (LEN18 or LEN24), and apatinib. PFS was also improved in in aMTC patients received CAB 140 mg/d (CAB140), CAB60, or anlotinib. A significantly greater improvement on the performance of OS was seen in CAB60, LEN24, anlotinib, and sorafenib in RAIR-DTC patients, but which in aMTC patients were lack of statistical differences. Compared with the low-dose of MKIs, high-dose of MKIs such as CAB, LEN, and vandetanib increased the incidence of adverse events. CAB60, LEN, and apatinib are promising topical MKIs with statistically significant primary outcomes in RAIR-DTC patients, while CAB and anlotinib are effective in prolonging PFS in aMTC patients.

Current Advances in Radioactive Iodine-Refractory Differentiated Thyroid Cancer.

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. 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.

Palliative treatment of generalized metastatic follicular carcinoma of thyroid after operation: A case report and literature review.

Follicular carcinoma of thyroid is a rare pathological type of thyroid carcinoma, accounting for 4.5% of the total. At present, the main treatment methods include surgery, iodine therapy, thyroid hormone inhibitors, etc. Targeted drug therapy is very important for distant metastasis and iodine-refractory differentiated thyroid cancer. This clinical case is a 51-year-old male patient with follicular carcinoma of thyroid. After 7 years of total thyroidectomy, multiple distant metastasis occurred to bilateral lungs, bones, multiple lymph nodes, etc. After multidisciplinary consultation in the department of oncology, thoracic surgery, nuclear medicine and other departments, he received targeted drug therapy of Lenvatinib. After 3 months, his condition was partially relieved, and his quality of life was significantly improved. After 11 months of treatment, the evaluated efficacy was still in remission. Late metastatic thyroid cancer is faced with dilemma of radioiodine refractory after traditional treatment. This will provide further evidence for therapeutic intervention in similar patients in the future.

Radioactive iodine refractoriness in Middle Eastern differentiated thyroid cancer: clinical outcome and risk factor analysis.

Radioactive iodine refractory differentiated thyroid cancer (RAIR-DTC) has received increasing attention due to its poor prognosis. However, outcomes may vary among patients with RAIR-DTC. The role of clinico-pathological and molecular prognostic factors in survival remains controversial, resulting in difficulty in selecting patients for new targeted therapies. We assessed mortality rate and DTC-specific survival in Middle Eastern RAIR-DTC to identify prognostic factors associated with survival. This single center, retrospective study enrolled 268 patients with RAIR-DTC. Mortality rate and DTC-specific survival were analyzed to identify prognostic factors related to survival. Univariate and multivariate analysis were performed using Cox proportional hazards model. Of the 268 cases of RAIR-DTC, 40.3% (108/268) had absent 131I uptake (either on diagnostic or post-therapy whole body scan), 15.3% (41/268) had progressive disease (PD) despite 131I, 7.5% (20/268) had persistent disease despite cumulative activity of I131 of >600 mCi and 36.9% (n=99/268) developed distant metastasis. On multivariate analysis, age (more than 45 years), presence of metastatic disease and tumors harboring telomerase reverse transcriptase (TERT) promoter mutations were independent prognostic factors for poor DTC-specific survival. Subjects were divided into 3 groups according to the number of risk factors; low risk (no risk factors); intermediate (≤ 2 risk factors); and high risk (all the 3 risk factors). Ten-year DTC-specific survival rates in low, intermediate and high-risk groups were 100.0%, 92.9% and 53.6%, respectively. The contribution of age greater than 45 years to RAIR-DTC mortality is impactful. Older age, presence of distant metastasis and TERT mutations could be used as early predictors of RAIR-DTC cases. The identification of prognostic factors for poor survival in RAIR-DTC may improve the selection of patients for more personalized surveillance and therapeutic modalities.

A Prospective Cohort Study Exploring the Effect of Lenvatinib Planned Drug Holidays in Treatment of Differentiated Thyroid Cancer.

Background: Although lenvatinib is the preferred treatment for unresectable radioactive iodine-refractory differentiated thyroid cancer (RR-DTC), this agent exerts considerable toxicities, which can lead to frequent dose interruptions and modifications. The adoption of planned drug holidays has been recently suggested as one means of minimizing or avoiding these severe adverse events. Our retrospective study demonstrated that planned drug holidays appear to be a promising strategy for continuing of lenvatinib. However, the benefits of planned drug holidays in a prospective study have yet to be clarified. Here, we investigated the impact of planned drug holidays on clinical outcomes in patients treated with lenvatinib in the COLLECT study. Methods: In COLLECT, a prospective observational study, patients with RR-DTC were treated with lenvatinib in a real-world clinical setting. Lenvatinib was administered orally at a dose of 24 mg daily. Dose modification for toxicities was permitted. Furthermore, planned drug holidays were allowed to avoid severe or intolerable toxicities. The present post hoc analysis focused on evaluating the impact of planned drug holidays on clinical outcomes, including overall survival (OS), time to treatment failure (TTF), time to failure strategy (TFS), and progression-free survival (PFS), in patients in the COLLECT study who were treated with lenvatinib. Results: In total, 262 patients were included. Of the 253 patients evaluable for efficacy, 73 undertook a planned drug holiday at the discretion of the attending physician. OS, TTF, TFS, and PFS were significantly longer in patients who used a planned drug holiday than in those who did not. The planned drug holiday group demonstrated notable clinical outcomes, with a 1-year OS of 95.8% and a 1-year PFS of 94.5%. Moreover, planned drug holidays demonstrated a clinically meaningful advantage in clinical outcomes. The planned drug holiday group had a significantly longer duration of administration at a dose of ≥10 mg. Conclusions: Planned drug holidays for lenvatinib were associated with significantly improved clinical outcomes compared to daily oral administration. Further investigation of the optimal treatment schedule for lenvatinib is warranted. Clinical Trial Registration: UMIN000022243.

The clinical value of iodine-125 seed implantation in the treatment of iodine-refractory differentiated thyroid carcinoma.

To explore the clinical benefits of 125I seed implantation for iodine-refractory differentiated thyroid cancer (RAIR-DTC). A retrospective analysis was conducted on 36 patients with RAIR-DTC who underwent radioactive 125I seed implantation from January 2015 to February 2022, involving 73 lesions. Prescription dose: 80~120 Gy. All cases were followed up at 1, 3, and 5 months postoperatively to monitor changes in tumor size, serum thyroglobulin (Tg), and serum anti-thyroglobulin antibody levels in thyrotropin-inhibited states, pain scores, and postoperative adverse reactions. The data were processed and analyzed using IBM SPSS 26.0. LER (Local Effective Rate) and LCR (Local Control Rate) were expressed as n (%), tumor diameter, Tg, and pain scores were represented as Median (Q1, Q3). Pairwise comparisons were conducted using the Wilcoxon signed-rank test, and a p-value of less than 0.05 indicated statistical significance. Tumor size was significantly reduced after treatment (all P < 0.001): tumor length diameters were 32.67 (17.70, 45.72) mm, 27.45 (12.30, 39.98) mm, 20.70 (11.98, 37.58) mm, and 20.39 (10.56, 33.20) mm in the preoperative, 1-, 3-, and 5-months postoperative periods, respectively. Additionally, two consecutive post-treatment results were more minor and statistically significant than the previous results (P < 0.001). The LER at 1-, 3-, and 5-months post-surgery was 23.73%, 38.98%, and 52.54%, respectively, while the LCR at the same time points was 98.31%, 96.61%, and 94.92%, respectively. Patients' serum Tg levels decreased significantly after surgery. (P < 0.001). Serum Tg levels were measured before surgery and 1-, 3-, and 5-months post-surgery. The results showed that serum Tg levels were 249.45 (79.39, 4718.75) ng/ml, 193.40 (44.53, 2829.00) ng/ml, 192.10 (25.58, 1758.00) ng/ml, and 136.25 (16.57, 1553.25) ng/ml, respectively. Two consecutive post-treatment results were more minor and statistically significant than the previous results (P < 0.001). The patients' pain symptoms were significantly relieved after 125I brachytherapy (P < 0.001). The pain scores before 125I seed implantation and at 1, 3, and 5 months after the operation were 5.00 (4.00, 6.00), 3.00 (2.25, 4.00), 2.00 (2.00, 3.00), and 2.00 (1.00, 3.00), respectively. Most lesions treated with 125I seed implantation in RAIR-DTC patients showed shrinkage and improved pain symptoms. https://www.clinicaltrials.gov, identifier NCT06362772.

Early Structural, Biochemical, and Metabolic Responses to Anlotinib in Patients With Progressive Radioactive Iodine Refractory Differentiated Thyroid Cancer

ObjectiveWe aimed to assess the early efficacy of anlotinib in patients with progressive radioactive iodine refractory differentiated thyroid cancer at the structural, biochemical, and metabolic levels. MethodsTen eligible patients were prospectively enrolled to receive anlotinib. Their responses were assessed at 6 weeks. Apart from the structural response according to Response Evaluation Criteria in Solid Tumors version 1.1, the biochemical response was assessed by serum thyroglobulin (Tg), and the metabolic response was assessed by 2-deoxy-2-[18F] fluoro-D-glucose positron emission tomography/computed tomography (18F-FDG PET/CT) according to the European Organization for Research and Treatment of Cancer criteria. A safety profile was recorded. ResultsStructurally controlled disease (20% partial response + 80% stable disease) was observed in all patients. The median longest diameter of target lesions shrank from 20.8 mm (IQR, 14.9-27.5) to 17.0 mm (IQR, 14.1-23.7) (P < .001), and the average shrinkage rate was −15.1 ± 14.1%. Sharp serum Tg reduction by 72.8 ± 16.4% was observed in 8 measurable patients. The 18F-FDG PET/CT-mapped glucose metabolic response was not quite comparable to the structural response, with 90% of the patients having controlled disease (30% partial metabolic response + 60% stable metabolic disease), whereas 10% presented progressive metabolic disease. The most common treatment-emergent adverse events (AEs) were hypertension (100%) and proteinuria (70%). Most AEs were grade 1 or 2, whereas grade 3 AEs occurred only in hypertension. ConclusionAnlotinib is generally well tolerated and can bring early disease control within the initial 6 weeks of treatment. The sharp biochemical response suggests Tg to be an early sensitive biomarker to anlotinib, whereas the heterogeneous metabolic response might play a complementary role.

Redifferentiation Therapy in Iodine Refractory Differentiated Thyroid Cancer: The Verdict Is Still Out

Redifferentiation Therapy in Iodine Refractory Differentiated Thyroid Cancer: The Verdict Is Still Out

Pathogenesis and signaling pathways related to iodine-refractory differentiated thyroid cancer.

Thyroid cancer is the most common malignant neoplasm within the endocrine system and the field of head and neck surgery. Although the majority of thyroid cancers, more than 90%, are well-differentiated thyroid carcinomas with a favourable prognosis, the escalating incidence of this disease has contributed to an increasing number of patients with a propensity for recurrent disease, rapid disease progression, and poor or no response to conventional treatments. These clinical challenges are commonly attributed to alterations in key thyroid oncogenes or signaling pathways, thereby initiating tumour cell dedifferentiation events, accompanied by reduced or virtually absent expression of the sodium/iodine symporter (NIS). As a result, the disease evolves into iodine-refractory differentiated thyroid cancer (RAIR-DTC), an entity that is insensitive to conventional radioiodine therapy. Despite being classified as a differentiated thyroid cancer, RAIR-DTC has an extremely poor clinical prognosis, with a 10-year survival rate of less than 10%. Therefore, it is of paramount importance to comprehensively elucidate the underlying pathogenesis of RAIR-DTC and provide specific targeted interventions. As the pathogenic mechanisms of RAIR-DTC remain elusive, here we aim to review recent advances in understanding the pathogenesis of RAIR-DTC and provide valuable insights for the development of future molecularly targeted therapeutic approaches.

Tyrosine Kinase Inhibitors for Radioactive Iodine Refractory Differentiated Thyroid Cancer.

Patients with differentiated thyroid cancer usually present with early-stage disease and undergo surgery followed by adjuvant radioactive iodine ablation, resulting in excellent clinical outcomes and prognosis. However, a minority of patients relapse with metastatic disease, and eventually develop radioactive iodine refractory disease (RAIR). In the past there were limited and ineffective options for systemic therapy for RAIR, but over the last ten to fifteen years the emergence of tyrosine kinase inhibitors (TKIs) has provided important new avenues of treatment for these patients, that are the focus of this review. Currently, Lenvatinib and Sorafenib, multitargeted TKIs, represent the standard first-line systemic treatment options for RAIR thyroid carcinoma, while Cabozantinib is the standard second-line treatment option. Furthermore, targeted therapies for patients with specific targetable molecular abnormalities include Latrectinib or Entrectinib for patients with NTRK gene fusions and Selpercatinib or Pralsetinib for patients with RET gene fusions. Dabrafenib plus Trametinib currently only have tumor agnostic approval in the USA for patients with BRAF V600E mutations, including thyroid cancer. Redifferentiation therapy is an area of active research, with promising initial results, while immunotherapy studies with checkpoint inhibitors in combination with tyrosine kinase inhibitors are underway.

Clinicopathological features of differentiated thyroid carcinoma as predictors of the effects of radioactive iodine therapy

BackgroundPatients with differentiated thyroid cancer (DTC) usually have an excellent prognosis; however, 5 %–15 % develop radioactive iodine-refractory (RAIR) DTC (RAIR-DTC), which has a poor prognosis and limited treatment options. The aim of the present study was to investigate the clinicopathological characteristics of RAIR-DTC in order to provide clinical evidence for timely prediction of the effects of iodine therapy. MethodsClinicopathological data for 44 patients with RAIR-DTC and 50 patients with radioiodine-avid DTC (RAIA-DTC) were retrospectively analyzed. The risk factors for RAIR-DTC were evaluated and a RAIR-DTC prediction model was established. ResultsRAIR-DTC showed unique clinicopathological features that differed from those of RAIA-DTC; these included age >55 years, a high-risk histological subtype, a large tumor size, a late TNM stage, calcification, distant metastasis, and more than six metastatic lymph nodes. Patients with RAIR-DTC also developed earlier tumor progression. Binary logistic regression analysis showed that distant metastasis, a high-risk histological subtype, and a maximum tumor diameter of ≥12.5 mm were independent risk factors for RAIR-DTC, and the specificity and sensitivity of a combination of these three parameters for the prediction of RAIR-DTC were 98.0 % and 56.8 %, respectively. Decision curve analysis and the calibration curve revealed that the combined prediction of these three parameters had good repeatability and accuracy. ConclusionThe clinicopathological features of DTC can effectively predict the effects of iodine therapy. A combination of distant metastasis, a high-risk histological subtype, and a maximum tumor diameter of ≥12.5 mm showed significantly higher prediction accuracy.

Clinical Outcomes of Radioactive Iodine Redifferentiation Therapy in Previously Iodine Refractory Differentiated Thyroid Cancers.

Objective: Redifferentiation therapy (RDT) can restore radioactive iodine (RAI) uptake in differentiated thyroid cancer (DTC) cells to enable salvage 131I therapy for previously RAI refractory (RAIR) disease. This study evaluated the clinical outcomes of patients who underwent RDT and identified clinicopathologic characteristics predictive of RAI restoration following RDT. Methods: This is a retrospective case series of 33 patients with response evaluation criteria in solid tumors (RECIST)-progressive metastatic RAIR-DTC who underwent RDT between 2017 and 2022 at the Mayo Clinic (Rochester, MN). All patients underwent genomic profiling and received MEK, RET or ALK inhibitors alone, or combination BRAF-MEK inhibitors for 4 weeks. At week 3, those with increased RAI avidity in metastatic foci received high-dose 131I therapy. Baseline and clinicopathologic outcomes were comprehensively reviewed. Results: Of the 33 patients, 57.6% had restored RAI uptake following RDT (Redifferentiated subgroup). 42.1% (8/19) with papillary thyroid cancers (PTC), 100% (4/4) with invasive encapsulated follicular variant PTCs (IEFV-PTCs), and 100% (7/7) with follicular thyroid cancers (FTC) redifferentiated. All (11/11) RAS mutant tumors redifferentiated compared with 38.9% (7/18) with BRAF mutant disease (6 PTC and 1 IEFV-PTC). 76.5% (13/17) of redifferentiated and 66.7% (8/12) of non-redifferentiated patients achieved a best overall RECIST response of stable disease (SD) or non-complete response/non-progressive disease. Both subgroups had a median 12% tumor shrinkage at 3 weeks on drug(s) alone. The redifferentiated subgroup, following high-dose 131I therapy, achieved an additional median 20% tumor reduction at 6 months after RDT. There were no statistically significant differences between both groups in progression free survival (PFS), time to initiation of systemic therapy, and time to any additional therapy. Of the entire cohort, 6.1% (2/33) experienced histologic transformation to anaplastic thyroid cancer, 15.1% (5/33) died, and all had redifferentiated following RDT and received 131I therapy. Conclusion: RDT has the potential to restore RAI avidity and induce RECIST responses following 131I therapy in select patients with RAIR-DTC, particularly those with RAS-driven "follicular" phenotypes. In patients with PTC, none of the evaluated clinical outcomes differed statistically between the redifferentiated and non-redifferentiated subgroups. 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 anaplastic transformation.

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

The Role of Stereotactic Radiotherapy in Deferring the Need for Systemic Therapies in Patients with Progressive Oligometastatic Iodine-Refractory Thyroid Cancer

Differentiated thyroid cancer (DTC) is usually associated with a good prognosis, although development of metastases in iodine-refractory patients adversely affects quality of life and survival. The advent of tyrosine-kinase inhibitors drugs (TKI) allowed for a significant improvement in patients' outcome: however, in case of oligometastatic disease, a locoregional ablative approach such as Stereotactic Radiation Therapy (SBRT) may be proposed. The aim of our study is to assess if SBRT in oligometastatic DTC patients could effectively control tumor progression and possibly defer the need of systemic therapies. We retrospectively analyzed patients with differentiated oligometastatic iodine refractory thyroid cancer treated with SBRT in our Radiation Oncology Unit from 2011 to 2022. We collected demographics and treatment-related characteristics. Local Control (LC), Progression Free Survival (PFS), Overall Survival (OS) and the need for systemic therapy were evaluated. Patients with anaplastic histology, incomplete treatment or without follow-up information were excluded. Twenty-two patients were included in our analysis, accounting for 63 tumors: 26 were located in bones (41,2%), 21 in lymph nodes (33,3%), 7 in the brain (11,1%), 6 in the lungs (9,5%) and 3 visceral (4,7%). SBRT was delivered in 1-8 fractions, with a median dose of 30Gy (range 24-60Gy). Median follow-up was 36,8 months (range 6,1-130,9 months). After SBRT we observed a complete response in 29 lesions (46,0%), partial response in 20 (31,7%), stable disease in 13 (20,6%) and only 1 progressive lesion (1,6%). We observed 10 local recurrences (15,8%) with an actuarial LC of 92,4% and 76,1% at 24 and 48 months respectively, while PFS was 62,8% and 52,3% at 12 and 24 months respectively. The OS at 24 and 48 months was 89,2% and 82,3% respectively. Patients with oligoprogressive disease were treated with further SBRT, while patients with polymetastatic progression of disease or oligoprogression not suitable for ablative treatment received systemic therapy. Eleven patients (50%) needed to start TKI treatment (6 Lenvatinib, 3 Sunitinib and 2 Sorafenib) for progressive disease: median time to first systemic treatment from SRT was 18,5 months (range 0,5-67 months). At the time of this analysis, 11 patients (50%) were still without systemic therapy, showing a good disease control after a median follow-up of 26,2 months (range 5,7-83). Freedom from systemic therapy rate from the time of SBRT was 85,6% and 57,6% at 12 and 24 months respectively. In our experience, SBRT yields satisfying local control rates in oligometastatic Iodine-refractory DTC, potentially allowing for a deferral of systemic therapies, and should always be considered in these patients.

The efficacy and safety in radioactive iodine refractory thyroid cancer patients treated with sorafenib.

Sorafenib included in Chinese medical insurance is the earliest targeted drug for radioactive iodine refractory differentiated thyroid cancer (RR-DTC). This study is to further demonstrate the clinical efficacy and safety of sorafenib used in Zhujiang Hospital of Southern Medical University. RR-DTC patients treated at our Department of Nuclear Medicine in Zhujiang Hospital of Southern Medical University (October 2017-May 2020) were retrospectively analyzed. Treatment effects, progression-free survival (PFS), and adverse effects (AEs) during medication were evaluated. Of the 31 patients included, 26 patients were evaluated for efficacy with a median follow-up time of 17.5 months (4.0-51.0 months). The disease control rate (DCR) was 57.7% (n = 15) and the objective response rate (ORR) was 26.9% (n= 7). Most patients with disease control had thyroglobulin decreases of more than 60% (p = 0.004), ORRs were favorable in patients with lung metastasis and lung-only metastasis (p = 0.010 and 0.001, respectively). The PFS of the 26 patients analyzed was 16.5 months (95%CI: 14.41 -23.90 months). In the subgroup analysis, female, patients with lung-only metastasis, hand-foot skin syndrome (HFS), and thyroglobulin response ≥ 60% observed longer PFS (p = 0.038, 0.045, 0.035, and 0.000, respectively), while patients with bone metastasis had lower PFS (p = 0.035). The most common toxicity profile was HFS (93.5%), followed by diarrhea (83.9%), alopecia (74.2%). All the side effects were mainly grade 1-2. Grade 3-4 adverse reactions were more common in diarrhea and HFS. Sorafenib has promising efficacy in RR-DTC, especially in patients with lung metastasis and lung-only metastasis. The AEs of sorafenib were generally mild, and the main AE was HFS.

Molecular basis and targeted therapy in thyroid cancer: Progress and opportunities.

Thyroid cancer (TC) is the most prevalent endocrine malignant tumor. Surgery, chemotherapy, radiotherapy, and radioactive iodine (RAI) therapy are the standard TC treatment modalities. However, recurrence or tumor metastasis remains the main challenge in the management of anaplastic thyroid cancer (ATC) and radioiodine (RAI) radioactive iodine-refractory differentiated thyroid cancer (RR-DTC). Several multi-tyrosine kinase inhibitors (MKIs), or immune checkpoint inhibitors in combination with MKIs, have emerged as novel therapies for controlling the progression of DTC, medullary thyroid cancer (MTC), and ATC. Here, we discuss and summarize the molecular basis of TC, review molecularly targeted therapeutic drugs in clinical research, and explore potentially novel molecular therapeutic targets. We focused on the evaluation of current and recently emerging tyrosine kinase inhibitors approved for systemic therapy for TC, including lenvatinib, sorafenib and cabozantinib in DTC, vandetanib, cabozantinib, and RET-specific inhibitor (selpercatinib and pralsetinib) in MTC, combination dabrafenib with trametinib in ATC. In addition, we also discuss promising treatments that are in clinical trials and may be incorporated into clinical practice in the future, briefly describe the resistance mechanisms of targeted therapies, emphasizing that personalized medicine is critical to the design of second-line therapies.

Clinical role of 18F-FDG PET/CT for detection of radioactive iodine refractory differentiated thyroid cancer.

In clinical settings, an estimated 10% differentiated thyroid cancer (DTC) cases become radioactive iodide refractory (RAIR), which lack a molecular marker and have fewer treatment selections. A higher uptake of 18F-fluorodeoxyglucose (18F-FDG) might indicate poor prognosis for DTC. This study aimed to evaluate the clinical value of 18F-FDG psitron emission tomography/computed tomography (PET/CT) for the early diagnosis of RAIR-DTC and high-risk DTC. A total of 68 DTC patients were enrolled and underwent 18F-FDG PET/CT for the detection of recurrence and/or metastasis. 18F-FDG uptake was evaluated in patients with different postoperative recurrence risks or TNM stages and compared between RAIR and non-RAIR-DTC based on its maximum standardized uptake value and tumor/liver (T/L) ratio. The final diagnosis was judged by histopathology and follow-up data. Of 68 DTC cases, 42 were RAIR and 24 non-RAIR, with 2 not determined. A total of 263 of 293 lesions detected on 18F-FDG PET/CT were confirmed to be locoregional or metastatic after follow-up. The T/L ratio was significantly higher for RAIR than for non-RAIR (median 5.18 vs 1.44; P < .01) and also significantly higher in postoperative patients at high-risk of recurrence than at low to medium risk (median 4.90 vs 2.16; P < .01). 18F-FDG PET/CT exhibited a sensitivity of 83.3% and specificity of 87.5% for identifying RAIR, with a cutoff T/L value of 2.98. 18F-FDG PET/CT has the potential to diagnose RAIR-DTC early and identify the high-risk DTC. The T/L ratio is a useful parameter for the detection of RAIR-DTC patients.

A multicenter, single-arm phase 2 study of surufatinib plus toripalimab for patients with locally advanced or metastatic radioactive iodine-refractory differentiated thyroid cancer.

6089 Background: For patients (pts) with radioactive iodine–refractory differentiated thyroid cancer (RAIR-DTC), there presents a considerable therapeutic challenge with poor long-term outcomes. The open-label, multi-cohort, single-arm phase 2 study was performed to evaluate surufatinib (a small-molecule inhibitor of VEGFR 1-3, FGFR1 and CSF-1R) in combination with toripalimab (an anti-PD-1 antibody) in pts with RAIR-DTC. Methods: Eligible pts were with locally advanced or metastatic RAIR-DTC who were not amenable for surgery or external beam radiotherapy, with a radiologically confirmed disease progression within 12 months before treatment, and with ≥6 months since last radioiodine treatment. Enrolled pts received surufatinib 250 mg orally, QD, plus toripalimab 240 mg IV, Q3W, until disease progression or reaching the maximum treatment duration with toripalimab of 24 months, or other protocol-specified criteria. The primary endpoint was objective response rate (ORR) per RECIST 1.1. Results: From March 2020 to November 2021, 15 pts were enrolled and received a median duration of 11.1 months of the combination treatment, with a median age of 61 years (range: 37-74). 9 (60%) pts were male, and 12 (80%) had papillary thyroid cancer. Of the 13 pts with PD-L1 immunochemical results, 6 pts had PD-L1 CPS ≥1%. As of 28 Dec 2022, the median follow-up duration was 22.11 months. Of the 15 pts with at least one post-baseline tumor assessment, the confirmed ORR was 33.3% (5 PRs) and DCR was 93.3%. mDoR was 8.34 months. mPFS (95%CI) was 10.91 months (4.01, NA). mOS was not reached, and 12-month OS rate was 100%. 14 (93.3%) pts had treatment-emergent adverse events (TEAEs), and 10 (66.7%) pts reported grade ≥3 TEAEs, most commonly (≥10% pts) with hypocalcemia (20%), diarrhea (20%) and hypertension (13%). There was no death due to TEAE in the study. Conclusions: Surufatinib plus toripalimab showed encouraging antitumor activity and tolerable safety profile in pts with locally advanced or metastatic RAIR-DTC. Clinical trial information: NCT04169672 .

Prognostic value of serum stimulating thyroglobulin in metastatic radioactive iodine refractory differentiated thyroid cancer

Purpose: To investigate the prognostic value of serum-stimulated thyroglobulin (ps-Tg) before the first 131I therapy in patients with metastatic radioactive iodine-refractory differentiated thyroid cancer (RR-DTC). Methods: From August 2017 to August 2020, the clinical data for 160 patients with thyroid papillary carcinoma (PTC) who received thyroidectomy and 131I treatment were analyzed retrospectively. Differences in clinical data and related thyroid indices were compared. Univariate and multivariate logistic regression analyses were used to analyze the related factors affecting the occurrence of RR-DTC. Receiver-operator characteristic (ROC) curves were used to determine the discriminative power of ps-Tg in predicting RR-DTC, while the Kaplan-Meier survival curve of ps-Tg for RR-DTC was drawn. Results: A total of 160 patients with thyroid cancer were enrolled, including 47 males, and 113 females (70.62 %). Overall mean age was 39 ± 13 years old. The follow-up results showed that 68 patients with thyroid cancer were refractory to radioactive iodine. The ps-Tg of the iodine-refractory group was higher than that of the iodine-receptive group (p &lt; 0.001). Multivariate logistic regression showed that ps-Tg was an independent risk factor for RR-DTC (OR = 1.086, p = 0.000). The optimal cut-off value of ps-Tg for predicting progression to RR-DTC was 19.21 μg/L. Kaplan-Meier survival curve showed that the risk of iodine refractory in patients with thyroid cancer (≥ 19.21 μg/L) was higher than that of patients with thyroid cancer &lt; 19.21 μg/L (p &lt; 0.001). Conclusion: The ps-Tg before the first 131I therapy independently predicts the occurrence of metastatic RR-DTC when ps-Tg is greater than the risk of RR-DTC increase. This finding will be helpful in predicting the occurrence of RR-DTC, in order to determine the best time to start treatment and make individualized treatment decisions.

Redifferentiation Therapy for Iodine Refractory Differentiated Thyroid Cancers: Current Status.

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