Radioiodine-refractory Differentiated Thyroid Carcinoma Research Articles

Questions and Controversies in the Clinical Application of Tyrosine Kinase Inhibitors to Treat Patients with Radioiodine-Refractory Differentiated Thyroid Carcinoma: Expert Perspectives.

Notwithstanding regulatory approval of lenvatinib and sorafenib to treat radioiodine-refractory differentiated thyroid carcinoma (RAI-R DTC), important questions and controversies persist regarding this use of these tyrosine kinase inhibitors (TKIs). RAI-R DTC experts from German tertiary referral centers convened to identify and explore such issues; this paper summarizes their discussions. One challenge is determining when to start TKI therapy. Decision-making should be shared between patients and multidisciplinary caregivers, and should consider tumor size/burden, growth rate, and site(s), the key drivers of RAI-R DTC morbidity and mortality, along with current and projected tumor-related symptomatology, co-morbidities, and performance status. Another question involves choice of first-line TKIs. Currently, lenvatinib is generally preferred, due to greater increase in progression-free survival versus placebo treatment and higher response rate in its pivotal trial versus that of sorafenib; additionally, in those studies, lenvatinib but not sorafenib showed overall survival benefit in subgroup analysis. Whether recommended maximum or lower TKI starting doses better balance anti-tumor effects versus tolerability is also unresolved. Exploratory analyses of lenvatinib pivotal study data suggest dose-response effects, possibly favoring higher dosing; however, results are awaited of a prospective comparison of lenvatinib starting regimens. Some controversy surrounds determination of net therapeutic benefit, the key criterion for continuing TKI therapy: if tolerability is acceptable, overall disease control may justify further treatment despite limited but manageable progression. Future research should assess potential guideposts for starting TKIs; fine-tune dosing strategies and further characterize antitumor efficacy; and evaluate interventions to prevent and/or treat TKI toxicity, particularly palmar-plantar erythrodysesthesia and fatigue.

18F-FDG-PET/CT in Patients with Advanced, Radioiodine Refractory Thyroid Cancer Treated with Lenvatinib.

Simple SummaryIn patients with advanced radioiodine refractory differentiated thyroid carcinoma (DTC), therapeutic options are limited. In the “Study of (E7080) Lenvatinib in Differentiated Cancer of the Thyroid (SELECT)”, Lenvatinib significantly prolonged the progression-free survival, resulting in a more frequent use in clinical practice for this patient group. Due to considerable side effects, an accurate assessment of response to treatment is crucial in these patients. Therefore, we aimed to improve treatment individualization and reduce unnecessary therapies by selecting patients who will most likely benefit from Lenvatinib treatment using 2-deoxy-2-[18F] fluoro-D-glucose positron-emission-tomography/computed-tomography.Background: The tyrosine kinase inhibitor (TKI) Lenvatinib represents one of the most effective therapeutic options in patients with advanced radioiodine refractory differentiated thyroid carcinoma (DTC). We aimed to assess the role of 2-deoxy-2-[18F] fluoro-D-glucose positron-emission-tomography/computed-tomography (18F-FDG-PET/CT) in the monitoring of functional tumor response compared to morphological response. Methods: In 22 patients, a modified Positron Emission Tomography Response Criteria In Solid Tumors (mPERCIST) evaluation before treatment with Lenvatinib and at 3 and 6 month follow up was performed. Further PET-parameters and morphologic tumor response using Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 were assessed and their prediction of progression-free survival (PFS) and disease-specific survival (DSS) was evaluated. Results: Most patients were rated stable in morphological evaluation and progressive using a metabolic response. All patients who responded to therapy through RECIST showed a decline in nearly all Positron Emission Tomography (PET)-parameters. For both time-points, non-responders according to mPERCIST showed significantly lower median PFS and DSS, whereas according to RECIST, only DSS was significantly lower. Conclusion: Tumor response assessment by 18F-FDG-PET outperforms morphological response assessment by CT in patients with advanced radioiodine refractory DTC treated with Lenvatinib, which seems to be correlated with clinical outcomes.

Systemtherapien bei metastasierten Schilddrüsenkarzinomen – zugelassene Therapien und neue Ansätze

The treatment of radioiodine-refractory differentiated thyroid carcinoma (rrDTC) and medullary thyroid carcinoma (MTC) remains challenging. Based on phaseIII clinical studies, four multi-kinase inhibitors (MKI) are approved for the treatment of progressive thyroid cancer in Germany. The indications for starting systemic treatment remain a challenge as the diseases can be stable and asymptomatic over long periods of time. In contrast, MKI treatment, which slows the disease progression but is not curative, is often associated with side effects that can impair quality of life. For this reason, an aim is to develop more specific treatments with low off-target effects. In this context selective RET kinase inhibitors represent a promising new approach, which is currently tested intensively in clinical trials, e.g. for advanced symptomatic MTC.

265O Anlotinib in locally advanced or metastatic radioiodine-refractory differentiated thyroid carcinoma: A randomized, double-blind, multicenter phase II trial

265O Anlotinib in locally advanced or metastatic radioiodine-refractory differentiated thyroid carcinoma: A randomized, double-blind, multicenter phase II trial

LBA88 Anlotinib in locally advanced or metastatic radioiodine-refractory differentiated thyroid carcinoma: A randomized, double-blind, multicenter phase II trial

Anlotinib is a novel multikinase inhibitor targeting VEGFR, PDGFR, FGFR, and c-Kit. This study investigated the potency of anlotinib in treating locally advanced or metastatic radioiodine-refractory differentiated thyroid carcinoma (RAIR-DTC).

Targeting Integrins with Radiolabeled RGD Analogues for Radiotheranostics of Metastatic Radioactive Iodine Nonresponsive Thyroid Cancer: New Avenues in Personalized Medicine.

ThyroidVol. 30, No. 4 Editorial and CommentariesTargeting Integrins with Radiolabeled RGD Analogues for Radiotheranostics of Metastatic Radioactive Iodine Nonresponsive Thyroid Cancer: New Avenues in Personalized MedicineJoanna Klubo-Gwiezdzinska and Xiaoyuan ChenJoanna Klubo-GwiezdzinskaAddress correspondence to: Joanna Klubo-Gwiezdzinska, MD, PhD, MHSc, Thyroid Tumors and Functional Thyroid Disorders Section, Metabolic Disease Branch, National Institutes of Diabetes, Digestive and Kidney Diseases, National Institutes of Health, 10 Center Drive, Building 10m room 9c103, Bethesda, MD 20892 E-mail Address: joanna.klubo-gwiezdzinska@nih.govThyroid Tumors and Functional Thyroid Disorders Section, Metabolic Disease Branch, National Institutes of Diabetes, Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland.Search for more papers by this author and Xiaoyuan ChenMolecular Imaging and Nanomedicine Laboratory, National Institutes of Biomedical Imaging and Bioengineering, National Institutes of Health, Bethesda, Maryland.Search for more papers by this authorPublished Online:15 Apr 2020https://doi.org/10.1089/thy.2020.0169AboutSectionsView articleView Full TextPDF/EPUB Permissions & CitationsPermissionsDownload CitationsTrack CitationsAdd to favorites Back To Publication ShareShare onFacebookTwitterLinked InRedditEmail View articleFiguresReferencesRelatedDetailsCited byEvaluation of integrin αvβ3-targeted imaging for predicting disease progression in patients with high-risk differentiated thyroid cancer (using 99mTc-3PRGD2)19 December 2022 | Cancer Imaging, Vol. 22, No. 1Radiometal-theranostics: the first 20 years*24 November 2022 | Journal of Radioanalytical and Nuclear Chemistry, Vol. 132Theranostic Options for Radioiodine-Refractory Differentiated Thyroid Carcinoma: Recent Advances, Challenges, and Road Ahead12 July 2022 | Frontiers in Endocrinology, Vol. 13Investigation of the Presence of Integrin Alpha-3 and Beta-1 Receptors on Tumor Tissue, Metastatic Lymph Node and Normal Tissue in Thyroid Cancer1 June 2022 | Molecular Imaging and Radionuclide Therapy, Vol. 31, No. 2Translating Molecules into Imaging—The Development of New PET Tracers for Patients with Melanoma29 April 2022 | Diagnostics, Vol. 12, No. 5Multimodal Imaging of Target Detection Algorithm under Artificial Intelligence in the Diagnosis of Early Breast CancerJournal of Healthcare Engineering, Vol. 2022Bioinspired peptide adhesion on Ti implants alleviates wear particle-induced inflammation and improves interfacial osteogenesisJournal of Colloid and Interface Science, Vol. 605Non-Cationic RGD-Containing Protein Nanocarrier for Tumor-Targeted siRNA Delivery17 December 2021 | Pharmaceutics, Vol. 13, No. 12IVUS\IVPA hybrid intravascular molecular imaging of angiogenesis in atherosclerotic plaques via RGDfk peptide-targeted nanoprobesPhotoacoustics, Vol. 22 Volume 30Issue 4Apr 2020 InformationCopyright 2020, Mary Ann Liebert, Inc., publishersTo cite this article:Joanna Klubo-Gwiezdzinska and Xiaoyuan Chen.Targeting Integrins with Radiolabeled RGD Analogues for Radiotheranostics of Metastatic Radioactive Iodine Nonresponsive Thyroid Cancer: New Avenues in Personalized Medicine.Thyroid.Apr 2020.476-478.http://doi.org/10.1089/thy.2020.0169Published in Volume: 30 Issue 4: April 15, 2020Online Ahead of Editing: March 2, 2020PDF download

Efficacy and Limitations of Lenvatinib Therapy for Radioiodine-Refractory Differentiated Thyroid Cancer: Real-World Experiences.

Background: The ultimate clinical goal of advanced cancer treatment is improvement of survival. Tyrosine kinase inhibitors (TKIs) were recently approved for radioiodine-refractory differentiated thyroid carcinoma (RR-DTC) that is resistant to conventional therapies since they have significant potential to improve survival in patients who previously had no more treatment strategies available. However, eligible patients are limited in clinical practice, making it difficult to accurately determine the efficacy of TKIs. Patients and Methods: We retrospectively analyzed the efficacy of lenvatinib at a single institution, enrolling 42 RR-DTC patients. Results: The best overall response was partial remission in 26 (62%) patients, stable disease in 10 (24%) patients, and progressive disease (PD) in 6 (14%) patients. The results indicated three-year overall survival (OS) and progression-free survival rates of 51.0% and 32.4%, respectively. Twenty-three (55%) patients had backgrounds that did not match the inclusion criteria of the Study of (E7080) Lenvatinib in Differentiated Cancer of the Thyroid (SELECT) trial. Furthermore, PD-experienced patients individually decided whether to continue lenvatinib, and 17 (41%) made the decision themselves; these patients had a three-year OS of 43.0% and postprogression survival (PPS) of 13.3 [95% confidence interval 6.1-not reached] months. Conclusions: Our real-world investigation revealed that patients have wide-ranging background characteristics, and the decision regarding continuation of therapy after PD is based on the patient's general condition. Our management protocol resulted in good PPS. Furthermore, our results indicated equivalent efficacy of lenvatinib as in the SELECT trial. In conclusion, lenvatinib proved effective for RR-DTC patients in a real-world setting.

Prognostic role of the lymphocyte-to-monocyte ratio for clinical outcomes of patients with progressive radioiodine-refractory differentiated thyroid carcinoma treated by sorafenib.

The lymphocyte-to-monocyte ratio (LMR) reflects the status of tumour-infiltrating immune cells and host immunity. The LMR has been reported as a prognostic marker in various cancers. The present study evaluated the role of the LMR as a prognostic marker in patients with progressive radioiodine-refractory (RAIR) differentiated thyroid carcinoma (DTC). Retrospective cohort study. Forty patients with progressive RAIR DTC who were treated by sorafenib with available baseline complete blood cell count data. We assessed the response rate, progression-free survival (PFS) and overall survival (OS). The patients were divided into low and high LMR groups based on their baseline LMRs (<4, n=22, 55% and ≥4, n=18, 45%, respectively). There were no significant differences in baseline characteristics between the groups. The OS curves differed significantly based on the LMR. The median OS of the low LMR group was 24.3months and that of the high LMR group was not reached until the end of observation period (P=.015). The PFS curves and median PFS also differed significantly based on the LMR values (P=.019). In multivariate analysis, low LMR was an independent risk factor for all-cause mortality in patients with progressive RAIR DTC (hazard ratio, 2.64; 95% confidence interval: 1.04-6.72, P=.041). A low LMR was associated with poor response rate, PFS and OS in patients with progressive RAIR DTC treated with sorafenib. Thus, LMR could be a simple prognostic biomarker in patients with progressive RAIR DTC.

Treatment-related adverse effects with TKIs in patients with advanced or radioiodine refractory differentiated thyroid carcinoma: a systematic review and meta-analysis.

BackgroundTyrosine kinase inhibitors (TKIs) have been administered to advanced or radio-iodine refractory differentiated thyroid carcinoma (RR-DTC) patients for years. We performed a pooled analysis to explore the frequency of severe adverse effects in advanced or RR-DTC patients treated with sorafenib and lenvatinib.MethodsWe performed a comprehensive search of computerized databases, including PubMed, Web of Science, Ovid, EMASE, and the Cochrane Library, from the drugs’ inception to July 2018 to identify clinical trials. All grade and severe adverse events (AEs; grade ≥3) were analyzed. This meta-analysis was conducted in accordance with PRISMA guidelines.ResultsIn total, seve studies published from 2012–2018 with 657 patients were eligible for this study. We included two studies (238 patients) that received 200 mg sorafenib twice and five studies (419 patients) that received 24 mg lenvatinib daily. The frequency of AEs was different among the two drugs. Patients in the sorafenib group had a significantly higher frequency of all grade hand-foot syndrome, hypocalcemia, rash, elevated alanine aminotransferase (ALT), and elevated aspartate aminotransferase (AST). Conversely, the lenvatinib group experienced more frequent all grade voice change, hypertension, nausea, and vomiting compared with those with sorafenib. For grade ≥3 adverse effects, hand-foot syndrome, hypocalcemia, and elevated ALT were more frequent in sorafenib-treated patients. Moreover, lenvatinib-treated patients had a significantly higher incidence of severe weight loss, hypertension, and nausea.ConclusionSignificant differences in common adverse effects, such as all-grade and severe AEs, were detected between sorafenib and lenvatinib in the current study. Early intervention and management of treatment-related AEs (TRAEs) can minimize the impact on patients’ quality-of-life, and avoid unnecessary dose reductions and treatment-related discontinuations.

Radioiodine refractoriness score: A multivariable prediction model for postoperative radioiodine-refractory differentiated thyroid carcinomas.

ObjectiveThe purpose of the present study was to evaluate the clinical features of patients with radioiodine refractory (RAIR) differentiated thyroid carcinoma (DTC) and establish an effective risk score for postoperative radioiodine refractoriness.Subjects and methodsData were retrospectively collected from 5163 patients admitted to our center after thyroid surgery. Radioiodine refractoriness was defined according to criteria used in the 2015 American Thyroid Association guidelines. The scoring system was established by independent risk factors identified by univariate and multivariate analyses. The optimal index points for predicting the prevalence of radioiodine refractoriness and the model discriminatory power were assessed by receiver operating characteristic (ROC) curves.ResultsOne hundred and twelve (2.2%) patients developed RAIR DTC. Smoking, tumor type (follicular thyroid cancer), extrathyroid extension, lymph node metastasis number (≥4), lymph node metastasis rate (≥53%), and pN stage (N1) were highly positively correlated with the prevalence of RAIR DTC. The cutoff value of seven points was found to be the best for predicting the prevalence of RAIR DTC, and the scoring system presented better discrimination than other single independent predictors.ConclusionsBased on our multivariable prediction model, patients with ≥7 index points may need to undergo more active surveillance or aggressive treatment due to the high risk of RAIR DTC.

Correction to: Tertiary Care Experience of Sorafenib in the Treatment of Progressive Radioiodine-Refractory Differentiated Thyroid Carcinoma: A Korean Multicenter Study, by Kim M, Kim TH, Shin DY, Lim DJ, Kim EY, Kim WB, Chung JH, Shong YK, Kim BH, and Kim WG on behalf of Korean Thyroid Cancer Study Group (KTCSG). Thyroid 2018;28(3)340-348. DOI: 10.1089/thy.2017.0356.

Correction to: Tertiary Care Experience of Sorafenib in the Treatment of Progressive Radioiodine-Refractory Differentiated Thyroid Carcinoma: A Korean Multicenter Study, by Kim M, Kim TH, Shin DY, Lim DJ, Kim EY, Kim WB, Chung JH, Shong YK, Kim BH, and Kim WG on behalf of Korean Thyroid Cancer Study Group (KTCSG). Thyroid 2018;28(3)340-348. DOI: 10.1089/thy.2017.0356.

A Phase 2 Trial of Cabozantinib for the Treatment of Radioiodine-Refractory Differentiated Thyroid Carcinoma in the First-Line Setting

A Phase 2 Trial of Cabozantinib for the Treatment of Radioiodine-Refractory Differentiated Thyroid Carcinoma in the First-Line Setting

Tertiary Care Experience of Sorafenib in the Treatment of Progressive Radioiodine-Refractory Differentiated Thyroid Carcinoma: A Korean Multicenter Study.

Sorafenib, a multi-kinase inhibitor, is approved for the treatment of patients with radioactive iodine (RAI)-refractory differentiated thyroid cancer (DTC). This study evaluated the efficacy and safety of sorafenib in real-world clinical practice and compared the results to those of the DECISION trial. The clinical features associated with better clinical outcomes after sorafenib treatment were also evaluated. This multicenter, retrospective cohort study evaluated 98 patients with progressive RAI-refractory DTC who were treated with sorafenib in six tertiary hospitals in Korea. The primary objective was the progression-free survival (PFS) according to Response Evaluation Criteria In Solid Tumors v1.1. Overall survival, response rate (defined as the best objective response according to Response Evaluation Criteria In Solid Tumors v1.1), and safety were also evaluated. The median PFS was 9.7 months; median overall survival was not reached during follow-up. Partial responses and stable disease were achieved in 25 (25%) and 64 (65%) patients, respectively. Stable disease of >6 months was achieved in 41 (42%) patients. Subgroup analyses identified several prognostic indicators of a better PFS: absence of disease-related symptoms (hazard ratio [HR] = 0.5; p = 0.041), lung-only metastasis (HR = 0.4; p = 0.048), a daily maintenance dose ≥600 mg (HR = 0.3; p = 0.005), and a thyroglobulin reduction ≥60% (HR = 0.4; p = 0.012). The mean daily dose of sorafenib was 666 ± 114 mg, and drug withdrawals due to adverse events (AEs) occurred in 13% of patients. AEs and serious AEs were reported in 93 (95%) and 40 (41%) patients, respectively. The most frequent AE was hand-foot skin reaction (76%). The PFS of progressive RAI-refractory DTC patients treated with sorafenib was consistent with the findings of the DECISION trial. Disease-related symptoms, lung-only metastasis, a daily maintenance dose, and thyroglobulin reduction were significantly associated with PFS. These results suggest that sorafenib is an effective treatment option for patients with progressive RAI-refractory DTC.

Research progress of redifferentiation of radioiodine-refractory differentiated thyroid carcinoma

The effect of 131I therapy for primary and metastatic lesions of thyroid carcinoma depends on the ability of iodine uptake. The loss or down-regulation of iodine-metabolizing genes represents dedifferentiation of DTC, which results in the disability to take up and accumulate 131I and eventually leads to radioiodine-refractory DTC (RR-DTC). The management of RR-DTC is extremely difficult and the prognosis is poor. It is important for the treatment and prognosis of RR-DTC to investigate the mechanism of redifferentiation. The up-regulation of thyroid iodine-metabolizing genes expression, inhibition of the changes in epigenetic modifications and intervention of the abnormal activation of signaling pathways are reviewed in this article. Key words: Thyroid neoplasms; Radiotherapy; Iodine radioisotopes; Treatment failure; Redifferentiation; Trends

MiRNA-106a directly targeting RARB associates with the expression of Na(+)/I(-) symporter in thyroid cancer by regulating MAPK signaling pathway.

BackgroundSerum miRNAs profiles between papillary thyroid carcinoma (PTC) patients with non-131I and 131I-avid lung metastases are differentially expressed. These miRNAs have to be further validated and the role of these miRNAs in the molecular function level of thyroid cancer cell lines has not been investigated.MethodsExpression levels of six identified miRNAs were assessed via quantitative real-time PCR (qRT-PCR) in the serum of eligible patients. Dual-luciferase reporter assay was used to determine the potential target of miR-106a. Cell viability and apoptosis were evaluated by MTT assay and flow cytometry analysis, respectively. The change of gene expression was detected by qRT-PCR and western blotting analysis. In vitro iodine uptake assay was conducted by a γ-counter.ResultsCompared to PTC patients with 131I-avid lung metastases, miR-106a was up-regulated in the serum of patients with non-131I-avid lung metastases. The results of dual-luciferase reporter assay demonstrated that miR-106a directly targeted retinoic acid receptor beta (RARB) 3′-UTR. miR-106a-RARB promoted viability of thyroid cancer cells by regulating MEKK2-ERK1/2 and MEKK2-ERK5 pathway. miR-106a-RARB inhibited apoptosis of thyroid cancer cells by regulating ASK1-p38 pathway. Moreover, miR-106a-RARB could regulate the expression of sodium iodide symporter, TSH receptor and alter the iodine uptake function of thyroid cancer cells.ConclusionsmiRNA-106a, directly targeting RARB, associates with the viability, apoptosis, differentiation and the iodine uptake function of thyroid cancer cell lines by regulating MAPK signaling pathway in vitro. These findings in the present study may provide new strategies for the diagnosis and treatment in radioiodine-refractory differentiated thyroid carcinoma.

Survival and prognostic factors of radioiodine refractory pulmonary metastatic differentiated thyroid carcinoma (DTC).

6093 Background: The challenging key point of management of radioiodine refractory DTC patients is to define those who could benefit from experimental drugs in clinical trials. Methods: We reviewed clinical and pathological data of patients with refractory pulmonary metastatic DTC treated in our center from 1990 to 2011. Survival was estimated with the method of Kaplan-Meier. Associated prognostic factors were studied in Cox model based analyses. Results: Among 167 pulmonary metastatic DTC, 46% (n=76) met a criterion of radioiodine refractory disease: at least one metastases without I131 uptake: 61% (n=46); progressive disease despite I131: 22% (n=17) and absence of complete response despite a cumulated dose &gt;600mCi: 17% (n=13). There were 63% of female (n=48) and the median age was 64 years (range 18-87). The initial treatment was total thyroidectomy in 92% (n=70), lymph node dissection in 71%, (n=54) and radioiodine therapy in 100% of patients. Pathological features were papillary histology in 61% (n=46), follicular histology in 29% (n=22) and poor differentiated histology in 10% (n=8). pT stage was 1ab, 2, 3, and 4 in 11%, 13%, 63% and 13% respectively, pN stage after lymph node dissection was 0, 1a and 1b in 33%, 7% and 60% respectively. Metastasis were present at diagnosis in 45% (n=34) of cases. The refractory feature was established at the time of diagnosis and in the follow-up in 18% and 82% of cases respectively. When the disease was considered as refractory, the median overall survival was 5.5 years. The refractory feature at the initial diagnosis was the only independent prognostic factor correlated with poor survival (p&lt;0.001). Conclusions: Patients who are considered as radioiodine refractory at the initial diagnosis of DTC have poor prognosis and should be considered for clinical trials in case of progression.

Long-term analysis of the efficacy and tolerability of sorafenib in advanced radio-iodine refractory differentiated thyroid carcinoma: final results of a phase II trial

We conducted a prospective phase II clinical trial to determine the efficacy of sorafenib in patients with advanced radio-iodine refractory differentiated thyroid cancer. In this article, the long-term results are presented. Thirty-one patients with progressive metastatic or locally advanced radioactive iodine refractory differentiated thyroid cancer received sorafenib 400 mg orally twice daily. The study end points included response rate, progression-free survival (PFS), overall survival (OS), best response by Response Evaluation Criteria in Solid Tumors criteria 1.0, and toxicity. Median PFS was 18 months (95% confidence interval (95% CI): 7-29 months) and median OS was 34.5 months (95% CI: 19-50 months). Eight patients (31%) achieved a partial response and 11 patients (42%) showed stable disease after a median follow-up of 25 months (range 3.5-39 months). Toxicity mostly included hand foot syndrome, weight loss, diarrhea, and rash. Sorafenib has clinically relevant antitumor activity in patients with progressive metastatic or locally advanced radio-iodine refractory differentiated thyroid cancer. Sorafenib can nowadays be considered as the standard option in these patients.