Radioiodine-refractory Differentiated Thyroid Cancer Research Articles

Real-world analysis of use of lenvatinib in differentiated thyroid cancers.

e18075 Background: Lenvatinib is one of the approved treatments for radioiodine refractory differentiated thyroid cancers. However, there is very limited data from India on real-world efficacy and adverse events of Lenvatinib and hence this analysis was performed. Methods: This was a retrospective analysis in which patients of radioiodine refractory differentiated thyroid cancer as per the select study criteria who received lenvatinib were selected for the study over the last 4 years. The baseline demographic characteristics, adverse events of lenvatinib, the date of progression and the date of overall survival (OS) were extracted from the electronic medical records (EMR) of the Tata Memorial Hospital. SPSS version 20 was used for analysis. Results: Thirty patients were identified. The median age was 54.5 years (25-77). The male: female ratio was1:1. The Eastern Cooperative Oncology Group (ECOG) performance status (PS) was 0-1 in 21(70%), 2 in 4(13.3%) and 3 in 5(16.7%). The thyroid status was hypothyroid in 10 patients (33.3%), euthyroid in 12(40%) and hyperthyroid in 8(26.7%). In 5 patients it had to be stopped because of toxicity, these were proteinuria in 2, a hand-foot syndrome in 2 and diarrhoea in 1. The response rate was 56.7% (n = 17). The median progression-free survival (PFS) on lenvatinib was 366 days(95%CI 170.3-561.67) and the 2 year PFS was 29.3% (standard error 12.1) The median overall survival (OS) on lenvatinib was 411 days (95%CI 95.5-726.6). The 2 year OS was 38.8% (standard error -12.5%) and 5 year OS was 14.6% (standard error 12.1). Conclusions: In the real world lenvatinib provides a 2 year PFS and OS of 29.3% and 38.8% which is lower than that reported in the pivotal SELECT study.

Cabozantinib (C) versus placebo (P) in patients (pts) with radioiodine-refractory (RAIR) differentiated thyroid cancer (DTC) who have progressed after prior VEGFR-targeted therapy: Outcomes in prespecified subgroups based on prior VEGFR-targeted therapy.

6083 Background: Based on the results of the phase 3 COSMIC-311 trial, the multikinase inhibitor C was recently approved by the FDA for the treatment of RAIR DTC pts who progress after prior VEGFR-targeted therapies, such as lenvatinib (L) or sorafenib (S), and for whom there was no standard of care (Brose et al. Lancet Oncol. 2021). In an extended follow-up of the intent-to-treat (ITT) population, C-treated pts achieved a median (m) progression-free survival (PFS) of 11 months (mo) vs 1.9 mo with P (HR 0.22, 96% CI 0.15–0.32, P <.0001); here we present outcomes for prespecified subgroups who received prior L, S, or both. Methods: Pts were randomized 2:1 to C (60 mg QD) or P. P pts could cross over to open-label C upon disease progression per confirmation by blinded independent radiology committee (BIRC). The primary endpoints were PFS (ITT) and objective response rate (first 100 randomized pts), per RECIST v1.1 by BIRC. Pts must have received L or S and progressed during or after 1–2 prior VEGFR inhibitors. Results: After a median follow-up of 10.1 mo, 258 pts (170 C, 88 P) had been randomized (data cutoff 8 Feb 2021); 96 (̃37%) had received prior S (no L), 102 (̃40%) prior L (no S), and 60 (̃23%) prior S and L. Median PFS was 16.6 for C vs 3.2 mo for P in prior S (no L) (HR 0.13, 95% CI 0.06–0.26); 5.8 vs 1.9 mo in prior L (no S) (HR 0.28, 95% CI 0.16–0.48), and 7.6 vs 1.9 mo in prior S and L (HR 0.27, 95% CI 0.13–0.54). In the C arm, 21% of pts in prior S (no L), 3% in prior L (no S), and 8% in S and L subgroups had confirmed partial response, and 1 pt had a confirmed complete response in prior L (no S); there were no responses with P. Stable disease as best response was 67% for C vs 45% for P in prior S (no L), 68% vs 32% in prior L (no S), and 74% vs 38% in prior S and L. Median duration of C-exposure was 7.0 mo in prior S (no L), 5.6 mo in prior L (no S) and 5.9 mo in prior S and L. Grade 3/4 treatment-emergent adverse events (TEAE) occurred in 63% pts in prior S (no L), 57% in prior L (no S), and 69% in prior S and L. Discontinuations of C due to TEAE occurred in 16% of pts in prior S (no L), 13% in prior L (no S), and 23% in prior S and L. There were no treatment-related deaths. Conclusions: In the extended follow-up, C maintained its superior PFS vs P irrespective of prior L and/or S. AEs in each subgroup were consistent with that of the overall population. This is also the first phase 3 study demonstrating a clinical benefit with C after prior L in RAIR DTC pts. Clinical trial information: NCT03690388.

Cabozantinib versus placebo in patients (pts) with radioiodine-refractory (RAIR) differentiated thyroid cancer (DTC) who progressed after prior VEGFR-targeted therapy: Outcomes in prespecified subgroups based on histology subtypes.

6081 Background: DTC comprises multiple histology subtypes, the most common being papillary and follicular. Based on results of the phase 3 COSMIC-311 trial, the multikinase inhibitor cabozantinib was recently approved by FDA for the treatment of pts with RAIR DTC who progressed after prior VEGFR-targeted therapy (Brose et al. 2021). In an extended follow-up, median (m) progression-free survival (PFS) was 11 months (mo) for cabozantinib vs 1.9 mo for placebo (HR 0.22, 96% CI 0.15–0.32, P<.0001) in the intent-to-treat (ITT) population (Capdevila et al. ESMO 2021. Abstr LBA67). Here we present outcomes for prespecified subgroups based on the baseline histology subtypes of papillary and follicular thyroid cancers. Methods: Pts were randomized 2:1 to cabozantinib (60 mg QD) or placebo. Placebo pts could cross over to open-label cabozantinib upon disease progression per blinded independent radiology committee (BIRC). Primary endpoints were PFS (ITT) and objective response rate (ORR, first 100 randomized pts), per RECIST v1.1 assessed by BIRC. Results: After a median follow-up of 10.1 mo, 258 pts (170 cabozantinib, 88 placebo) had been randomized (data cutoff 8 Feb 2021); 150 pts (96 cabozantinib, 54 placebo) had papillary thyroid cancer (PTC) and 113 pts (78 cabozantinib, 35 placebo) had follicular thyroid cancer (FTC), with the PTC and FTC subgroups each including 5 pts with both PTC and FTC. Sixty-three pts (̃56%) within the FTC subgroup had Hurthle cell and poorly differentiated variants. mPFS was 9.2 mo for cabozantinib vs 1.9 mo for placebo in the PTC subgroup (HR 0.27, 95% CI 0.17–0.43) and 11.2 mo vs 2.6 mo in the FTC subgroup (HR 0.18, 95% CI 0.10–0.31). The mPFS was 11.1 mo for cabozantinib and 1.9 mo for placebo for pts with Hurthle cell and poorly differentiated variants (HR 0.12, 95% CI 0.05–0.27). The ORR was 15% for cabozantinib vs 0% for placebo in the PTC subgroup and 8% vs 0% in the FTC subgroup. Median duration of cabozantinib exposure was 5.5 mo for the PTC subgroup and 7.3 mo for FTC. Grade 3/4 treatment-emergent adverse events (TEAE) in the cabozantinib arm occurred in 59% of pts in the PTC subgroup and 68% of pts in the FTC subgroup; discontinuations due to TEAE occurred in 17% and 15% of pts, respectively. Conclusions: In the extended follow-up, cabozantinib maintained superior efficacy vs placebo irrespective of histology subtype, including the aggressive Hurthle cell and poorly differentiated variants. The moderately higher rates of grade 3/4 TEAE in the FTC vs the PTC subgroup could be attributed to the longer median duration of exposure of cabozantinib in the FTC subgroup. Clinical trial information: NCT03690388.

A phase II study to evaluate the efficacy and safety of camrelizumab plus famitinib in advanced or metastatic thyroid cancer.

6085 Background: Many studies have confirmed that the combination with anti-vascular drugs can significantly improve the efficacy of anti-PD-1/PD-L1 inhibitor in a variety of tumors. Camrelizumab is a humanized anti-programmed cell death receptor 1 (PD-1) antibody. Famitinib is a tyrosine kinase inhibitor which exhibits anti-angiogenesis and antiproliferative effects via targeting VEGFR-2, c-Kit and PDGFR-β. Herein, we aimed to evaluate the efficacy and safety of camrelizumab plus famitinib in the treatment of advanced or metastatic thyroid cancer. Methods: A single-arm, open-label phase II study was conducted, patients (pts) with advanced or metastatic thyroid cancer were recruited, including radioiodine-refractory differentiated thyroid cancer (group 1), differentiated thyroid cancer ineligible for 131I treatment (group 2), medullary thyroid cancer (group 3) and anaplastic thyroid cancer (group 4). Pts received camrelizumab 200mg i.v. on day 1 of each 21-day cycle and oral famitinib 20mg po qd in 21-day cycles until progressive disease or drug intolerance. The primary endpoint was objective response rate (ORR). The secondary endpoints were safety, adverse events (AEs), duration of response (DoR), disease control rate (DCR), progression-free survival (PFS) and overall survival (OS). Results: Between Jan 14, 2020 and Feb 9, 2022, 74 pts were enrolled. There were 12/26/5/31 pts in group 1/2/3/4 respectively. Median follow-up time was 11.4 months. In group 1, of 12 evaluable pts, confirmed ORR, ORR and DCR accounted for 33.3%, 41.7% and 100.0%, respectively. In group 2, of 25 evaluable pts, the confirmed ORR and DCR were 44.0% and 96.0%, respectively. In group 3, of 5 evaluable pts, the confirmed ORR and DCR were 40.0% and 100.0%, respectively. In group 4, of 24 evaluable pts, the confirmed ORR, ORR and DCR were 62.5%, 75% and 95.8%, respectively. PFS and OS were not yet mature for group 1-3, and in group 4, of all enrolled pts, estimated median PFS was 8.4 months and estimated median OS was 13.6 months. 73 pts were included in safety set. The most common treatment related AEs were diarrhea (37.0%), palmoplantiplanar swelling syndrome (34.2%), hypertension (31.5%) and fatigue (31.5%). Conclusions: Camrelizumab plus famitinib demonstrated promising anti-tumor efficacy with acceptable toxicity in pts with advcanced or metastatic thyroid cancer. Clinical trial information: NCT04521348.

The efficacy and safety of anti–PD-1 antibody toripalimab combined with surufatinib in neoadjuvant treatment of locally advanced thyroid cancer: A phase II study.

6084 Background: Surgery is the primary treatment for locally advanced thyroid cancer. However, some locally advanced patients are not candidates for R0/1 resection. There is limited evidence of neoadjuvant treatment in locally advanced thyroid cancer. Surufatinib targets multiple kinases (VEGFR1-3, FGFR1 and CSF-1R) involved in tumor angiogenesis and tumor immune evasion. It is efficient, tolerable and safe for patients with radioiodine-refractory differentiated thyroid cancer to receive surufatinib. In addition, surufatinib plus toripalimab (an anti-PD-1 antibody) showed encouraging antitumor activity and an acceptable safety profile in advanced solid tumors. This study aimed to evaluate the efficacy and safety of surufatinib plus toripalimab in locally advanced thyroid cancer in the neoadjuvant setting. Methods: In this single-arm phase II study, patients with pathologically confirmed diagnosis of unresectable or borderline resectable differentiated thyroid cancer were eligible and received a combination of 250 mg surufatinib (oral, qd) with 240 mg toripalimab (IV, q3w). Treatment was continued until satisfied for curative surgery, disease progression, withdrawal of consent, unacceptable toxicity or investigator decision. Primary endpoint was objective response rate (ORR) by RECIST 1.1. Secondary endpoints included R0/1 resection rate, disease control rate (DCR), time to remission (TTR), adverse events (AEs), etc. Results: This study is ongoing. 10/10 patients were enrolled. 6 patients received ≥4 cycles of surufatinib plus toripalimab treatment and were also evaluated for efficacy. The ORR was 66.7% with 4 partial response (PR) and 2 stable disease (SD). 4 PR and 1 SD patients received R0 resections after neoadjuvant treatment. The safety was consistent with previously reported. No grade ≥3 AEs were observed. Specific AEs data are still being counted. Conclusions: Surufatinib in combination with toripalimab as neoadjuvant therapy for locally advanced thyroid cancer was feasible and majority of patients achieved R0 resection. AEs were mainly grade 1-2, and this combination was well-tolerated. The combination of these two agents should be further investigated for neoadjuvant treatment of locally advanced thyroid cancer based on good results. Clinical trial information: NCT04524884.

A Multicenter Randomized Phase II Study of Single Agent Efficacy and Optimal Combination Sequence of Everolimus and Pasireotide LAR in Advanced Thyroid Cancer.

Simple SummaryPrior clinical studies showed modest activity for single agent everolimus and somatostatin analogues in different subtypes of thyroid cancer; the combination of everolimus and somatostatin analogue was synergistic in preclinical models of thyroid cancer. This randomized trial showed that the combination was more effective than a single agent and the sequence of single agent everolimus followed by the delayed combination of everolimus and pasireotide-LAR achieved the best efficacy and was the optimal combination strategy.Purpose: Aberrant mTOR pathway and somatostatin receptor signaling are implicated in thyroid cancer and offer potential therapeutic targets. We assessed the clinical efficacy of everolimus and Pasireotide long-acting release (LAR) in radioiodine-refractory differentiated thyroid cancer (DTC) and medullary thyroid cancer (MTC). Patients and methods: Adults with progressive MTC and DTC untreated or treated with no more than one systemic agent were eligible. The trial was designed to establish the most promising regimen and the optimal combination sequence. Patients were randomized to start treatment with single agent everolimus (10 mg QD; Arm A), pasireotide-LAR (60 mg intramuscular injection, Q4 weeks; Arm B), or the combination (Arm C). At initial progression (PFS1), patients on Arm A or B switched to the combination and continued until progression (PFS2). Efficacy was measured by RECIST criteria. Results: Study enrolled 42 patients: median age 65 years; female 17 (40.5%); White 31 (73.8%), African American 6 (14.3%), others 5 (11.9); DTC 32 (76.2%); MTC 10 (23.8%). There was no objective response by RECIST criteria across the three arms. Median and 1-year PFS1 rates were 8.3, 1.8, 8.1 months and 49.9%, 36.4%, 25.0% for Arms A, B, C, respectively. Median and 1-year PFS2 rates were 26.3, 17.5, 8.1 months and 78.4%, 70.0%, 25% for Arms A, B, C, respectively. The most frequent adverse events were anemia, stomatitis, fatigue, hyperglycemia, and hypercholesterolemia. Conclusions: The combination of everolimus and pasireotide-LAR showed promising efficacy over single agent. The delayed combination of everolimus and pasireotide-LAR following progression on single agent everolimus appeared intriguing as a combination strategy.

68Ga-DOTA-FAPI-04 PET/CT imaging in radioiodine-refractory differentiated thyroid cancer (RR-DTC) patients.

This study aimed to assess the potential of 68Ga-DOTA-FAPI-04 PET/CT for the detection of the radioiodine-refractory differentiated thyroid cancer (RR-DTC) lesions. We analyzed the 68Ga-DOTA-FAPI-04 PET/CT imaging data of 24 RR-DTC patients (7 men and 17 women; 49.6 ± 10.5 year). Clinical data were collected including history, last post-therapeutic radioiodine whole body scan, contemporary CT, thyroglobulin, and antithyroglobulin. Target lesions were selected and measured by the RECIST 1.1. The mean growth rates of the target lesions in the past 6months were recorded. Tumor uptake of lesions were quantified by SUVmax and the tumor-to-background ratios. The correlation between SUVmax and target lesion growth rate and thyroglobulin was analyzed. On patient-based analysis, positive metastases were detected in 87.5% (21/24) patients. Except for the lymph node (LN) metastasis of 3 patients (patient 6, 12 and 17#) and the lung metastasis of another 3 patients (patient 9, 13 and 21#), most of the lesions were positive on 68Ga-DOTA-FAPI-04 PET/CT images, including LN metastasis and distant metastasis such as lung, bone and pleura. There were altogether 33 target lesions including 30 lung metastases and 3LN metastases with the mean SUVmax and the growth rate were 4.25 and 6.51%, respectively. SUVmax was statistically associated with the growth rates of the target lesions (p = 0.047). No statistically significant correlation was found between the SUVmax and the serum thyroglobulin levels (p = 0.139). 68Ga-DOTA-FAPI-04 PET/CT has a promising detection rate for RR-DTC metastasis. The FAPI uptake of the tumor may provide a potential therapeutic target for RR-DTC. NIH Clinical Trials.gov (NCT04499365).

Clinical experience with tyrosine kinase inhibitors in radioiodine-refractory differentiated thyroid cancer

Clinical experience with tyrosine kinase inhibitors in radioiodine-refractory differentiated thyroid cancer

Cabozantinib versus placebo in patients with radioiodine-refractory differentiated thyroid cancer (DTC) who have progressed after prior VEGFR-Targeted yherapy: updated results from the phase 3 COSMIC-311 trial and prespecified subgroup analyses based on prior therapy

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Lenvatinib for the Treatment of Radioiodine-Refractory Differentiated Thyroid Cancer: Treatment Optimization for Maximum Clinical Benefit.

BackgroundLenvatinib is a multitargeted tyrosine kinase inhibitor approved for treating patients with locally recurrent or metastatic progressive radioiodine-refractory differentiated thyroid cancer (RR-DTC). In this review, we discuss recent developments in the optimization of RR-DTC treatment with lenvatinib.SummaryInitiation of lenvatinib treatment before a worsening of Eastern Cooperative Oncology Group performance status and elevated neutrophil-to-lymphocyte ratio could benefit patients with progressive RR-DTC. The median duration of response with lenvatinib was inversely correlated with a smaller tumor burden, and prognosis was significantly worse in patients with a high tumor burden. An 18 mg/day starting dose of lenvatinib was not noninferior to 24 mg/day and had a comparable safety profile. Timely management of adverse events is crucial, as patients with shorter dose interruptions benefitted more from lenvatinib treatment. Caution should be exercised when initiating lenvatinib in patients who have tumor infiltration into the trachea or other organs, or certain histological subtypes of DTC, as these are risk factors for fistula formation or organ perforation. The Study of (E7080) LEnvatinib in Differentiated Cancer of the Thyroid (SELECT) eligibility criteria should be considered prior to initiating lenvatinib treatment.ConclusionsCurrent evidence indicates that patients benefit most from lenvatinib treatment that is initiated earlier in advanced disease when the disease burden is low. A starting dose of lenvatinib 24 mg/day, with dose modifications as required, yields better outcomes as compared to 18 mg/day. Appropriate supportive care, including timely identification of adverse events, is essential to manage toxicities associated with lenvatinib, avoid longer dose interruptions, and maximize efficacy.

Interdisciplinary databank in oncoendocrinology: radioiodine refractory differentiated thyroid cancer

High achievements in personalized evidence-based medicine and oncology, particularly in developed countries, are associated with the successful development of clinical carceral registries of patients (SEER, NCDB, etc.), which are multimodal data banks. They are a data matrix for the development of analytical and prognostic tools in the study of diagnostic features, clinical disease course, therapy response, assessment of prognostic factors, etc. From the point of view of medical digital data banks, data redundancy and duplication are not as critical as information incompleteness or inconsistency when making medical decisions.
 This study aimed to present a multimodal database of patients with radioiodine refractory differentiated thyroid cancer, which is essentially a modern interdisciplinary digital medical registry.
 Along with demographic and nosological data that is typical for epidemiological registers, the multimodal data banks consider key clinical and paraclinical data, such as the results of laboratory, morphological, and instrumental research methods, and various imaging methods, such as ultrasound, computed tomography (CT), magnetic resonance imaging, single-photon emission computed tomography/CT, and positron emission tomography/CT. The multimodal data banks present the molecular genetic profile results of the tumor, of which the clinical usefulness in the choice of treatment tactics is undoubted today. All these data are accumulated in the multimodal data banks, noting the execution time and the revision results (second opinion), considering standardized qualitative and quantitative parameters (factors) that potentially affect the clinical course, treatment response, complication development, and outcomes.

Assessment of Treatment Response to Lenvatinib in Thyroid Cancer Monitored by F-18 FDG PET/CT Using PERCIST 1.0, Modified PERCIST and EORTC Criteria-Which One Is Most Suitable?

Simple SummaryIn patients with progressive metastatic radioiodine-refractory differentiated thyroid cancer, tyrosine kinase inhibitor (TKI) therapy with lenvatinib improves progression-free survival. Early identification of patients with therapeutic responses to the TKI therapy is clinically relevant due to common side effects and toxicity. The use of metabolic response criteria derived from F-18 fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) imaging can help to identify those patients who benefit from treatment. In our study, we evaluated different response criteria, namely, the Positron Emission Tomography Response Criteria In Solid Tumors (PERCIST) and European Organization for Research and Treatment of Cancer (EORTC) criteria, to find out which system might be more reliable and suitable in everyday clinical practice. The EORTC criteria could be applied to all patients, and the different PERCIST criteria, in 80% and 88%, respectively. Regarding their survival and treatment responses, patients with a progressive disease could be reliably identified by using all the criteria.Background: We aimed to compare the established metabolic response criteria PERCIST and EORTC for their applicability and predictive value in terms of clinical response assessment early after the initiation of lenvatinib therapy in patients with metastatic radioiodine-refractory (RAI) thyroid cancer (TC). Methods: In 25 patients treated with lenvatinib, baseline and 4-month follow-up F-18 FDG PET/CT images were analyzed using PERCIST 1.0, modified PERCIST (using SUVpeak or SUVmax) and EORTC criteria. Two groups were defined: disease control (DC) and progressive disease (PD), which were correlated with PFS and OS. Results: PERCIST, mPERCIST, PERCISTmax and EORTC could be applied in 80%, 80%, 88% and 100% of the patients based on the requirements of lesion assessment criteria, respectively. With PERCIST, mPERCIST, PERCISTmax and EORTC, the patients classified as DC and PD ranged from 65 to 68% and from 32 to 35%, respectively. Patients with DC exhibited a longer median PFS than patients with PD for EORTC (p < 0.014) and for PERCIST and mPERCIST (p = 0.037), respectively. Conclusion: EORTC and the different PERCIST criteria performed equally regarding the identification of patients with PD requiring treatment changes. However, the applicability of PERCIST 1.0 using SULpeak seems restricted due to the significant proportion of small tumor lesions.

Historical aspects and modern concepts in the treatment of patients with differentiated thyroid cancer, refractory to radioactive iodine therapy

Radioiodine therapy for differentiated thyroid cancer has been used for a long time, mainly in patients of intermediate and high risk, as well as in the presence of distant metastases. However, about 30–40 % of patients are refractory to radioiodine therapy, which significantly worsens the prognosis. In patients with radioiodine-refractory differentiated thyroid cancer, therapy with targeted agents, primarily tyrosine kinase inhibitors, is indicated.This review addresses the criteria for refractoriness and criteria for prescription of targeted therapy, and presents the results of clinical studies of the targeted agents used. As of today, lenvatinib is the most well-known targeted agent. In particular. In SELECT trial lenvatinib demonstrated efficacy in terms of progression-free survival and overall survival in patients with radioiodine-refractory differentiated thyroid cancer. As a result, lenvatinib was included in the international and Russian clinical guidelines for the management of this group of patients as a drug of the 1st line of targeted therapy.

A proposed clinical scoring system for initiation of lenvatinib treatment in radioiodine-refractory thyroid cancer patients.

The optimal timing for starting lenvatinib treatment in patients with radioiodine-refractory differentiated thyroid cancer (RR-DTC) has long been controversial because of the relatively slow-growing nature of differentiated thyroid cancer. The aim of this study was to establish a scoring system using known clinical factors to simplify decision-making in when to start lenvatinib in RR-DTC patients. We retrospectively analyzed RR-DTC patients treated with lenvatinib. We developed the clinical indication scoring algorithm on the basis of age, tumor-related symptoms, histology, metastatic sites, neutrophil-to-lymphocyte ratio, size of lung metastases, baseline sum of tumor diameters, and tumor-volume doubling time that was used to categorize patients into low-, intermediate-, and high-risk groups. A total of 59 patients were analyzed; 13 low-risk, 36 intermediate-risk, and 10 high-risk. The respective median progression-free survival from the initiation of lenvatinib was 93.7 months in the low-risk group, 20.3 months in the intermediate-risk group, and 6.2 months in the high-risk group (p < 0.02). Patients in the high-risk group had significantly worse overall survival compared with those in the low-risk (hazard ratio [HR] 6.59, 95% confidence interval [CI] 1.25-34.90, p < 0.03) or intermediate-risk (HR 2.99, 95% CI 1.03-8.63, p < 0.05) group. Using our proposed algorithm, patients in the intermediate-risk group showed treatment outcomes similar to that were observed in the pivotal trial of lenvatinib, and were the optimal patients to start lenvatinib. Our proposed scoring system can separate treatment outcomes and prognosis of RR-DTC patients treated with lenvatinib. This simple algorithm can be helpful for oncologists in deciding whether to start lenvatinib treatment in patients with RR-DTC.

Radioiodine Refractory Differentiated Thyroid Cancer.

Patients with radioactive iodine (RAI) refractory locally advanced or metastatic differentiated thyroid cancer have a poor prognosis. This article reviews the definition of RAI-refractory thyroid cancer and the management approach. Watchful waiting should be considered for patients with asymptomatic and non-progressive disease, while oral targeted agent with tyrosine kinase inhibitors can be considered for patients who are symptomatic or whose disease would cause irreversible complications if treatment has not been initiated. Since these targeted agents only improve disease-free survival and are associated with adverse events, physicians should assess both clinical and tumor factors carefully to decide on the right timing of start of palliative treatment.

Novel Fibroblast Activation Protein Inhibitor-Based Targeted Theranostics for Radioiodine-Refractory Differentiated Thyroid Cancer Patients: A Pilot Study.

Background: This exploratory study was meant to assess clinical and safety data with a novel fibroblast activation protein inhibitor-based targeted theranostics as a salvage treatment option in radioiodine-refractory differentiated thyroid cancer (RR-DTC) patients who had progressed on tyrosine kinase inhibitors. Methods: Patients with metastatic RR-DTC who progressed on sorafenib/lenvatinib were prospectively recruited. If [68Ga]Ga-DOTA.SA.FAPi positron emission tomography/computed tomography scan demonstrated moderate-to-excellent uptake in metastases, and patients had given informed consent, they received intravenous [177Lu]Lu-DOTAGA.(SA.FAPi)2 as therapy at eight-weekly intervals. The primary endpoints were thyroglobulin (Tg) response and functional imaging response. The secondary endpoints were visual analog score (VAS) and Eastern Cooperative Oncology Group (ECOG) performance status. The grading of toxicities was performed by using Common Terminology Criteria for Adverse Events (CTCAEV5.0). The sequential images were acquired by a dual-headed gamma camera, and dosimetric calculations were performed by using OLINDA/EXM V2.1. Results: Fifteen patients were recruited [age: 55 ± 9 years (range: 39-67)]. [177Lu]Lu-DOTAGA.(SA.FAPi)2 had median whole-body Teff of 88.06 hours (interquartile range [IQR]: 86.6-99). The colon was identified as a critical organ. The whole-body effective dose was 1.62E-01 ± 1.53E-02 mSv/MBq. A total of 45 cycles were administered, and the median cumulative administered activity was 8.2 ± 2.7 GBq (range 5.5-14 GBq). The median absorbed doses to the tumor lesions were 1.08E+01 (IQR: 4.16E+00 to 8.97E+01) mSv/MBq per cycle. The Serum Tg level significantly decreased after treatment [(median Tg: baseline-10,549 ng/mL (IQR: 3066.5-39,450) versus at the time of assessment: 5649 ng/mL (IQR: 939.5-17,099), p = 0.0005)]. Molecular response assessment revealed no complete response; however, partial response was documented in four, and stable disease in three patients. The VASmax scores [pre-therapy: 9 (IQR: 8-10) versus follow-up: 6 (3-6) (p-0.0001)], and ECOG [3, (IQR: 2-3 vs. 2, (IQR: 2-3) (p-0.0078)] performance scores significantly improved after treatment. None of the patients experienced grade III/IV hematological, renal, or hepatotoxicity. Conclusion: These preliminary data suggest that the novel molecule [177Lu]Lu-DOTAGA.(SA.FAPi)2 is safe, seems effective, and, most importantly, opens up a new avenue for the treatment of aggressive RR-DTC patients who have exhausted all standard line of treatments.

Cortisol Deficiency in Lenvatinib Treatment of Thyroid Cancer: An Underestimated Common Adverse Event.

Background: Lenvatinib treatment has shown a significant improvement in progression-free survival in patients with metastatic, progressive, radioiodine-refractory differentiated thyroid cancer, although its use is associated with considerable toxicity. Fatigue is one of the most frequent adverse events (AEs). It has been reported that adrenal insufficiency (AI) may be involved in lenvatinib-related fatigue. In our study, we assessed the pituitary/adrenal axis before and during treatment, and the possible involvement of AI in lenvatinib-related fatigue. This was done to clarify the incidence, development, and time course of AI during lenvatinib treatment.Methods: We studied 13 patients who were selected for lenvatinib therapy. Adrenal function was evaluated by measuring cortisol and adrenocorticotropic hormone (ACTH) levels and through the ACTH (250 μg) stimulation test.Results: During treatment, seven patients (54%) developed AI. High levels of ACTH were observed in accordance with the diagnosis of primary AI (PAI). By evaluating the first ACTH test, before starting lenvatinib treatment, we found that patients with <646.6 nmol/L cortisol peak had an increased risk of developing PAI during lenvatinib treatment. Fatigue was observed in 11 patients (84.6%) during lenvatinib treatment. Cortisone acetate treatment induced an improvement in fatigue in six of seven patients (85.7%) in the PAI group, without the need to change the lenvatinib dosage.Conclusions: PAI may be considered one of the most common AEs associated with lenvatinib. Our data strongly suggest that PAI could be involved in lenvatinib-associated fatigue, particularly in patients with extreme fatigue. In this context, early diagnosis of PAI is essential, especially since glucocorticoid replacement therapy can induce a significant improvement in fatigue, without the need to reduce the dosage of lenvatinib. However, further studies are required to confirm these preliminary findings.

Radioiodine Refractory Follicular Thyroid Cancer and Surgery for Cervical Relapse.

Simple SummaryDifferentiated thyroid cancer includes papillary (PTC) and follicular thyroid cancer (FTC). Eighty-five percent of patients are cured by thyroidectomy and one single radioiodine treatment. Relapse is rare and can mostly be cured by a second radioiodine therapy. Between 5% and 10% of differentiated thyroid cancers are, or become, unresponsive to radioiodine treatment during the course of disease. For these patients repeated surgery is the only curative option: chemotherapy and external beam radiation play a minor role, targeted therapy is started in a palliative setting for rapidly progressing tumors. In most studies on radioiodine refractory differentiated thyroid cancer, there is a predominance of PTC, due to its higher incidence compared to FTC. In the present study we critically evaluate indications and outcome of repetitive cervical surgery for radioiodine refractory FTC at our university clinic.Compared to its more common counterpart papillary thyroid cancer (PTC), follicular thyroid cancer (FTC) has a less favorable outcome, due to its higher incidence of distant metastases and advanced stages at diagnosis. Despite radioiodine (RAI) avidity, metastatic FTC often progresses after radioiodine treatment (RAIT). We aimed at evaluating the indications and outcomes of surgery for cervical relapse of radioiodine refractory FTC. Patients receiving RAIT between 2005 and 2015 at the University Hospital of Cologne, Germany, were screened. Patients with FTC were identified. Demographics, clinic-pathologic characteristics, treatment, and outcome of patients diagnosed with RAI refractory FTC, who underwent cervical surgery in the course of disease, were analyzed. FTC accounted for 8.8% of all thyroid carcinomas undergoing RAIT. In 35.2% of FTC patients, disease persisted or recurred despite a cumulative mean RAI activity of 18.7 GBq ± 11.6 (follow-up 83.5 ± 56.7 months). Distant metastases were diagnosed in 75% of these patients, as bone (57.6%), lung (54.6%), and liver metastases (12.1%). Cervical relapse occurred in 63.6% of these patients and was treated in 57.1% with surgery with, and without, external beam radiation therapy (EBRT). Despite surgery and EBRT, in 75% of patients, cervical relapse recurred again. In conclusion, surgery for cervical radioiodine refractory FTC relapse is often performed in metastatic setting. With and without EBRT, cure is rare, although metastases can appear radioiodine avid. Early biological marker and systemic treatments for these patients are still needed.

Current Status and Future Perspective of the Treatment for Radioiodine Refractory Differentiated Thyroid Cancer

Other SectionsAbstract최초의 항암 표적치료제인 방사성요오드의 사용NIS의 재발현 유도를 위한 재분화요법초기의 표적치료제/키나제 억제제들의 임상시험 결과DECISION과 SELECT 임상: sorafenib과 lenvatinib을 이용한 전향적 3상 임상연구실제 임상에서의 결과(Real world data)갑상선암 치료에서 정밀의료순차적 구제요법향후의 전망감사의 말씀Conflicts of InterestReference

Personalized therapy with lenvatinib for progressive radioiodine refractory differentiated thyroid cancer in routine clinical practice

Among the differentiated forms of thyroid cancer, the least favorable clinical prognosis is observed in radioiodine-refractory differentiated thyroid cancer. The next step in the treatment of such patients is effective and potential toxicity multi-kinase inhibitors. Often, patients with refractory radioiodine thyroid cancer have a high tumor burden, various symptoms and comorbidity; therefore, clinicians may decide to initiate therapy at a reduced starting dose. In a randomized clinical multicenter study 211 higher objective response rate at 24th weeks were observed in the group of patients receiving lenvatinib at a dose of 24 mg per day compared with patients receiving Lenvatinib at a dose of 18 mg per day, while the difference in the incidence of serious adverse events grade 3–4 (SAE) at the 24th week of treatment were insignificant. Real clinical practice differs from randomized clinical trials regarding to the population of patients, their selection for treatment, adherence to drug dosage regimens, follow-ups, etc. In this paper, we analyzed the world and domestic clinical practice of the treatment of radioiod-refractory thyroid cancer and assessed the effect of the starting dose of lenvatinib and the duration of breaks in its administration on the effectiveness and safety of therapy.