Radioiodine Plus Low-Dose Lenvatinib in Radioiodine-Sensitive High-Volume Metastatic Differentiated Thyroid Cancer: A Pilot Study.

Background: Some patients with metastatic differentiated thyroid cancer (DTC) lack iodine avidity and are therefore unsuitable for radioactive iodine (RAI) therapy. Limited experience suggests that single-agent selective mitogen-activated protein kinase (MAPK) pathway inhibitors can restore expression of the sodium-iodide symporter rendering RAI refractory (RAIR) DTC patients amenable to RAI therapy. The aim of this study was to assess the feasibility of mutation-guided MAPK-pathway blockade combined with thyroid hormone withdrawal (THW) for redifferentiation. Methods: This is a retrospective review of metastatic RAIR DTC and driver mutation in MAPK pathway, treated on a redifferentiation protocol. All patients had metastatic disease that had never been RAI-avid and/or imaging and biochemical progression despite treatment with RAI within the past 12 months. Patients with tumors harboring an NRAS mutation were treated with an MEK inhibitor (trametinib), and tumors with a BRAFV600E mutation with combined BRAF and MEK inhibition (dabrafenib and trametinib; or vemurafenib and cobimetinib) for four weeks. Thyrotropin stimulation was performed by THW for four weeks. Restoration of RAI uptake was determined by 124I positron emission tomography/computed tomography imaging. The response was assessed at least three months post-RAI. Results: From 2015 to 2017, six patients (age 45-70, four females) received redifferentiation therapy. Three patients had an NRAS mutation; two with follicular thyroid carcinoma (FTC) and one with a poorly differentiated thyroid carcinoma (PDTC); and three patients had a BRAFV600E mutation and papillary thyroid carcinoma (PTC). One NRAS and all BRAFV600E mutation cases demonstrated restoration of RAI uptake and proceeded to RAI therapy with a median follow-up of 16.6 months (range 13.5-42.3 months). The patient with an NRAS mutation and two of three patients with a BRAFV600E demonstrated partial imaging response beyond a three-month follow-up. Grade 3 adverse events (acneiform rash) were observed in two patients with NRAS mutations. Conclusions: Mutation-guided MAPK pathway inhibition with MEK inhibitor or a combination of BRAF inhibitor and MEK inhibitor under concurrent THW is a feasible and a promising strategy to redifferentiate RAIR DTC, thereby rendering them suitable for RAI therapy with satisfactory retention following treatment.

The management guidelines of radioactive Iodine (RAI) therapy for distinct types of differentiated thyroid carcinoma (DTC) were the same in clinical practice. However, in distinct types DTC, differences in RAI avidity and response existed and the effect of RAI therapy could not be equated. DTC patients' data in SEER database were extracted to perform retrospective analysis. The differences between case group and control group were compared by chi-square tests. We used Kaplan-Meier statistics and Cox regression analyses to investigate cancer-specific survival (CSS). Propensity score-matched was performed to make 1:1 case-control matching. 105195 patients who receiving total thyroidectomy were identified in SEER database. Compared to papillary thyroid carcinoma (PTC) (52.3%), follicular thyroid carcinoma (FTC) (63.8%) and oncocytic carcinoma of thyroid (OCA) (64.4%) had higher rates of RAI therapy. In the multivariable Cox regression model, RAI therapy was independent prognosis factor in PTC but not in OCA and FTC. In subgroup analysis, RAI therapy could improve prognosis in PTC when gross extrathyroidal extension or lymph node metastases or early survival when distant metastases (DM) were presented. However, OCA and FTC patients with DM rather than regional lesions only could benefit from RAI therapy. High-risk patients receiving RAI therapy showed a better prognosis in PTC but not in OCA and FTC. RAI therapy was an effective treatment for DTC and should be considered individually in PTC, OCA and FTC patients. Our results provided further guideline for treatment selection in DTC.

Refractory differentiated thyroid carcinoma (DTC) and anaplastic thyroid carcinoma (ATC) are associated with poor prognoses. Molecularly targeted agents such as lenvatinib are expected to significantly improve outcomes. However, data from real-world settings remain limited. A retrospective analysis was conducted in 48 patients with thyroid carcinoma treated with lenvatinib at Kyushu University Hospital between April 2015 and October 2024. We compared overall survival (from time of treatment initiation to death, censoring, or data cutoff) and progression-free survival (from time of treatment initiation to tumor progression as confirmed by image examination) using Kaplan-Meier analysis. A subgroup analysis was also conducted for patients who had and had not received prior radioactive iodine (RAI) therapy. The analysis included 29 female and 19 male cases. The histologic types were papillary thyroid carcinoma in 26 patients, follicular thyroid carcinoma in seven patients, and ATC in 15 patients. Of 33 DTC cases, RAI was not administered in nine cases. The median progression-free survival was 30 months for papillary thyroid carcinoma, 18 months for follicular thyroid carcinoma, and four months for ATC. The median progression-free survival for patients with DTC who received RAI therapy was 19 months, whereas that for patients with DTC without RAI therapy was 46 months. No significant difference was found between the two groups (p=0.243). Lenvatinib may be effective in patients with DTC in whom RAI treatment is not feasible in real-world settings.

Effects of I-131 therapy on gonads and pregnancy outcome in patients with thyroid cancer

BackgroundIn some patients with metastatic differentiated thyroid cancer, even if they had substantial of radioactive iodine (RAI) uptake, the RAI therapy response was poor. We investigated the usefulness of FDG PET/CT for the early prediction of RAI therapy response in the patients with metastatic differentiated thyroid cancer (DTC).MethodsThe 54 metastatic DTC patients who underwent both RAI therapy scan and FDG PET/CT at the same period were enrolled in the study. Clinical information and several parameters from RAI therapy scan and FDG PET/CT were investigated. Therapeutic response of RAI was assessed as two categories: response rate (RR) and disease control rate (DCR).ResultsTwenty-two patients (41%) had therapeutic response to RAI therapy, whereas 32 (59%) patients did not. There were no significant differences in age, sex, stage, histology, metastasis site, stimulated Tg or Tg-Ab, therapeutic doses, and even RAI uptake pattern among two groups. However, there was a significant negative correlation between FDG avidity of metastatic lesions and RR (OR = 0.233; p = 0.016). Although the patient group with only RAI uptake showed a significant correlation with RR (OR = 5.833; p = 0.01), the patient group with both RAI and FDG uptake did not show any significant correlation with RR. In the subgroup analysis, uptake grades of RAI or FDG was well correlated with DCR.ConclusionsThe patient group with FDG uptake in metastatic DTC showed poor response to RAI therapy regardless of the degree of RAI uptake. Therefore, FDG PET/CT may help us identify the patients with radioiodine refractory DTC and establish an appropriate treatment strategy in the early period.

This study aimed to investigate the influence of radioactive iodine (RAI) therapy on liver function in patients with differentiated thyroid cancer (DTC), with emphasis on sex and dose accumulation. Liver function after the first RAI ablation with ~3700 MBq (100 mCi) dosage was compared with baseline liver function in 357 patients with DTC (male: 110 and female: 247). Further comparisons were conducted in patients after regular and successive RAI therapies with available data, 126 patients (male: 37 and female: 89) with two RAI therapies, 52 patients (male: 16 and female: 36) with three RAI therapies, and 19 patients (male: 5 and female: 14) with four RAI therapies. Analyses were performed to evaluate the potential effect of RAI on liver function, including total protein (TP), albumin (ALB), globulin (GLO), alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), γ-glutamyltransferase (GGT), lactic dehydrogenase, total bilirubin (TBIL), and direct bilirubin (DBIL) in both sexes. Continuous variables were analyzed by using nonparametric analysis. Compared with the original hepatic function, TP (P<0.01), ALB (P<0.05), GLO (P<0.01), ALT (P<0.05), ALP (P<0.01), and GGT (P<0.01) declined significantly after the first RAI ablation in both sexes. TP, GLO, and GGT declined significantly in both sex subgroups, whereas ALT (P<0.05), ALP (P<0.01), and lactate dehydrogenase (P<0.05) showed significant decline in male subgroup, and TBIL (P<0.05) in female subgroup. As to the level of liver function after the second RAI therapy, TP (P<0.01), GLO (P<0.01), ALP (P<0.01), GGT (P<0.01), and DBIL (P<0.05) showed a significant decreasing trend. In both sex subgroups, TP, GLO, and GGT reduced significantly. Moreover, only ALP (P<0.01) significantly decreased in the male subgroup. As to the level of liver function after the third RAI therapy session, TP (P<0.01) and GLO (P<0.01) reduced significantly, whereas DBIL (P<0.05) was higher than the original level. In sex subgroups, TP (P<0.05) decreased significantly in the male subgroup, and GLO (P<0.01) decreased significantly in the female subgroup, but DBIL (P<0.05) increased significantly in the female subgroup. As to the level of liver function after the fourth RAI therapy, TBIL (P<0.05) and DBIL (P<0.01) increased significantly. In sex subgroups, TBIL (P<0.05) and DBIL (2.09±0.92 vs. 2.91±1.14 μmol/l, P<0.05) showed an increasing trend in the female subgroup only. Liver function of patients with DTC after the first RAI ablation decreased significantly, including TP, ALB, GLO, ALT, ALP, and GGT. However, after multiple and regular RAI therapies, TBIL and DBIL showed an increasing trend. Particularly, TBIL and DBIL showed an increasing trend in the female subgroup only.

PurposeManagement of progressive, metastatic radioactive iodine refractory differentiated thyroid cancer (RAIR-DTC) has been a great challenge due to its poor prognosis and limited treatment options. Recently, apatinib, an orally anti-angiogenic tyrosine kinase inhibitor (TKI) is reported to be useful for treatment of progressive RAIR-DIC. The aim of this study was to evaluate the antitumour effect of apatinib and the combination therapy with radioactive iodine (RAI) in patients with progressive metastatic DTC.MethodsFive patients (all female, mean age 62 ± 8 years, ranged from 51 to 69 years) with distant metastatic DTC (dmDTC) after total thyroidectomy (TTE) and neck lymph node dissection were treated with apatinib at a dose 500 mg per day after 18F-Fluorodeoxyglucose (18F-FDG) PET/CT. The effects of apatinib on DTC were evaluated at 4 ± 1 months after treatment with apatinib. RAI therapy was then initiated. The response to apatinib and the combination therapy with RAI treatment was evaluated by Response Evaluation Criteria in Solid Tumours (RECIST, version 1.1) and metabolic activity using serum thyroglobulin (Tg) and 18F-FDG PET/CT.ResultsPositive 18F-FDG PET/CT results were found in all patients before apatinib therapy. The immunohistochemical analysis of primary tumour tissues showed high expression of vascular endothelial growth factor receptor-2 (VEGFR-2). Four patients with follicular thyroid carcinoma (FTC) showed partial response (PR) with significant decrease in tumour size and maximum standardized uptake value (SUVmax) after 4 ± 1 month’s treatment with apatinib. Further significant reduction of tumour size and SUVmax were observed in three patients after combination therapy with apatinib and RAI. Only one patient with both FTC and papillary thyroid cancer (PTC) demonstrated progressive disease (PD) after treatment with apatinib alone, however, a decrease in tumour size and SUVmax as well as serum Tg levels was achieved after the combination with RAI therapy and apatinib.ConclusionsApatinib had significant antitumour effects on progressive distant metastatic DTC. Moreover, beneficial synergistic and complementary effects were shown when apatinib combined with RAI therapy.Clinical Trial RegistrationNCT 04180007, Registered November 26, 2019.

The association between radioactive iodine (RAI) therapy and reduced fertility has remained controversial, in part because no large-scale randomized clinical trials or prospective studies have been done in this regard. Hence, we performed this meta-analysis to investigate the association between radioactive iodine therapy and birth rates in female patients in their reproductive years diagnosed with well- differentiated thyroid cancer. Relevant articles were retrieved from PubMed Central and PubMed according to the established inclusion criteria, followed the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) statement. Each article was assessed by the Newcastle-Ottawa Scale (NOS). The overall relative risk (RR) and 95% confidence intervals (CI) were calculated to estimate the association between radioactive iodine (RAI) therapy and birth rates. Random effect or fixed-effect model was used to calculate the pooled OR, based on heterogeneity significance. Subgroup analysis was conducted based on different age groups (<25 years old vs. 25-34 years old vs. >35 years old). Sensitivity analysis and publication bias detection were also performed. All statistical analyses were performed using RevMan software (version 5.3; Cochrane library) and STATA 12.0 software (Stata Corp., College Station, TX), and all P values were two-tailed, the test level was 0.05. 105 articles were obtained from the database search, and 6 articles were obtained from other sources. Three articles involving 32237 participants were included. All studies were considered moderate to high quality. Overall, no statistically significant association was observed (RR 1.02; 95% CI: 0.71,1.48, p=0.91, I2=96%). In subgroup analysis, groups with age <24 y/o (RR 0.87; 95% CI:0.76,0.99,p= 0.04, I2=0%), and age >35 y/o (RR 0.71; 95%CI: 0.59, 0.85, p=0.0002, I2=0%), there was an associated reduction in birth rates in patients who received radioactive iodine treatment. In contrast, in the group between 25 and 34 years of age, no statistically significant observation was made (RR 0.99; 95% CI:0.79,1.22, p= 0.89, I2=82%). Sensitivity analysis confirmed the stability of the result. Egger’s test, and Begg’s test found no publication bias of analysis (p= 0.824; p=0.602). This meta-analysis demonstrated that overall, no statistically significant association between RAI treatment and birth rates in female patients within their reproductive ages diagnosed with well- differentiated thyroid cancer. However, in the subgroup analysis, an association was found between RAI treatment and reduced birth rates in females <25 years old and those >35 years old. In contrast, no association of RAI treatment with birth rates in females 25-34 years old was found. More highly powered prospective studies of this topic are needed in the future to further elucidate the impact of RAI treatment on birth rates and fertility.

Our aim was to evaluate the effectiveness of off-label use of sunitinib in patients with advanced differentiated thyroid carcinoma (DTC) refractory to radioactive iodine (RAI) therapy. We performed a retrospective analysis of patients treated in the setting of clinical practice in a University General Hospital. Eleven consecutive patients (5 women, 6 men, mean age 63.0±12.9year) with advanced papillary (n=7) or follicular (n=4) thyroid carcinoma not suitable for curative surgery or RAI therapy were studied. Two patients were treated with one line of tyrosine kinase inhibitors before sunitinib therapy. All patients had evidence of objective progressive disease (PD). We analysed the objective response rate (ORR) and changes in thyroglobulin levels during therapy. Complete response was achieved in 1 patient (9%) and partial response (PR) in 2 patients (18%). Five patients (45%) had stable disease (SD). Therefore, ORR was 27% and disease control rate was 72%. We found that the decrement in thyroglobulin concentrations was significantly higher in patients with radiological disease control than in patients with PD. Most frequent grade 1 and 2 adverse events were fatigue, mucositis, hand-and-foot syndrome, hyporexia, rash, hypertension, and edema. In routine clinical practice, sunitinib appears to be effective and feasible in patients with advanced RAI-refractory DTC. Most patients achieved SD or PR, despite having PD at the start of treatment, and safety profile was consistent with that reported in previous clinical trials.

PurposeThe aim of this study was to evaluate the value of preablative stimulated thyroglobulin (presTg) and thyroglobulin reduction index (TRI) to predict the different responses to second radioactive iodine (RAI) therapy in differentiated thyroid cancer (DTC) patients with structural incomplete response (SIR).Patients and MethodsA single-center retrospective study analyzed the different clinical outcomes after second RAI therapy in 206 patients with SIR. PresTg1 and presTg2 were measured before first and second RAI management and TRI was the reduction index of presTg1 and presTg2. Cut-off values of presTg and TRI were obtained using receiver operating characteristic analysis. The univariate logistic regression analysis was performed to confirm these parameters as prognostic factors to predict different responses to second RAI therapy.ResultsOnly ATA risk stratification, the post-therapy whole-body scanning (Rx-WBS) findings, presTg1, presTg2, TRI, were different in patients with SIR. After second RAI therapy, 28.2% (58/206) of patients with SIR initially were reclassified as excellent response (ER). PresTg1 <6.6 ng/mL, presTg2 <1.2ng/mL, and TRI >74.2% were excellent indications to predict ER from non-ER after second RAI treatment. PresTg1 >14.9 ng/mL, presTg2 >1.8ng/mL and TRI <66.5% were well markers to predict poor outcome (SIR). High risk and distant metastases could still be considered as risk factors.ConclusionDTC patients with SIR could benefit through second RAI treatment. PresTg before each RAI therapy and TRI could be considered as effective decision-making markers for second RAI therapy and as predictive indications for clinical outcomes.

The study objective was to investigate the role of 18 F-fluorodeoxyglucose (18 F-FDG) positron emission tomography combined with computed tomography (PET-CT) as an indirect determination of the differentiation status of metastases and for the prediction of radioactive iodine (RAI) therapy response in patients with metastatic differentiated thyroid cancer.Materials and methods. The 40 metastatic differentiated thyroid cancer patients were enrolled in the study that underwent both post-therapeutic radioiodine scan and PET-CT at the same period.Results. The study found that 12 (30 %) patients responded to RAI therapy. The remaining 28 (70 %) patients not responded to RAI therapy showed stabilization or progression. The accumulation of radioiodine by metastases positively correlated with the total response rate, while the 18 F-FDG avidity is negative. Significant direct correlation with response rate was observed in the group with only radioiodine uptake. However, this correlation was not observed in the patients with both tracers uptake. The patients with 18 F-FDG-positive metastases showed poor response to RAI therapy, regardless of the degree of radioiodine uptake.Conclusion. The 18 F-FDG uptake by metastases is a predictor of a poor response to RAI therapy, even in the presence of RAI uptake. The use of 18 F-FDG PET-CT in patients with metastatic differentiated thyroid cancer can be recommended at the beginning of RAI therapy to clarify the prognosis and provide a personalized approach to the treatment and observation of the most difficult category of patients.

The psychological health of thyroid cancer patients cannot be ignored; however, few studies have been conducted on the psychological status and influencing factors of thyroid cancer patients before radioactive iodine (RAI) therapy. The aim of this study was to investigate the incidence and risk factors for anxiety and depression in thyroid cancer patients prior to RAI therapy. Clinical data were collected from patients with differentiated thyroid cancer (DTC) patientspreparing for RAI therapy. Anxiety and depression were measured before RAI therapy using the Generalized Anxiety Disorder Questionnaire (GAD-7) and Patient Health Questionnaire (PHQ-9). We used the chi-square test and logistic regression analysis to identify independent risk factors for anxiety and depression. A total of 112 patients with thyroid cancer were included. Of these, 72.32% (n = 81) were female, with a mean age of 41.50years. Anxiety and depression were reported by 46 (41.08%) and 38 (33.93%) patients, respectively. Based on the chi-square test and univariate logistic regression analysis, being female and having ever-experienced RAI therapy were significant risk factors for anxiety and depression among DTCs prior to RAI therapy. On multivariable analysis, the results of model 2 which included age, sex, education level, and ever suffering radioactive iodine therapy showed that being female was markedly associated with anxiety and depression in these patients, while having ever undergone RAI therapy was significantly related to anxiety but not depression. The incidence of anxiety and depression among patients withDTCprior to RAI therapy were 41.08% and 33.93%, respectively.Being female and having ever experienced RAI therapy significantly influenced anxiety and depression. Based on these findings, anxiety and depression assessment should be an important part of pre-RAI therapy in patients with DTC, and appropriate psychological nursing intervention can be carried out for key patients.

One of the presumed advantages of prophylactic central neck dissection (pCND) is offering staging basis for more aggressive radioactive iodine (RAI) therapy, which postulates the necessity of high dose for treatment efficacy. The present study aims to compare the effectiveness between low-dose and high-dose RAI in a select cohort of cN0 papillary thyroid cancer (PTC) patients with pathological N1a (pN1a) disease revealed by pCND in terms of ablation rate and response to therapy. The frequency of short-term adverse effects between the two groups was also compared. From January 2014 to April 2016, cN0 PTC patients with pN1a disease revealed by pCND in our hospital were retrospectively reviewed. Patients with other indications for high-dose RAI, such as the presence of extrathyroidal extension, vascular invasion or suspicions of distant metastasis, were excluded. For the included patients, high dose (3700 MBq) was administered between January 2014 and August 2015 and low dose (1110 MBq) between August 2015 and April 2016. Ablation assessment was performed 6 months after RAI therapy. Response evaluation after RAI therapy was performed after 46.3 ± 9.5 months for high-dose group and 29.1 ± 2.6 months for low-dose group. All patients were also evaluated for short-term adverse effects 24 and 72 hours after RAI administration. A total of 84 patients were enrolled. Among them, 42 were in the high-dose group and the other 42 in the low-dose group. There was no significant difference in ablation rate (P = 0.7707) and response to RAI therapy (P = 0.6454) between the two groups. Twenty-four hours after RAI administration, neck pain and swelling (33.3% VS. 11.9%; P = 0.0372) and gastrointestinal discomfort (45.2% vs. 21.4%; P = 0.0373) were significantly more frequent in the high-dose group. High-dose RAI therapy, with higher frequency of short-term adverse effects, appears to be not superior to low-dose RAI therapy for cN0 PTC patients with pN1a disease revealed by pCND to achieve better response to therapy. Further randomized studies with larger series of patients and longer follow-up duration, especially with the low-dose group, are needed to validate our results.

Current methods, such as serum thyroglobulin measurement and medical imaging, have limitations in the routine monitoring of the disease status and treatment response of patients with differentiated thyroid cancers (DTCs), and additional methods remain to be explored. The aim of this study was to investigate the clinical value of the sodium/iodide symporter (NIS) expression and epithelial-mesenchymal transition (EMT) phenotypes of circulating tumor cells (CTCs) in monitoring the disease status and treatment response of DTC. Blood samples were obtained from DTC patients before (1 to 3months after total thyroidectomy) and 4 to 6months after radioactive iodine-131 (RAI) therapy for the CTC assessments. The number, NIS expression, and EMT phenotypes of CTCs were enumerated and characterized with CanPatrol™ CTC enrichment and mRNA in situ hybridization. Postoperative NIS high expression was independently correlated with a better response to first RAI therapy and good treatment efficacy. Postoperative NIS-/epithelial-/mesenchymal+ CTCs presence was independently correlated with a worse response to first RAI therapy. The numbers of total NIS+ CTCs and NIS+/epithelial+/mesenchymal+ CTCs after first RAI therapy were negatively correlated with a better response to RAI therapy only in univariate analyses. Univariate and multivariate analyses showed that a decreased or unchanged number of total NIS+ CTCs after RAI therapy may denote good efficacy and effective RAI therapy. These preliminary data suggest that assessment of the NIS expression and EMT phenotypes of CTCs may serve as potential adjuncts for predicting and monitoring the curative effect of RAI therapy in DTC patients and avoid ineffective treatment. Further validation is warranted.

Purpose: Our aim was to evaluate the effect of prophylactic pilocarpine on acute salivary symptoms after radioactive iodine (RAI) therapy in patients with differentiated thyroid cancer. Methods: We enrolled 88 patients (76 women and 12 men; mean age: 47 years; range: 20-74 years) with differentiated thyroid cancer who received RAI. Patients were divided into pilocarpine (51 patients) and control (37 patients) groups. Pilocarpine was given orally, at a dose of 5 mg three times a day, from 2 days before and 12 days after RAI therapy. Symptoms and signs of acute sialadenitis within 3 months of RAI therapy were recorded. Results: During the 3 months after RAI therapy, 13 of the 88 patients (14.7%) developed acute symptomatic sialadenitis (swelling or pain of salivary glands). Acute salivary symptoms were reported by 4 (7.8%) and 9 (24.3%) patients in the pilocarpine and control groups, respectively. Acute salivary symptoms were less frequent in the pilocarpine than control group (p = 0.04), but did not differ by age, sex, or RAI dose (p = 0.3357, p = 0.428, and p = 0.2792). Conclusions: Pilocarpine reduced the likelihood of acute sialadenitis after RAI therapy in patients with differentiated thyroid cancer.