Metastatic Differentiated Thyroid Cancer Patients Research Articles

Comparative Uptake Patterns of Radioactive Iodine and [18F]-Fluorodeoxyglucose (FDG) in Metastatic Differentiated Thyroid Cancers.

Background: Metastatic differentiated thyroid cancer (DTC) represents a molecularly heterogeneous group of cancers with varying radioactive iodine (RAI) and [18F]-fluorodeoxyglucose (FDG) uptake patterns potentially correlated with the degree of de-differentiation through the so-called "flip-flop" phenomenon. However, it is unknown if RAI and FDG uptake patterns correlate with molecular status or metastatic site. Materials and Methods: A retrospective analysis of metastatic DTC patients (n = 46) with radioactive 131-iodine whole body scan (WBS) and FDG-PET imaging between 2008 and 2022 was performed. The inclusion criteria included accessible FDG-PET and WBS studies within 1 year of each other. Studies were interpreted by two blinded radiologists for iodine or FDG uptake in extrathyroidal sites including lungs, lymph nodes, and bone. Cases were stratified by BRAF V600E mutation status, histology, and a combination of tumor genotype and histology. The data were analyzed by McNemar's Chi-square test. Results: Lung metastasis FDG uptake was significantly more common than iodine uptake (WBS: 52%, FDG: 84%, p = 0.04), but no significant differences were found for lymph or bone metastases. Lung metastasis FDG uptake was significantly more prevalent in the papillary pattern sub-cohort (WBS: 37%, FDG: 89%, p = 0.02) than the follicular pattern sub-cohort (WBS: 75%, FDG: 75%, p = 1.00). Similarly, BRAF V600E+ tumors with lung metastases also demonstrated a preponderance of FDG uptake (WBS: 29%, FDG: 93%, p = 0.02) than BRAF V600E- tumors (WBS: 83%, FDG: 83%, p = 1.00) with lung metastases. Papillary histology featured higher FDG uptake in lung metastasis (WBS: 39%, FDG: 89%, p = 0.03) compared with follicular histology (WBS: 69%, FDG: 77%, p = 1.00). Patients with papillary pattern disease, BRAF V600E+ mutation, or papillary histology had reduced agreement between both modalities in uptake at all metastatic sites compared with those with follicular pattern disease, BRAF V600E- mutation, or follicular histology. Low agreement in lymph node uptake was observed in all patients irrespective of molecular status or histology. Conclusions: The pattern of FDG-PET and radioiodine uptake is dependent on molecular status and metastatic site, with those with papillary histology or BRAF V600E+ mutation featuring increased FDG uptake in distant metastasis. Further study with an expanded cohort may identify which patients may benefit from specific imaging modalities to recognize and surveil metastases.

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

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

No difference in the outcome of metastatic thyroid cancer patients when using recombinant or endogenous TSH.

At present, recombinant TSH cannot be used for the treatment of metastatic differentiated thyroid cancer patients. The aim of this study was to evaluate if the type of TSH stimulation, recombinant or endogenous, had an impact on the outcome of these patients. We compared the outcome of two propensity score-matched groups of metastatic patients, stimulated by either only recombinant TSH (n = 43) or only endogenous TSH (n = 34). As expected from the matching procedure, the clinical-pathological features and the cumulative 131-I activities administered to the two groups were very similar. After 4 years of follow-up, 4% of patients were cured, 3% had biochemical disease and 93% had structural disease. However, 91% of patients obtained a clinical benefit from this therapy in terms of stabilization of the disease or complete remission or partial response. When considering the two groups separately, we did not find any difference in their outcome. When considering the response to 131-I therapy of the single type of metastases, 8% of lymph node metastases and 8% of lung metastases disappeared but none of the bone metastases. The response to 131-I therapy of the single type of metastases was similar when we looked at the two groups separately. This study shows (i) an overall clinical benefit of the 131-I therapy, since the majority of patients remained affected but with a stable disease, and (ii) that the preparation with either recombinant or endogenous TSH has no impact on the 131-I therapy efficacy and the outcome of our two groups of patients.

Significance of Dynamic Risk Assessment in the Follow-up of Non-distant Metastatic Differentiated Thyroid Cancer Patients with Intermediate and High Risk

Objective To tailor the subsequent treatment and follow-up strategy,this study dynamically assessed the response to initial therapy in non-distant metastatic differentiated thyroid cancer (DTC) patients with intermediate and high risk. Methods A total of 184 non-distant metastatic DTC patients (intermediate-risk 111 cases and high-risk 73 cases) were retrospectively enrolled in this study. Based on the results of initial response assessment (6-12 months after initial therapy),patients were divided into two groups:excellent response (ER) group (n=113) and non-excellent response (non-ER) group (n=71). We compared the differences in clinicopathological features between these 2 groups and evaluated the changes of dynamic response to therapy at the initial and final assessments after initial therapy in all patients. Results Compared with the ER group,the non-ER group showed a larger tumor size (U=2771.500,P=0.000),higher proportion of extrathyroidal invasion (χ 2=4.070,P=0.044),and higher preablative-stimulated thyroglobulin levels (U=1367.500,P=0.000). ER was achieved in 31% of patients in the initial non-ER group [including indeterminate response (IDR) and biochemical incomplete response (BIR)] at the final follow-up only by thyroid stimulating hormone (TSH) suppression therapy,among which 63.6% were with intermediate risk (especially the patients with IDR) and 36.4% at high risk. In addition,5.2%(6/113) of patients in the initial ER group were reassessed as IDR,BIR,or even structural incomplete response at the end of the follow-up (among which one patient developed into cervical lymph node recurrence,as confirmed by pathology);the TSH level in these patients fluctuated at 0.56-10.35 μIU/ml and was not corrected in time during the follow-up after initial therapy. Conclusions Some of non-distant metastatic DTC patients with intermediate and high risks who presented initial non-ER may achieve ER only by TSH suppression therapy over time;in contrast,the patients presented initial ER may develop into non-ER without normalized TSH suppression therapy. The dynamic risk assessment system may provide a real-time assessment of recurrence risk and tailor the subsequent treatment and follow-up strategies.

<sup>18</sup>F-fluorodeoxyglucose positron emission tomography combined with computed tomography for the prediction of radioiodine therapy response in patients with metastatic differentiated thyroid cancer

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.

FDG PET/CT for the early prediction of RAI therapy response in patients with metastatic differentiated thyroid carcinoma.

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.

Tumor doubling time predicts response to sorafenib in radioactive iodine-refractory differentiated thyroid cancer.

Sorafenib has emerged as an effective therapeutic option for radioactive iodine (RAI)-refractory, locally advanced or metastatic differentiated thyroid cancer (DTC). We investigated the efficacy and safety of sorafenib treatment in a real-world setting and unveil predictive markers of responsiveness to sorafenib. The treatment response, progression-free survival (PFS), overall survival, and adverse events (AEs) of sorafenib-treated RAI-refractory, locally advanced or metastatic DTC patients at three institutes were retrospectively reviewed, and their tumor doubling time was calculated by three investigators. Total eighty-five patients were treated with sorafenib, and seven patients discontinued sorafenib due to AEs before the first tumor assessment. The median PFS was 14.4 months, and the objective response rate was 10.3% in 78 patients who were able to evaluate the tumor response. Age, sex, histologic type, tumor location, RAI avidity, or the presence of FDG-PET uptake did not affect PFS. However, smaller tumor size (≤1.5 cm) of the target lesions in lung showed better PFS (hazard ratio [HR] 0.39, p = 0.01), and tumors with the shortest doubling time (≤6 months) had worse outcome (HR 2.70, p < 0.01). Because of AEs, dose reductions or drug interruptions were required in 64% of patients, and eventually, 23% of patients discontinued sorafenib permanently. The most common AE was hand-foot skin reaction (HFSR). Patients with severe HFSR showed better PFS, but there were no statistical significance (HR 0.65, p = 0.05). In conclusion, small tumor size and long doubling time of each target lesion can be a prognostic marker to predict the responsiveness to sorafenib in RAI-refractory DTC patients.

Quantitative thyroglobulin response to radioactive iodine treatment in predicting radioactive iodine-refractory thyroid cancer with pulmonary metastasis

ObjectiveCurrent diagnosis of radioactive iodine (RAI)-refractory (RAIR) differentiated thyroid cancer (DTC) is based on the imaging technique, which is of a high cost. Serum thyroglobulin (Tg) is a sensitive and easily obtained biomarker. Hence, we aimed to assess the predicting value of quantitative response of Tg in earlier identifying the RAIR-DTC with pulmonary metastasis.Patients and methodsPulmonary metastatic DTC patients who underwent total or near-total thyroidectomy and at least two times of RAI therapy were included in this study. The pre-ablative stimulated Tg at the first and second RAI therapy were defined as pstim-Tg1 and pstim-Tg2, while the suppressed Tg before and after the second RAI therapy were designated sup-Tg1 and sup-Tg2. The predicted value of pstim-Tg2/Tg1 and sup-Tg2/Tg1 ratio were detected using the receiver operating characteristic (ROC) curve and logistic regression analyses.ResultsTotally 115 patients were involved in this study. ROC curves showed a cut-off value of 0.544 for pstim-Tg2/ pstim-Tg1 in detecting RAIR, with a sensitivity of 0.9 and specificity of 0.477, and an area under the curve (AUC) of 0.744. Similarly, the cut-off of sup-Tg2/ sup-Tg1 was 0.972, with a sensitivity of 0.733 and specificity of 0.935, and AUC of 0.898. Univariate analysis illustrated that age, tumor size, pstim-Tg2/Tg1, sup-Tg2/ sup-Tg1 and BRAFV600E mutation were eligible to predict RAIR. While from multivariate analysis, only age, pstim-Tg2/Tg1, sup-Tg2/ sup-Tg1 and BRAFV600E mutation were verified to be the independent predictive factors.ConclusionThe quantitative Tg response was encouraging in identifying RAIR-DTC with pulmonary metastasis. Age, BRAFV600E mutation and Tg response were independent predictors in predicting RAIR-DTC.

EFFICACY AND SAFETY OF MULTI-TARGETED KINASE INHIBITORS IN PROGRESSIVE, RADIOIODINE-REFRACTORY DIFFERENTIATED THYROID CANCERS: A META-ANALYSIS

Purpose: A meta-analysis was conducted to evaluate the impact of oral multitargeted kinase inhibitors (MTKIs) in radioactive-iodine refractory locally advanced, recurrent/metastatic differentiated thyroid cancer (DTC) on disease control rate (DCR), progression-free survival (PFS) and overall survival (OS) rates. Materials and Methods: The PubMed/MEDLINE, CANCERLIT, EMBASE, Cochrane Library database and other search engines were searched to identify randomised controlled trials (RCTs) comparing MTKIs with placebo in locally advanced, recurrent/metastatic DTC. Pooled data were expressed as odds ratio (OR), with 95% con dence intervals (CIs, Mantel–Haenszel xed-effect model). Results: Three RCTs with a total patient population of 954 patients were identi ed. The use of MTKIs was associated with improved PFS (OR: 0.262, 95% CI: 0.19–0.35; heterogeneity (I2) = 22.4%; P &lt; 0.0001), improved DCR (complete and partial responses + stable disease, P &lt; 0.0001) and improved OS 0.66, 95% CI: 0.46–0.96 (I2 = 43%, P = 0.034). Lenvatinib (compliance = 87%) was associated with more grade ≥3 hypertension. However, its other adverse effects were much lower than sorafenib (compliance = 56%) and vandetanib. Conclusion: In radioactive iodine-refractory recurrent, metastatic DTC patients, lenvatinib and sorafenib were associated with improved PFS, DRC and OS rates, while the compliance was better with lenvatinib. Key words: Meta-analysis, multitargeted kinase inhibitors, progressive differentiated thyroid cancer, radioactive iodine- refractory

Cabozantinib in Thyroid Cancer.

Cabozantinib is an oral once-daily multitarget tyrosine kinase inhibitor of MET, VEGFR2, RET, acting against KIT, AXL, FLT3 and Tie-2. Cabozantinib has shown anti-cancer effects in preclinical and clinical models of cancers derived from both epithelial and mesenchymal origins [prostate cancer, non small lung cancer, medullary thyroid cancer (MTC) and differentiated thyroid cancer (DTC), renal cell carcinoma, etc.]. In a Phase III clinical study, cabozantinib improved PFS (11.2 months versus 4.0 months in the placebo group) of patients with MTC (independently of age, bone metastases, RET status and prior treatment). Cabozantinib was approved in 2012 by FDA for metastatic MTC and in 2013 by EMA. Cabozantinib has been also evaluated in metastatic DTC patients, because they have activation on tyrosine kinases, including MET, VEGFR2 and RET, suggesting the possible use of cabozantinib in metastatic DTC. Actually, two Phase II trials of cabozantinib in DTC patients resistant to RAI are ongoing. To increase the antineoplastic effect of cabozantinib, and to overcome the occurrence of drug resistance, combination studies with other anticancer agents are ongoing. In conclusion, cabozantinib has shown to exert an important therapeutic effect in patients with MTC improving PFS. In DTC patients, cabozantinib has shown promising results.

Sorafenib Prolongs Progression-free Survival of Metastatic Differentiated Thyroid Cancer Patients by Five Months

Sorafenib Prolongs Progression-free Survival of Metastatic Differentiated Thyroid Cancer Patients by Five Months

Role of 18F-FDG-PET and PET/CT imaging in thyroid cancer

In patients affected by differentiated thyroid cancer (DTC), the lacking of 131Iodine trapping by metastatic tissue does not allow 131Iodine whole body scintigraphy to visualize matastatic spread as well as the use of 131Iodine therapy to cure such metastatic spread. Prognosis of 131Iodine-negative DTC metastasis, so-called non-functioning metastasis, is significantly worst. In these patients an early diagnosis of non-functioning metastasis and their surgical extirpation remains the optimal therapeutic approach. In this view, a high sensitive localizing imaging different form 131Iodine whole body scintigraphy is required. Ultrasonography is characterized by a relatively high sensitivity in these patients but it is highly operator-dependent and, moreover, it can be used to explore neck alone. Computed tomography (CT) scan and magnetic resonance (MR) imaging are characterized by a relatively low sensitivity even if they are useful to provide the surgeon with anatomical information of the operating basin. Various tumor-seeking radiotracers have been proposed, mainly using SPECT as 201Thallium, 99mTc-Sestamibi and 99mTc-Tetrofosmin with good results. Even more favorable results have been reported with some positron radiotracers, mainly the 18F-FDG with PET and more recently with PET/CT tomographs. The typical indication to performing with examination is the DTC patient previously treated by total thyroidectomy and 131Iodine ablative therapy, with increased serum thyroglobulin (Tg) or anti-thyroglobulin (TgAb) antibodies during follow-up but with negative 131Iodine whole body scintigraphy even obtained after high, therapeutic 131Iodine doses. Several studies in literature have reported high sensitivity (up to 85%) and specificity (up to 95%) of FDG-PET in metastatic DTC patients. The integrated PET/CT fusion imaging systems, seem able to provide some additional advantages over PET alone, mainly related to a better anatomical localization of the hypermetabolic metastatic lesions. A change in the management of DTC patients affected by non-functioning metastatic spread not visualized by other imaging techniques has been reported in 30% of patients. Lastly, the role of PET and PET/CT fusion imaging systems seem to be promising also in patients affected by medullary thyroid carcinoma (MTC), especially for the detection of neck and mediastinal lesions, with a sensitivity superior to the other currently available imaging methods, however the data reported on medullary cancer are little and further studies are needed to elucidate the preliminary promising results.