High-risk Differentiated Thyroid Cancer Patients Research Articles

The Effect of Thyrotropin Suppression on Survival Outcomes in Patients with Differentiated Thyroid Cancer: A Systematic Review and Meta-Analysis.

Background: Long-term management of intermediate- and high-risk differentiated thyroid cancer (DTC) involves thyrotropin (TSH) suppression with thyroid hormone to prevent potential stimulation of TSH receptors on DTC cells, leading to tumor growth. However, the current guidelines recommending TSH suppression are based on low- to moderate-quality evidence. Methods: We performed a systematic review and meta-analysis of studies evaluating the role of TSH suppression in intermediate- and high-risk DTC patients (≥18 years) treated as per regional guideline-based therapy with a follow-up duration of 5 years (PROSPERO #252396). TSH suppression was defined as "below normal reference range" or, when known, <0.5 mIU/L. Primary outcome measures included (i) composite of progression-free survival (PFS), disease-free survival (DFS), and relapse-free survival (RLFS), and (ii) composite of disease-specific survival (DSS), and overall survival (OS). Secondary outcome included a composite of cardiac or skeletal adverse events. All outcomes and comparisons were represented as TSH suppression versus TSH nonsuppression. Randomized controlled trials, cohort studies, and case-control studies were included for analysis. Pooled hazard ratio (HR) and 95% confidence interval (CI) were calculated using random-effects model. Results: Abstract screening was performed on 6,369 studies. After the exclusion of irrelevant studies and full-text screening, nine studies were selected for the final meta-analysis. Based on seven studies (3,591 patients), the composite outcome of PFS, DFS, and RLFS was not significantly different between TSH suppression and nonsuppression groups (HR: 0.75; 95% CI: 0.48-1.17; I2 = 76%). Similarly, a DSS and OS composite outcome assessment based on four studies (3,616 patients) did not favor TSH suppression (HR: 0.69; 95% CI: 0.31-1.52; I2 = 88%). Even after excluding studies of lower quality, the primary outcomes were not significantly different between the TSH suppression and nonsuppression cohorts. The secondary outcome, obtained from two studies (1,294 patients), was significantly higher in the TSH-suppressed groups (HR: 1.82; 95% CI: 1.30-2.55; I2 = 0%). Significant study heterogeneity was noted for primary outcomes. Conclusion: TSH suppression in intermediate- and high-risk DTC may not improve survival outcomes but may increase the risk of secondary complications. However, the limited evidence and study heterogeneity warrant cautious interpretation of our findings. Registration: PROSPERO #252396.

Evaluation of integrin αvβ3-targeted imaging for predicting disease progression in patients with high-risk differentiated thyroid cancer (using 99mTc-3PRGD2)

BackgroundHigh-risk differentiated thyroid cancer (DTC) needs effective early prediction tools to improving clinical management and prognosis. This cohort study aimed to investigate the prognostic impact of 99mTc-PEG4-E[PEG4-c(RGDfK)]2 (99mTc-3PRGD2) SPECT/CT in high-risk DTC patients after initial radioactive iodine (RAI) therapy.MethodsThirty-three patients with high-risk DTC were prospectively recruited; all patients underwent total thyroidectomy and received 99mTc-3PRGD2 SPECT/CT before RAI ablation. Follow-up was done with serological and imaging studies. The correlation between 99mTc-3PRGD2 avidity and remission rate for initial RAI therapy was evaluated using logistic regression analysis. The prognostic value of 99mTc-3PRGD2 SPECT/CT was evaluated by Kaplan-Meier curve and Cox regression analysis.Results99mTc-3PRGD2 avidity was significantly correlated with the efficacy of initial RAI ablation and an effective predictor for non-remission in high-risk DTC (OR = 9.36; 95% CI = 1.10–79.83; P = 0.041). 99mTc-3PRGD2 avidity was associated with poor prognosis in patients with high-risk DTC and an independent prognostic factor for shorter progression-free survival (PFS) (HR = 9.47; 95% CI = 1.08–83.20; P = 0.043). Survival analysis, which was performed between DTC patients with concordant (131I positive/99mTc-3PRGD2 positive) and discordant (131I negative/99mTc-3PRGD2 positive) lesions, indicated that patients with concordant lesions had significantly better PFS than those with discordant lesions (P = 0.022). Moreover, compared with repeated RAI, additional surgery or targeted therapy with multikinase inhibitors could lead to a higher rate of remission in 99mTc-3PRGD2-positive patients with progressive disease.Conclusions99mTc-3PRGD2 SPECT/CT is a useful modality in predicting progression of the disease after initial RAI and guiding further treatment in high-risk DTC patients.

The influence of age on disease outcome in 2015 ATA high-risk differentiated thyroid cancer patients.

Recent research suggests that the addition of age improves the 2015 American Thyroid Association (ATA) Risk Stratification System for differentiated thyroid cancer (DTC). The aim of our study was to investigate the influence of age on disease outcome in ATA-high risk patients with a focus on differences between patients with papillary (PTC) and follicular thyroid cancer (FTC). We retrospectively studied adult patients with high-risk DTC from a Dutch University hospital. Logistic regression and Cox proportional hazards models were used to estimate the effects of age (at diagnosis) and several age cutoffs (per 5 years increment between 20 and 80 years) on (i) response to therapy, (ii) developing no evidence of disease (NED), (iii) recurrence, and (iv) disease-specific mortality (DSM). We included 236 ATA high-risk patients (32% FTC) with a median follow-up of 6 years. Age, either continuously or dichotomously, had a significant influence on having an excellent response after initial therapy, developing NED, recurrence, and DSM for PTC and FTC. For FTC, an age cutoff of 65 or 70 years showed the best statistical model performance, while this was 50 or 60 years for PTC. In a population of patients with high-risk DTC, older age has a significant negative influence on disease outcomes. Slightly different optimal age cutoffs were identified for the different outcomes, and these cutoffs differed between PTC and FTC. Therefore, the ATA Risk Stratification System may further improve should age be incorporated as an additional risk factor.

Identification and validation of potential novel biomarkers to predict distant metastasis in differentiated thyroid cancer.

BackgroundDistant metastasis (DM) is not common in differentiated thyroid cancer (DTC). However, it is associated with a significantly poor prognosis. Early detection of high-risk DTC patients is difficult, and the molecular mechanism is still unclear. Therefore, the present study aims to establish a novel predictive model based on clinicopathological parameters and DM-related gene signatures to provide guidelines for clinicians in decision making.MethodsWeighted gene co-expression network analysis (WGCNA) was performed to discover co-expressed gene modules and hub genes associated with DM. Univariate and multivariate analyses were carried out to identify independent clinicopathological risk factors based on The Cancer Genome Atlas (TCGA) database. An integrated nomogram prediction model was established. Finally, real hub genes were validated using the GSE60542 database and various thyroid cell lines.ResultsThe midnightblue module was most significantly positively correlated with DM (R=0.56, P=9e-06) by as per WGCNA. DLX5 (AUC: 0.769), COX6B2 (AUC: 0.764), and LYPD1 (AUC: 0.760) were determined to be the real hub genes that play a crucial role in predicting DM. Meanwhile, univariate and multivariate analyses demonstrated that T-stage (OR, 15.03; 95% CI, 1.75–319.40; and P=0.024), histologic subtype (OR, 0.17; 95% CI, 0.03–0.92; and P=0.042) were the independent predictors of DM. Subsequently, a nomogram model was constructed based on gene signatures and independent clinical risk factors exhibited good performance. Additionally, the mRNA expressions of real hub genes in the GSE60542 dataset were consistent with TCGA.ConclusionsThe present study has provided a reliable model to predict DM in patients with DTC. This model is likely to serve as an individual risk assessment tool in therapeutic decision-making.

Assessing potential impact of 2015 American Thyroid Association guidelines on community standard practice for I-131 treatment of low-risk differentiated thyroid cancer: case study of Jordan

The 2015 American Thyroid Association (ATA) guidelines called for significantly more selective 131I therapy in patients with low-risk differentiated thyroid cancer (DTC). We hypothesized that application of these guidelines would significantly reduce the 131I activity utilized by an academic tertiary hospital in Jordan. All DTC patients managed at Jordan University Hospital (JUH) between 1/2009 and 6/2019 were classified according to the 2015 ATA risk category and 131I activity was assigned accordingly. The actual 131I activity administered was compared with that recommended by the 2015 ATA guidelines. In total, 135/182 DTC patients (74.2%) managed at JUH underwent 131I therapy. Of those, 58 (43%) had ATA low-, 58 (43%) intermediate-, and 19 (14%) high-risk disease. The low-, intermediate-, and high-risk DTC patients received an average (±SD) initial 131I activity of 3.53 ± 0.95, 4.40 ± 1.49, and 5.06 ± 2.52 GBq, respectively. Withholding 131I therapy altogether in the 2015 ATA low-risk patients would result in decreasing the 131I activity in the overall patient population by 37%. Withholding 131I therapy only in low-risk papillary thyroid microcarcinomas while administering 1.11 GBq of 131I to other low-risk patients would result in 28% reduction of 131I. This study demonstrates a significant reduction in 131I therapeutic activity that would be given to DTC patients in an academic tertiary setting in Jordan, following acceptance of the 2015 ATA recommendations. Institutions that adopted the 2015 ATA guidance should measure outcomes in comparison to their historical controls and report those findings, while long-term results of randomized controlled trials are forthcoming.

Evaluating the 2015 American Thyroid Association Risk Stratification System in High-Risk Papillary and Follicular Thyroid Cancer Patients.

Background: The 2015 American Thyroid Association (ATA) Risk Stratification System for differentiated thyroid cancer (DTC) is designed to predict recurring/persisting disease but not survival. Earlier studies evaluating this system evaluated the 2009 edition, comprised a low number of patients with ATA high-risk, had low numbers of patients with follicular thyroid cancer (FTC), or did not distinguish between papillary and FTC. Therefore, we evaluated the prognostic value of the 2015 ATA Risk Stratification System in a large population of high-risk thyroid cancer patients, which included a substantial proportion of FTC patients. Methods: We retrospectively studied adult patients with DTC who were diagnosed and/or treated at a Dutch university hospital between January 2002 and December 2015. All patients fulfilled the 2015 ATA high-risk criteria. Overall survival and disease-specific survival (DSS) were analyzed using the Kaplan-Meier method. Logistic regression and Cox proportional hazards models were used to estimate the effects of DTC subtype and ATA high-risk criteria on response to therapy, recurrence, as well as survival. Results: We included 236 patients with high-risk DTC (32% FTC) with a mean age of 56 years. Median follow-up was 6 years. At final follow-up, 69 patients (29%) had excellent response, while 120 (51%) had structural disease. All high-risk criteria, except large pathologic lymph nodes, were inversely related to excellent response and positively related to structural disease at final follow-up. During follow-up, 14% of the 79 patients who achieved excellent response developed a recurrence. Finally, 10-year DSS was much higher in the initial excellent response than in the initial structural disease group (100% vs. 61%, respectively). Conclusions: In a population of high-risk DTC patients harboring a large subset of FTC patients, the 2015 ATA Risk Stratification System is not only an excellent predictor of persisting disease but also of survival. As much as 14% of the high-risk patients who had an excellent response upon dynamic risk stratification experienced a recurrence during follow-up. Clinicians should thus be aware of the relatively high recurrence risk in these patients, even after an excellent response to therapy.

MON-549 How Does the 2015 American Thyroid Association Risk Stratification System Perform in High Risk Thyroid Cancer Patients?

Background The 2015 American Thyroid Association (ATA) risk stratification system for differentiated thyroid cancer (DTC) is designed to predict recurring/persisting disease but not survival. Previous studies evaluating this system comprised relatively few patients with High Risk and/or follicular thyroid carcinoma (FTC). Therefore, we evaluated response to therapy, risk of recurrence as well as survival in a large population of High Risk DTC patients with a substantial proportion of FTC patients. Methods Adult patients, who fulfilled the 2015 ATA High Risk criteria and were diagnosed and/or treated for DTC at a Dutch university hospital between January 2002 and December 2015, were retrospectively included. Response to therapy, recurrence, and mortality characteristics were obtained from patient records. Logistic regression and cox proportional hazards models were used to estimate the effects of ATA High Risk factors on response to therapy, recurrence and survival. Further, disease specific survival (DSS) was analyzed using the Kaplan-Meier method. Results We included 236 patients (63% women; 32% FTC) with mean age of 56 years. During follow-up, 49 patients (21%) died due to thyroid cancer. After initial therapy, 38 patients (16%) had excellent response, while 117 (50%) had structural disease. At final follow-up (median 72 months), 69 patients (29%) had excellent response, while 120 (51%) had structural disease. All risk factors, except large pathologic lymph nodes, were inversely related to excellent response at final follow-up. Recurrence occurred in 14% of the patients, and gross extra thyroidal extension at diagnosis increased the chance of recurrence significantly. Ten-year DSS was higher in the initial excellent response than in the structural disease group (100% vs. 61%). Conclusion In patients with High Risk DTC, the ATA risk stratification system is not only an excellent predictor of recurring/persisting disease, but also of survival. At final follow-up, half of the patients had persistent disease while one-third showed excellent response. Recurrence rates were higher than expected.

18F-FDG-PET/CT features of primary tumours for predicting the risk of recurrence in thyroid cancer after total thyroidectomy: potential usefulness of combination of the SUV-related, volumetric, and heterogeneous texture parameters.

This retrospective study examined whether the primary tumour 18F-FDG uptake features could predict the high-risk of recurrence in differentiated thyroid cancer (DTC) patients. The enrolled 114 DTC patients underwent preoperative 18F-FDG-PET/CT. SUVmax, SUVmean, metabolic tumour volume (MTV), total lesion glycolysis (TLG) and 6 texture parameters were obtained. Because the texture features can be confounded by the tumour volume effects, 18F-FDG-avid tumour patients were divided into two groups (tumours with MTV ≤ 10.0 cm3 and >10.0 cm3). Diagnostic performance for predicting the high-risk was evaluated by the area under the curve (AUC) by the ROC curve analysis. Eighty eight 18F-FDG-avid tumours revealed more advanced-risk classification (p = 0.015 → 0.02) than 26 18F-FDG-nonavid tumours, which yielded no high-risk patients. In the 44 MTV > 10.0 cm3 18F-FDG-avid tumour patients, 8 high-risk patients revealed significantly higher SUVmax, SUVmean, MTV, TLG, intensity variability and size-zone variability, and lower zone percentage than 36 non-high-risk patients (p < 0.001-0.016). Their AUC (diagnostic accuracy) ranged between 0.77 (66%) and 0.92 (91%). When each parameter was scored as 0 (negative for high-risk) or 1 (positive for high-risk) according to each threshold criterion, and the 7 parameter summed score ≥5 was defined as high-risk, the accuracy was 93.2% (AUC: 0.98) in the MTV > 10.0 cm3 18F-FDG-avid tumour patients. For primary MTV > 10.0 cm3 18F-FDG-avid DTCs, the combined use of SUV-related, volumetric, and texture parameters may be more useful to identify high-risk patients than the individual parameters. Combined use of SUV-related, volumetric, and texture parameters may be useful to identify high-risk DTC patients.

Initial [18F]FDG PET/CT in high-riskDTC patients. A three-year follow-up.

In a previous paper, we published the impact of initial [18F]FDG PET/CT (FDG-PET/CT) in high-risk patients with differentiated thyroid cancer (DTC) and described the changes in therapy management. The aim of the present study was to evaluate the prognostic impact of the initial FDG-PET/CT on a patient's follow-up over three years and the rate of complete remission. This study included 109 DTC patients who underwent radioiodine treatment (RIT), including post-therapeutic whole-body scintigraphy with FDG-PET/CT and a follow-up over three years. The follow-up included high-resolution sonography of the neck and determination of serum Tg as well as Tg antibodies every six months. The results of initial FDG-PET/CT and whole-body scintigraphy were compared with the status after three years of follow-up. 24/109 patients (22%) presented FDG-positive lesions, 22/109 patients (20%) only iodine-positive lesions, and 63/109 patients (58%) neither FDG-positive nor iodine-positive lesions. After three years, 83/109 patients (76%) revealed full remission, 15/109 patients (14%) tumour persistence and 11/109 patients (10%) a progressive disease. The negative predictive value (NPV) was calculated for patients without FDG-positive lesions (NPV 85%) and patients without any lesions (NPV 91%) regarding full remission in the follow-up. FDG-PET/CT has a high NPV (85% to 91%) in DTC patients regarding recurrence-free follow-up after three years. The change in patient management in patients with iodine-negative lesions can lead to a higher rate of full remissions in the follow-up after additional surgery. Therefore, FDG-PET/CT should be performed in all high-risk DTC patients in the context of the first RIT to improve patient management and risk stratification.

Thyroglobulin Test at 3 Weeks after Surgery in Well-Differentiated Thyroid Cancer and its Predictive Value: The Role of Endocrine–Metabolic Status

Aim &amp; methods: The present pilot study included 50 differentiated thyroid cancer (DTC) patients (mean age: 45.8 ± 1.8 years, range: 18–73 years) who were followed after surgery for in average 30.0 ± 2.6 months. All patients were subdivided into two groups as having either &lt;2 ng/ml or ≥2 ng/ml blood thyroglobulin level 3 weeks after the operation (3-WTT). Results: Subsequent tumor progression was revealed more often in patients with higher thyroglobulinemia (≥2 ng/ml) in both low- and high-risk DTC groups. Patients with high-risk DTC and 3-week thyroglobulin levels ≥2 ng/ml were more likely to have a higher pre-surgical thyrotropin (TSH) levels. On the contrary, patients with low-risk DTC and 3-week thyroglobulin level ≥2 ng/ml demonstrated tendency to higher preoperative serum insulin levels and higher BMI. Conclusion: These differential findings could suggest that, whereas maximal suppression of TSH is reasonable in high-risk DTC patients, in low-risk DTC patients, for whom this is not justified, a moderate TSH suppression supplemented by multivalent drugs, such as antidiabetic biguanide metformin, could be advised.

Focus on High-Risk DTC Patients

No parameters predicting recurrence are available for high-risk differentiated thyroid cancer (DTC) patients, and 2-year-follow-up is required to modify the initial prognostic classification. High thyroglobulin (Tg) levels before ¹³¹I-remnant-ablation, during L-thyroxine-withdrawal (ablation-Tg) have undetermined predictive/prognostic significance in low-risk DTC patients. Our study aimed to assess the positive predictive value (PPV) of ablation-Tg in high-risk DTC patients and to evaluate whether high ablation-Tg levels were associated with progression-free-survival (PFS) and overall survival (OS). We selected 243 high-risk DTC patients. All patients underwent total thyroidectomy and ¹³¹I-remnant-ablation (initial therapy). Clinical data obtained during a median 5-year follow-up were used to assess the response and outcome. The association between disease persistence/recurrence after initial therapy, ablation-Tg, and other risk-factors (T, N, G, histology, and MACIS score) was evaluated through univariate and multivariate analyses, as was the association between PFS, OS ablation-Tg, and other risk factors. Ablation-Tg of 50 μg/L or greater displayed the highest PPV(97%) for disease persistence. In the univariate analysis, high levels of ablation-Tg were confirmed in patients with persistent disease after initial therapy: the higher the odds ratios, the higher the ablation-Tg levels. On multivariate analysis, ablation-Tg was the best predictive factor, especially on comparing patients with ablation-Tg levels of 50 μg/L or greater and those with ablation-Tg less than 2 μg/L (adjusted OR, 818). In a multivariate Cox model, ablation-Tg was the factor most closely associated with PFS (HR, 65.9). The prognostic value of ablation-Tg was confirmed by the overall-survival curves and adjusted risk estimates (adjusted HR=26.7). Ablation-Tg levels of 50 μg/L or greater are a valuable initial predictor of disease persistence/recurrence in high-risk DTC patients. A significant association emerged between high ablation-Tg levels of 50 μg/L or greater and both progression-free survival (PFS) and overall survival (OS).

Early detection of isolated left ventricular diastolic dysfunction in high-risk differentiated thyroid carcinoma patients on TSH-suppressive therapy

L-Thyroxine-suppressive therapy benefits high-risk differentiated thyroid cancer patients by decreasing recurrence rates and cancer-related mortality. However, fully suppressed serum thyroid-stimulating hormone (TSH) implies a state of subclinical hyperthyroidism (SCH) with associated adverse cardiac effects. Because left ventricular (LV) diastolic dysfunction may be the first manifestation of more severe LV failure, and to balance the risks from thyroid cancer recurrence with risks of cardiac failure, the purpose of this study was to analyse new parameters of LV function in asymptomatic patients with exogenous SCH. Case-control study with 24 patients on TSH-suppressive therapy of short duration (≤ 4 years) after thyroid ablative therapy for differentiated thyroid carcinoma and 20 age- and sex-matched subjects. LV function [LV global strain and strain rate (SR) curves] was assessed by speckle tracking imaging echocardiography in each subject. Patients and controls do not differ in body mass index, systolic blood pressure and heart rate. No significant differences were observed in LV morphology (LV mass and relative wall thickness), cardiac output and parameters of LV systolic function between patients on suppressive therapy and controls. When compared with controls, patients with exogenous SCH had a significantly impaired longitudinal protodiastolic strain, SR and strain diastolic index but preserved radial strain and SR function. In subjects with SCH at the early phase of TSH-suppressive therapy, evidence of isolated longitudinal LV diastolic dysfunction was observed, despite a normal LV morphology. Further prospective studies to clarify the prognosis of picking-up early diastolic dysfunction in asymptomatic patients are needed before serial measurements could be recommended.

Should We Routinely Offer a Second Admission for Radioiodine to Patients with High-risk Differentiated Thyroid Cancer?

Aims To assess whether an elective second admission for radioiodine is useful for patients with high-risk differentiated thyroid cancer (DTC). Materials and methods A retrospective analysis was carried out on 47 high-risk DTC patients treated with a second admission for radioiodine at our centre during the 2007–2008 period. Results In 21 patients (45%), the surgeon described an incomplete resection. Twenty-six (55%) had surgical macroscopic complete resection, but cancer cells at the margin of excision histologically. Overall, at the second admission for radioiodine, 27 patients (57%) had a normal post-treatment scan and undetectable thyroid-stimulating hormone (TSH) stimulated thyroglobulin. Twenty patients (43%) had raised stimulated thyroglobulin at second admission for radioiodine, of whom only six (13%) had abnormal uptake (>0.1%) on the post-treatment scan. Conclusions A second admission for radioiodine could have been avoided in most patients. Instead, information from stimulated thyroglobulin and a diagnostic radioiodine scan would have been sufficient to guide further management. This study also provides interesting outcome data on incompletely resected DTC.