High-risk Differentiated Thyroid Cancer Research Articles

Association of Free Thyroxine with Progression-Free Survival in Intermediate and High Risk Differentiated Thyroid Cancer.

Supraphysiologic thyroxine (T4) doses are used in intermediate and high-risk patients with differentiated thyroid cancer (IR/HR-DTC) to suppress tumor progression by thyrotropin (TSH). However, preclinical data suggest that T4 can also act as a growth stimulus for cancer, but there is no clinical evidence supporting this claim. We analyzed the association between free T4 (FT4) and progression-free survival (PFS) in patients with IR/HR-DTC. This longitudinal cohort study, approved by multi-institutional review board, included patients with IR/HR-DTC treated uniformly with total thyroidectomy, radioiodine (RAI), and TSH suppression therapy, with at least three TSH and FT4 values available. Association between FT4 and PFS at landmarks 6, 12, and 18 months was assessed by Kaplan-Meier survival curves, while competing risks were assessed through Cox proportional hazards model. From 739 screened patients 382 met the inclusion criteria and were characterized by a median age of 46 (34-59) years, 64.1% women, treated with a median RAI dosage of 159 (110-410) mCi. During follow up of 7.1 (3.4-12.7) years 34.6% experienced disease progression.Elevated FT4, observed in 29.3% of patients, was not associated with worse PFS (HR 0.9, CI 0.54-1.5, p=0.69), while age (HR 1.02, CI 1.004-1.04, p=0.01), tumor size (HR 1.15, CI 1.04-1.28, p=0.01), and metastases to the lateral neck lymph nodes (HR 2.9, CI 1.7-4.74, p<0.001), bones (HR 4.87, CI 1.79-13.3, p=0.002), and brain (HR 5.56, CI 2.54-12.2, p<0.001) were associated with shorter PFS. Contrary to preclinical evidence, elevated FT4 levels do not affect PFS in patients with IR/HR-DTC.

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.

Comparison of Recombinant Human Thyroid-Stimulating Hormone and Thyroid Hormone Withdrawal for 131 I Therapy in Patients With Intermediate- to High-Risk Thyroid Cancer : A Systematic Review and Meta-analysis.

This meta-analysis and systematic review aimed to evaluate the therapeutic efficacy and advantages associated with the use of recombinant human thyroid-stimulating hormone (rhTSH) for radioactive iodine (RAI) therapy in patients with intermediate- to high-risk differentiated thyroid cancer. MEDLINE, EMBASE, and Cochrane databases were searched to identify relevant articles reporting clinical outcomes of rhTSH compared with thyroid hormone withdrawal (THW) in patients with intermediate- to high-risk differentiated thyroid cancer published between January 2012 and June 2023. Meta-analyses were performed (PROSPERO registration number: CRD42022340915) to assess the success rate of radioiodine remnant ablation (RRA) in patients with intermediate to high risk and determine the disease control rate among patients with distant metastases, evaluated using the RECIST criteria. Thirteen studies involving 1858 patients were included in the meta-analysis. Pooled analyses revealed significantly higher overall RRA success rate in the rhTSH group compared with the THW group, with a risk ratio (RR) of 1.12 (95% confidence interval [CI], 1.01-1.25). However, in the subgroup analysis of high-risk patients, pooled analyses showed no significant differences in RRA success rate between the rhTSH group compared with the THW group with a pooled RR of 1.05 (95% CI, 0.88-1.24). In patients with distant metastases, there were no significant differences in the disease control rate between groups, with a pooled RR of 1.06 (95% CI, 0.78-1.44). rhTSH for RAI therapy is a practical option for RAI therapy in patients with intermediate- to high-risk thyroid cancer, including those with distant metastases.

SAT519 Association of Free Thyroxine Level With Survival Outcome In Patients With Intermediate And High-Risk Differentiated Thyroid Cancer

Abstract Disclosure: R. Ghosh: None. S. Auh: None. S. Gubbi: None. P. Veeraraghavan: None. C. Cochran: None. L. Shobab: None. K.D. Burman: None. L. Wartofsky: None. J. Klubo-Gwiezdzinska: None. Background Total thyroidectomy followed by radioiodine (RAI) is a standard treatment for patients with intermediate and high-risk differentiated thyroid cancer (DTC). Long-term management consists of therapy with supraphysiologic doses of levothyroxine to suppress thyrotropin (TSH), as in vitro models have shown that TSH can act as a differentiation signal at physiologic concentrations, but as cancer proliferating stimulus in higher concentrations. On the other hand, preclinical studies have shown that thyroid hormones (T4/T3) can act as a growth stimulus in thyroid cancer cell lines. Moreover, supraphysiologic doses of T4/T3 are associated with an increased risk of atrial fibrillation and osteoporotic fractures. There are limited data on the role of elevated free T4 (FT4) on survival outcomes in patients with DTC. The goal of this study was to assess the association between FT4 levels and progression-free survival (PFS) in patients with intermediate-to-high-risk DTC. Material and Methods This cohort study was approved by the multi-institutional review board. Patients with DTC treated uniformly with total thyroidectomy and RAI between January 1, 1979, and March 1, 2015, and subjected to TSH suppression therapy, with at least 3 TSH and FT4 values available over time were included. The association between average FT4 level above the upper reference range (&amp;gt;1.8 ng/dl) at landmarks 6, 12, and 18 months was assessed by Kaplan-Meier survival curves. A Cox proportional hazards model was used to assess the contribution of competing risks such as age, sex, tumor size, lymph node, and distant metastases on PFS. Results The study included 382 patients, aged 46.6 ± 16.5 years, 245/382 (64.1%) women, treated with a median RAI dosage of 159 (110-410) mCi and followed for 8.5±6.2 years during which 132/382 (34.5%) experienced disease progression. During follow-up, 108/382 (28.3%) patients presented with an average FT4 of &amp;gt;1.8 ng/dl, while the remaining patients had FT4 within the normal range. Overall, elevated FT4 level was not associated with decreased PFS (HR 0.9, CI 0.54 -1.5, p=0.69), while age at diagnosis (HR 1.02, CI 1.004-1.04, p=0.01), tumor size (HR 1.15, CI 1.04 -1.28, p=0.01), lateral neck lymph node metastases (HR 2.9, CI 1.78 - 4.74, p&amp;lt;0.001), bone metastases (HR 4.87, CI 1.79 - 13.3, p=0.002) and brain metastases (HR 5.56, CI 2.54 - 12.2, p&amp;lt;0.001) were associated with shorter PFS. The landmark analysis performed to reduce the bias due to time-varying covariates at 6, 12, and 18 months confirmed these results. Conclusions Although high FT4 may stimulate thyroid cancer growth in vitro, elevated FT4 levels do not appear to worsen PFS. However, in managing patients with persistent DTC, clinicians must balance the benefits of TSH suppression with the potential detrimental effects of high FT4 on cardiovascular and bone health. Presentation Date: Saturday, June 17, 2023

Clinical role of 18F-FDG PET/CT for detection of radioactive iodine refractory differentiated thyroid cancer.

In clinical settings, an estimated 10% differentiated thyroid cancer (DTC) cases become radioactive iodide refractory (RAIR), which lack a molecular marker and have fewer treatment selections. A higher uptake of 18F-fluorodeoxyglucose (18F-FDG) might indicate poor prognosis for DTC. This study aimed to evaluate the clinical value of 18F-FDG psitron emission tomography/computed tomography (PET/CT) for the early diagnosis of RAIR-DTC and high-risk DTC. A total of 68 DTC patients were enrolled and underwent 18F-FDG PET/CT for the detection of recurrence and/or metastasis. 18F-FDG uptake was evaluated in patients with different postoperative recurrence risks or TNM stages and compared between RAIR and non-RAIR-DTC based on its maximum standardized uptake value and tumor/liver (T/L) ratio. The final diagnosis was judged by histopathology and follow-up data. Of 68 DTC cases, 42 were RAIR and 24 non-RAIR, with 2 not determined. A total of 263 of 293 lesions detected on 18F-FDG PET/CT were confirmed to be locoregional or metastatic after follow-up. The T/L ratio was significantly higher for RAIR than for non-RAIR (median 5.18 vs 1.44; P < .01) and also significantly higher in postoperative patients at high-risk of recurrence than at low to medium risk (median 4.90 vs 2.16; P < .01). 18F-FDG PET/CT exhibited a sensitivity of 83.3% and specificity of 87.5% for identifying RAIR, with a cutoff T/L value of 2.98. 18F-FDG PET/CT has the potential to diagnose RAIR-DTC early and identify the high-risk DTC. The T/L ratio is a useful parameter for the detection of RAIR-DTC patients.

Imaging Recommendations for Diagnosis, Staging, and Management of Cancer of the Thyroid, Parathyroid, and Salivary Glands

AbstractThyroid cancer ranks as the leading endocrine malignancy in adults. The foundation for primary diagnosis of thyroid cancer is a high-resolution ultrasound (US) of the thyroid gland including US-guided fine-needle biopsy (FNB) of suspected thyroid nodules. Advanced cross-sectional imaging, including computed tomography (CT), magnetic resonance imaging, and positron emission tomography, can be useful in selected patients. The mainstay of treatment of thyroid cancer is surgery. It may be supplemented by radioactive iodine ablation/therapy in high-risk differentiated thyroid cancer. Radiology plays a crucial role in both diagnostic and posttreatment follow-up imaging. Primary hyperparathyroidism (PHPT) is the third most common endocrine disorder with single parathyroid adenoma being its most common cause. The radiologist's aim in parathyroid imaging is to provide the clinician with an illustrative picture of the neck, locating lesions with respect to landmarks. Imaging helps in the detection of solitary versus multiglandular disease, ectopic and supernumerary glands with precise localization. US, nuclear imaging, and four-dimensional CT are the most commonly used imaging modalities for the preoperative localization of the parathyroid disease. Salivary gland tumors account for approximately 0.5% of all neoplasms, the most common location being the parotid gland (70%). Imaging is crucial in salivary gland tumors by defining its location, detecting malignant features, assessing local extension and invasion, staging the tumors according to the tumor-node-metastasis classification, and assessing the feasibility of surgery.

Utility of FDG PET at the Initial Radioiodine Therapy in Differentiated Thyroid Cancer.

Differentiated thyroid cancer (DTC) has a good prognosis, except in the case of patients with radioiodine therapy (RIT)-refractory cancer. However, since DTC is essentially a slowly progressing cancer, it is usually judged to be a DTC with a poor prognosis after multiple RITs and yearly follow-up with echo, computed tomography (CT), and serum thyroglobulin values. This study investigated whether fluorodeoxyglucose-positron emission tomography/CT (FDG PET/CT) combined with initial RIT could identify early-stage patients with poor prognosis. We evaluated 100 patients with high-risk DTC who underwent total thyroidectomy and received RIT at our institution. We analyzed the clinical outcomes of patients and 18F-FDG accumulation using univariate and multivariate Cox proportional hazards regression models. The 10-year overall survival (OS) was 87.9%, with no significant difference in OS between 18F-FDG accumulation at pre-total or near-total thyroidectomy (NTT) (p=0.180) and 131I accumulation at initial RIT (p=0.577). However, 18F-FDG positive patients had a significantly worse prognosis than negative patients (p=0.005) at initial RIT. 18F-FDG PET/CT plays an important role in both the diagnosis and prognostic prediction of RIT refractory disease in DTC patients. 18F-FDG PET/CT can be a useful tool particularly at the time of initial RIT since the 18F-FDG accumulation enables the screening of high-risk DTC with poor prognosis at a very early time stage.

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 utility of low-iodine diet in preparation for thyroid cancer therapy with radioactive iodine-A cohort study.

Objective: A low-iodine diet (LID) of <50μ iodine/day is recommended as preparation for radioactive iodine (RAI) therapy in patients with differentiated thyroid cancer (DTC). The 24-h urinary iodine excretion (UIE) is utilized to evaluate the iodine-depleted status. The aim of this study was to test the association between UIE and progression-free survival (PFS). Patients and methods: In total, 70 patients with intermediate- or high-risk DTC, post-total thyroidectomy, adhered to 2 weeks of LID and had UIE measured before RAI therapy. A Cox regression model was performed to study the contribution of UIE to PFS. Results: The study group consisted of 68% (48/70) of women, aged 41.5 [IQR 31.0, 54.0] years, with tumor size 2.8 [IQR 1.8–4.5] cm, and presence of distant metastases in 22.9% (16/70) of patients. Patients were treated with 1–5 RAI dosages with the median cumulative activity of 150 [IQR 102–314] mCi (5.5 [IQR 3.8–11.6] GBq). During the follow-up of 3.7 [IQR 1.5–6.5] years, 21.4% (15/70) of patients had disease progression. The risk of progression was significantly higher in patients with UIE ≥200 µg/day at the time of RAI administration than in those with UIE <200 µg/day (HR 3.35, 95% CI 1.09–10.34, and p = 0.02). However, the multivariate Cox proportional hazards regression analysis adjusted for age, tumor size, and presence of distant metastases suggested that only distant metastases were independently significantly associated with the risk of progression (HR 5.80 (1.17–28.67), p = 0.03). Conclusions: Although UIE ≥200 µg/day might be associated with worse PFS in RAI-treated DTC patients, the presence of distant metastases is a strong independent predictor of progression. Less stringent LID might be sufficient to achieve a UIE of <200 µg/day.

Incomplete response to therapy in intermediate- and high-risk thyroid cancer.

The American Thyroid Association (ATA) risk stratification system predicts risk of recurrence of differentiated thyroid cancer (DTC). Although the majority of patients achieve an excellent response, patients with intermediate- or high-risk DTC are at a significant risk of developing incomplete responses. We undertook this work to understand the factors associated with development of biochemically or structurally incomplete response in these two risk subgroups of DTC. We retrospectively reviewed 287 consecutive patients with intermediate- (213 patients) or high-risk (74 patients) DTC. All patients underwent total thyroidectomy with (223 patients) or without (64 patients) lymph node dissection and 94% of them received at least one dose of I-131ablation/therapy. Univariate and multivariate analysis and Kaplan Meier analysis were used to compare patients who achieved an excellent response with those who continued to have biochemically or structurally incomplete responses. In univariate and multivariate analyses, age (P 0.002, Odds ratio 4.8, 95% CI: 1.8-12.9), tumor size (P 0.027, Odds ratio 1.30, 95% CI: 1.03-1.64) and distant metastases (P &lt; 0.0001, Odds ratio 44.6, 95% CI: 10.7-184.5) were significantly associated with the risk of developing biochemically or structurally incomplete statuses. Patients ≥ 55 years, tumors &gt; 2.5 cm and presence of distant metastasis were associated with higher risk of incomplete response and death from DTC. However, when this analysis was performed on intermediate and high-risk groups separately, only age was consistently associated with risk of biochemically or structurally incomplete response in either and both groups. Age is a strong predictor of biochemically and structurally incomplete responses in patients with intermediate and high-risk DTC.

Advanced imaging and theranostics in thyroid cancer.

Thyroid cancers are endocrine neoplasms with diverse gene expression and behavior, for which constantly evolving anatomic and functional imaging/theranostic agents have an essential role for diagnosis, staging, and treatment. To achieve definitive diagnosis, neck ultrasound and associated risk stratification systems, notably Thyroid Imaging Reporting and Data System (TI-RADS), allow improved thyroid nodule characterization and management guidance. Radioactive iodine-131 (RAI) has long played a role in management of differentiated thyroid cancer (DTC), with recent literature emphasizing its effectiveness for intermediate-high risk cancers, exploring use of dosimetry for personalized medicine, and potential for retreatment with RAI following tumor redifferentiation. Iodine-124 positron emission tomography/computed tomography (PET/CT) has promising application for DTC staging and dosimetry. F18-fluorodeoxyglucose (FDG) PET/CT is used for staging of high risk DTC and identification of noniodine-avid disease recurrences, with metabolic uptake consistently portending poor prognosis. Poorly differentiated and anaplastic thyroid cancers are best assessed with anatomic imaging and F18-FDG PET/ CT, though recent studies show a potential theranostic role for Ga68/Lu177-prostate-specific membrane antigen. Medullary thyroid cancers are evaluated with ultrasound, CT, magnetic resonance imaging, and various positron-emitting radiotracers for PET imaging (F18-DOPA, F18-FDG, and recently Ga68-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA)-octreotate (DOTATATE)); the latter may enable treatment with Lu177-DOTATATE. Multidisciplinary collaboration is essential to streamline appropriate management, given the wide array of available imaging and new therapies for metabolic and genetically complex cancers.

The role of external beam radiation therapy in the management of thyroid carcinomas: A retrospective study in Iran Cancer Institute.

Thyroid cancers are histologically classified into three types; differentiated thyroid carcinoma (DTC), medullary thyroid carcinoma (MTC), and anaplastic thyroid carcinoma (ATC). Among the several therapeutic strategies for treatment and management of thyroid cancer, surgical resection in combination with radioactive iodine therapy (RAI) is indicated for moderate to high-risk differentiated thyroid cancer (DTC) patients- according to current guidelines. However, external radiation therapy (EBRT) can be a viable alternative treatment option for these patients and scarce evidence is available regarding the efficacy and effectiveness of EBRT on thyroid cancer. This study aims at evaluating the role of EBRT in the management of thyroid carcinomas. In this retrospective cohort study, the records of 59 patients with thyroid cancer were accessed who were treated by EBRT from 2008 to 2016. The indications for EBRT included unresectable primary (definitive) or loco-regional recurrences (salvage) not suitable for RAI, palliation for local disease or metastatic foci (palliative), and the adjuvant treatment for suspected residual disease following resection. Progression-free survival (PFS) and overall survival (OS) were calculated for different types of cancer. PFS was measured from the start of EBRT to the last uneventful follow-up, recurrence, or death. Kaplan-Meier model was used for the survival analysis. Fifty-nine patients were evaluated. The histopathology of the tumors was differentiated and poorly-differentiated, medullary and anaplastic thyroid carcinomas in 22 and 6, 15 and 16 patients, respectively. Twenty-seven patients received external beam radiotherapy (EBRT) as adjuvant therapy and 18 of the cases as palliative therapy while the remaining received salvage or definitive primary EBRT. The stage of patients' cancer was as follows: stage II in 3 and III in 1, IVA in 18 and IVB in 18 and IVC in 19. Stage-based median overall survival was 26 months for IVA, 44 for IVB, and 29 for IVC. The median PFS was 18, 22 and 21 months for stages IVA, IVB and IVC, respectively. Based on our findings, EBRT may still play a role in the management of patients with thyroid carcinoma and should be considered in the armamentarium against thyroid cancers.

Combination of Selumetinib and Radioactive Iodine Therapy Did Not Improve Outcomes in a Phase 3 Trial of High-Risk Differentiated Thyroid Cancer

Combination of Selumetinib and Radioactive Iodine Therapy Did Not Improve Outcomes in a Phase 3 Trial of High-Risk Differentiated Thyroid Cancer

Outcomes and Trends of Treatments in High-Risk Differentiated Thyroid Cancer.

To analyze the variant-specific survival benefits and usage patterns of standardized treatment combinations of surgery (S), radioactive iodine ablation (RAI), and thyroid-stimulating hormone suppression therapy (THST) for high-risk differentiated thyroid cancer. Retrospective cohort study. National Cancer Database. The 2004-2017 National Cancer Database was queried for patients receiving definitive surgery for high-risk papillary, follicular, or Hurthle cell thyroid cancer. Cox proportional hazards and Kaplan-Meier analyses assessed for treatment-associated survival. Of 21,076 cases, 18,214 underwent survival analysis with a mean ± SD age of 50.6 ± 17.1 years (71.3% female). When compared with surgery alone, S + RAI was associated with reduced mortality in papillary (hazard ratio [HR], 0.574; P < .001) and follicular (HR, 0.489; P = .004) thyroid cancer. S + RAI + THST was associated with reduced mortality in papillary (HR, 0.514; P < .001), follicular (HR, 0.602; P = .016), and Hurthle cell (HR, 0.504; P = .021) thyroid cancer. In papillary thyroid cancer, S + RAI (91.3%), S + THST (89.2%), and S + RAI + THST (92.7%) were associated with higher 5-year overall survival rates than surgery (85.4%, all P < .001). Papillary thyroid cancer treatments involving THST were associated with higher 5-year overall survival rates than corresponding regimens without THST (all P < .001). In follicular thyroid cancer, S + RAI (73.9%) and S + RAI + THST (78.7%) were associated with higher 5-year overall survival rates than surgery (65.6%, all P < .05). In Hurthle cell thyroid cancer, S + RAI (66.5%) and S + RAI + THST (73.4%) were associated with higher 5-year overall survival rates than surgery (53.7%, all P < .05). On linear regression, THST usage increased by 77.5% (R2 = 0.944, P < .001), while RAI usage declined by 11.3% (R2 = 0.320, P = .035). High-risk differentiated thyroid cancer exhibited varying susceptibilities to different treatment combinations depending on histology, with greatest responses to regimens that included RAI. Physician practices have trended toward decreased RAI and increased THST usage.

18F-FDG PET/CT concurrent with first radioiodine post-therapeutic scan in high risk differentiated thyroid cancer: a useful tool or just an expensive diversion?

Aim of the present study was to evaluate the clinical impact of fluorine-18F-fluorodeoxyglucose PET/CT (18F-FDG-PET/CT) concurrent with post-therapeutic whole-body radioiodine scan (TxWBS) after first radioiodine (RAI) treatment in patients with high-risk differentiated thyroid carcinoma (DTC). This was a retrospective, single-center study including 39 patients with DTC (22 females, 17 males, median age 54; IQR: 35-60 years, 87% papillary thyroid cancer, 13% follicular thyroid cancer). All patients underwent 18F-FDG-PET/CT and RAI treatment, both performed off L-T4 about 3 months after total thyroidectomy. TxWBS was obtained 3 days afterwards using planar technique and SPECT/CT of neck and thorax regions. Semiquantitative analysis was performed on positive 18F-FDG-PET/CT scans to assess SUV<inf>max</inf>, SUV<inf>ratio</inf>, MTV and TLG values in target lesions (hottest 18F-FDG-positive lesion present in each patient). Receiver operating characteristics (ROC) curve analysis was obtained to establish a cut-off point for SUV<inf>max</inf> able to predict the presence of RAI nonavid lesions. Univariate and multivariate analyses were executed to find out predictive factors for abnormal 18F-FDG-PET/CT imaging. In 11 (28%) patients 18F-FDG-PET/CT and TxWBS were both negative and in 9 (23%) both positive, showing loco-regional or distant metastases. In 14 patients (36%) 18F-FDG-PET/CT showed more lesions than TxWBS, while in 5 (13%) patients more lesions were present at TxWBS than 18F-FDG-PET/CT. Overall, 23 patients (59%) showed 18F-FDG avid lesions and 18F-FDG-PET/TC changed the management in 14 (36%), including the choice to perform RAI therapy with higher activities than expected, lymph-node dissection for loco-regional metastases, direct therapy for solitary bone metastases. Through ROC curve analysis, a value superior to 7.25 of SUV<inf>max</inf> was able to predict the presence of RAI non-avid lesion at TxWBS. Serum stimulated thyroglobulin and extranodal invasion resulted to be risk factors for abnormal 18F-FDG-PET/CT imaging. However, only extranodal invasion turned out to be an independent risk factor for abnormal 18F-FDG-PET/CT. The present study demonstrated the clinical value of RAI-concurrent 18F-FDG-PET/CT in patients with high-risk DTC. However, some questions remain open, including the pretherapeutic thyroglobulin level to use as indication to 18F-FDG-PET/CT and the predictive value of 18F-FDG-PET/CT semiquantitative parameters.

Functional imaging in thyroid cancer patients with metastases and therapeutic implications

Functional imaging plays a central role in the management of thyroid cancer patients.In patients with a differentiated thyroid cancer (DTC), radioactive iodine (RAI) is used mostly with a therapeutic intent, either post-operatively or as the first line systemic treatment in patients with known structural disease. A whole body scan is performed a few days after the RAI administration, and this procedure is very sensitive to detect all tumor foci with RAI uptake. PET/CT with 18F-FDG complements the use of RAI at the initial evaluation of patients with high-risk DTC, during follow-up in those with rising serum thyroglobulin levels over time, for the work-up of patients with documented structural disease and for assessing the efficacy of focal or systemic treatment modalities. 18F-FDG uptake is a prognostic indicator in all these clinical conditions. A dosimetric approach with 124I PET/CT showed encouraging results.Several functional imaging modalities are currently available for medullary thyroid carcinoma (MTC) patients. 18F-FDG-PET/CT may be sensitive in MTC patients with high FDG uptake that signals aggressive disease. 18F-DOPA is the most sensitive imaging technique to visualize small tumor foci, and is also highly specific in patients with a known MTC, but should be complemented by a CT scan of the chest and by a MRI of the liver to detect small metastases.

Delayed Initial Radioiodine Adjuvant Therapy Does Affect Biochemical Response in Intermediate- to High-Risk Differentiated Thyroid Cancer.

BackgroundThere are no definite recommendations on the optimal time of initiating radioactive iodine (RAI) therapy for differentiated thyroid cancer (DTC) patients in current relevant guidelines. This study aimed to investigate the relationship between the timing of initiating radioiodine adjuvant therapy (RAT) and the clinical outcomes based on dynamic follow-ups and assessments in intermediate- to high-risk DTC patients.MethodsA total of 206 patients with intermediate- to high-risk DTC receiving RAT of 150 mCi were retrospectively reviewed. According to the time interval (TI: between thyroidectomy and initial RAT), the patients were divided into 2 groups: Group 1: TI < 3 months (n=148), and Group 2: TI ≥ 3 months (n=58). The RAT therapy response was evaluated as excellent response (ER), indeterminate response (IDR), biochemical incomplete response (BIR), structural incomplete response (SIR). The univariate and multivariate analyses were conducted to screen out factors associated with incomplete response (IR= BIR+SIR). Finally, the prognostic nomogram was used to explain IR rates as a valuable tool in clinical practice.ResultsResponse to initial RAT was significantly different between 2 groups during dynamic follow-ups (all P<0.05). Group 2 had significantly lower ER rates (37.9 vs 63.5, 52.0 vs 73.9, 64.4 vs 80.3, all P<0.05, respectively) and higher IR rates (39.7 vs 14.9, 36.0 vs 9.7, 12.2 vs 3.9, all P<0.05, respectively) than group 1 during dynamic follow-ups. By univariate and multivariate analyses, prolonged TI (HR: 6.67, 95%CI: 2.241-19.857, P=0.001), soft tissue invasion (HR: 7.35, 95%CI: 1.624-33.296, P=0.010), higher sTg (HR: 7.21, 95%CI: 1.991-26.075, P=0.003) were manifested to be independent risk factors for IR. The nomogram showed that soft tissue invasion, sTg, and TI were the top 3 contributors to the IR.ConclusionsEarly RAT is associated with greater biochemical response but has no impact on SIR. Delayed initial RAT (≥3 months after thyroidectomy) related to IR in intermediate- to high-risk DTC.

A multicenter, prospective study to observe the initial management of patients with differentiated thyroid cancer in China (DTCC study)

BackgroundTo assess the gaps between the initial management of patients with differentiated thyroid cancer (DTC) in real clinical practice and the recommendations of the 2012 Chinese DTC guidelines.MethodsThis multicenter, prospective study was conducted at nine tertiary hospitals across China. Eligible patients were those having intermediate or high-risk DTC after first-time thyroidectomy. During 1 year of follow-up, comprehensive medical records were collected and summarized using descriptive statistics.ResultsOf 2013 patients, 1874 (93.1%) underwent standard surgery according to the guidelines (including total lobectomy plus isthmusectomy and total/near total thyroidectomy), and 1993 (99.0%) underwent lymph node dissection; only 56 (2.8%) had postoperative complications. Overall, 982/2013 patients (48.8%) received radioactive iodine (RAI) therapy after thyroidectomy. Of all enrolled patients, 61.4% achieved the target serum thyroid-stimulating hormone level, with a median time to target of 234.0 days (95% CI: 222.0–252.0). At 1 year of follow-up, proportions of patients with excellent response, incomplete structural response, biochemical incomplete response, and indeterminate response were 34.6, 11.2, 6.6, and 47.5%, respectively; recurrence or metastasis occurred in 27 patients (1.3%). During the overall study period, 209 patients (10.4%) had at least one adverse event: 65.1% of cases were mild, 24.9% moderate, and 10.1% severe.ConclusionsThis was the first large-scale prospective study of how patients with DTC in China are treated in actual practice. Initial DTC management is generally safe and adheres to the 2012 Chinese guidelines but could be improved, and the level of guideline adherence did not produce the anticipated treatment response at 1 year of follow-up.

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.