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Background: Surgery is the elective treatment for cervical relapse from differentiated thyroid cancer (DTC) but it is technically challenging, with risk of failure and morbidity. We explored the feasibility and the efficacy of radioguided occult lesion localization (ROLL) with intratumoral 99mTc radiolabeled human albumin macroaggregates ([99mTc]MAA) injection in this setting., Methods: Fifteen patients who underwent ROLL by ultrasonography (US)-guided intratumoral injection of [99mTc]MAA between December 2013 and October 2016 for DTC recurrence were considered for this study. A hand-held gamma-probe was employed for intrasurgical lesion detection. Mini-invasive ROLL-guided excision for soft tissue recurrence and ROLL-assisted modified radical neck dissection for lymph-node metastases were performed respectively., Results: DTC recurrence was located in loco-regional lymph-nodes (N.=8 patients) and in thyroid bed (N.=7 patients). A total of 27 lesions was identified and injected before surgery. On a total of 124 lesions resected, histology showed 38 DTC metastases. In particular, 26 out of 27 lesions injected with [99mTc]MAA were correctly detected intra-operatively and resected without surgical complications. Ten patients received subsequent radioactive iodine (RAI) treatment to verify the complete recurrence resection. At a median follow-up of 16 months patients were classified in complete response (N.=4), biochemical incomplete response (N.=3), indeterminate response (N.=1) with no evidence of structural disease. The remaining 7 patients were classified as structural incomplete response for cervical persistent disease (N.=2), for cervical recurrence (N.=2) and for both cervical and lung metastases progression (N.=3)., Conclusions: ROLL is a simple and safe procedure in the surgical management of DTC loco-regional relapse.

Purpose: Medullary thyroid carcinoma (MTC) originates from thyroid parafollicular C-cells and represents <5% of all thyroid cancers. Serum Calcitonin (CTn) is considered the most sensitive marker of persistent or recurrent disease and is measured in association to CEA. According to the American Thyroid Association (ATA) guidelines, following initial surgery when CTn level remains below 150 pg/mL, follow-up may rely on repeated serum marker determinations and on neck ultrasonography (US). When CTn level exceeds 150 pg/ml, additional imaging is required. In this review, we provide an overview of available imaging tools to monitor MTC course and propose an effective imaging strategy for MTC patients according to their clinical situation., Methods: A literature search focusing on available imaging tools to monitor MTC provided the currently available information for this review. Recent evidence-based reports and reviews were considered as priority over older evidence., Results: For MTC patients with detectable CTn levels and disease recurrence, PET/CT imaging with 18 F-DOPA or 68 Ga-DOTA-peptides present the best sensitivity for lesion detection. 18 F FDG PET/CT represents a prognostic tool and is useful in case of aggressive disease. Neck ultrasound, chest CT scan and MRI of the liver and of the axial skeleton represent complementary techniques. Beyond the diagnostic accuracy, the clinical impact of imaging is variable according to different disease settings and tumor marker levels. Finally, other applications of imaging such as response to focal and systemic treatments and new promising PET tracers should be further investigated., Conclusion: The role of imaging in MTC patients improved, especially with the use of 18 F-DOPA PET/CT that provides high quality diagnostic images. However, the impact on therapeutic management should be further evaluated in the different disease settings and in proper prospective trials., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Purpose: This is the first prospective trial evaluating the efficacy of alpha emitter Radium-223 in patients with bone metastases from radioactive iodine (RAI) refractory (RAIR) differentiated thyroid cancer., Methods: RADTHYR is a multicenter, single-arm prospective Simon two-stage phase II trial (NCT02390934). The primary objective was to establish the efficacy of three administrations of 55 kBq/kg of Radium-223 by 18 F-FDG PET/CT according to PERCIST criteria. Secondary objectives were to establish the efficacy of six administrations of Radium-223 by 18 F-FDG PET/CT, 99m Tc-HMDP bone scan and 18 FNa PET/CT, clinical benefits, changes in serum bone markers, thyroglobulin levels, and safety., Results: Ten patients were enrolled between July 2015 and December 2017 (4 M; median age 74 years). Prior to Radium-223 administration, patients received a median RAI cumulative activity of 15 GBq (7.4-35.6), external radiation therapy (n = 9), bone surgery (n = 8), cimentoplasty (n = 5), and cryoablation (n = 2). 18 F-FDG PET/CT showed stable disease (SD) in 4/10 and progressive disease (PD) in 6/10 cases after three administrations and SD in 4/10, PD in 5/10 cases, and 1/10 non-evaluable (NE) case after six administrations. After six injections, 99m Tc-HMDP bone scan showed SD in 9 cases and was NE in 1 case; 18 FNa PET/CT showed SD in 8 cases, partial response (PR) in 1 case, and was NE in 1 case. No significant clinical benefits were reported during the study. A skeletal event occurred in 6 patients (median time without skeletal event of 12.1 months). Seventy-seven adverse events were reported during treatment (7 of grade 3-4). Three patients developed an acute myeloid, a promyelocytic, and a chronic myeloid leukemia after the last Radium-223 administration considered as drug-related., Conclusion: The trial was stopped after interim analysis for lack of response of bone metastases from RAIR thyroid cancer to Radium-223. Severe hematological toxicity was observed in patients heavily pretreated with RAI and external radiation., Trial Registration Number: NCT02390934. Registration date 18.03.2015., (© 2021. The Author(s).)

Purpose: Aim of our study was to search for variables associated with worse outcomes in patients treated with radioactive iodine (RAI) for hyperthyroidism by a dosimetric-based approach., Methods: Four hundred twenty-four patients with hyperthyroidism related to Toxic Multinodular Goiter (TMG; n = 213), Grave's disease (GD; n = 150) and toxic adenoma (TA; n = 61) treated with RAI between 2000 and 2018 and with at least 12 months follow-up were retrospectively evaluated. Association between outcomes (response vs. no response) at 6 and 12 months and baseline TSH values, anti-thyroid drugs (ATD) duration and posology, RAI absorbed dose and dimensional reduction of target mass at ultrasound was evaluated by Mann-Whitney test. Risk factors for response vs. no-response were analysed by binary logistic regression model., Results: Overall response rate was 78.7 and 83% at 6 and 12 months, respectively. Both at 6 and 12 months higher TSH baseline values (p < 0.001), lower ATD duration (p = 0.004 and p = 0.043), lower ATD posology (p = 0.014 and p = 0.005), and lower dose to target (D T ) (327 vs. 373 Gy, p = 0.003) were associated to response. Longer ATD duration and higher ATD posology were independent risk factors for no response at 6 and 12 months in GD and TMG, with no response at 6 months in TA subgroups., Conclusions: Low TSH levels, longer duration and higher posology of ATD were associated with worse response to RAI. These data confirm that RAI therapy should be considered earlier in patients' management to allow better outcome and avoid ATD toxicity.

Background: Elevated postoperative serum calcitonin (Ctn) level indicates persistent/recurrent disease in patients with medullary thyroid carcinoma (MTC). Its location is a challenge. The aim of our study was to compare the disease detection rates of F-18-Dopa (fluoro dihydroxyphenylalanine) positron emission tomography (PET)/computed tomography (CT), whole-body (WB) magnetic resonance imaging (MRI), F-18-FDG (fluorodeoxyglucose) PET/CT, WB CT scanning, neck ultrasonography, and bone scintigraphy in MTC patients with increased Ctn levels and unknown localization of the source. Methods: We compared the independent reading of each imaging procedure with a reference assessment for structural disease defined by pathology or concordance between two imagings or with subsequent follow-up. The detection rate of each imaging modality was determined in per patient, per organ, and per lesion analysis. Results: Thirty-six consecutive patients (21 females, mean age: 57 years, sporadic MTC in 26 cases, median serum Ctn level: 760 pg/mL; range: 21-10,121) were analyzed. The reference assessment localized disease in 24 (64%) patients with 74 lesions detected in the thyroid bed (8), in neck lymph nodes (15), mediastinal lymph nodes (6), lungs (1), liver (2), bones (3), and other site (1). At the patient level, the detection rates were 64% (CI 0.48-0.80) for F-18-Dopa PET/CT with early acquisitions, 40% (CI 0.24-0.56) for F-18-FDG PET/CT, 40% (CI 0.24-0.56) for WB MRI, and 48% (CI 0.31-0.66) for WB CT scan. Conclusions: In MTC patients with increased Ctn and no known distant metastases, F-18-Dopa PET/CT is more sensitive to detect structural disease than any other imaging modality, including WB MRI.

The 2013/59 EURATOM directive defines all nuclear medicine applications for therapeutic purpose as a form of radiotherapy and underlines the need of both justification and optimization of these procedures, including radioactive iodine therapy (RAIT) with [131I] for metastatic differentiated thyroid cancer (DTC). In metastatic DTC, optimal activity to be administered to achieve the best response rate with limited toxicity is still a matter of debate and international guidelines do not provide univocal recommendations on the preferable use of empiric versus a dosimetry-based approach in these patients. The purpose of this literature review is to describe the possible limits of dosimetry in RAIT planning according to methodological aspects, tumoral heterogeneity and to report clinical data on the impact on patients' outcome of different approaches. Due to the lack of standardized dosimetry protocols and clinical data assessing the superiority of a dosimetry-based vs an empiric approach in these patients, there is a need of standardisation and prospective, properly conducted studies to validate and to assess the best approach.

A pre operatory assessment by neck US, F-DOPA and F-choline PET/CT was performed in a 43-year-old MEN 2A woman affected by hyperparathyroidism and medullary thyroid carcinoma (MTC). On F-DOPA, two thyroid uptakes were analyzed as multifocal MTC and two others in the central neck compartment as MTC metastatic lymph nodes. After surgery, multifocal intra thyroidal MTC and two parathyroid glands hyperplasias were proved without MTC adenopathies. We report a case of rare false positive uptake on F-DOPA. In case of several endocrine diseases coexistence as in MEN 2A, F-DOPA should be carefully analyzed.

The optimal management of radioactive iodine (RAI) treatment in patients with metastatic thyroid cancer (TC) is still a matter of debate. Methods: We retrospectively analyzed 352 patients with RAI-avid metastatic well-differentiated TC treated with 131 I by an empiric fixed activity of 3.7 GBq at Gustave Roussy (GR, n = 231) or by personalized activity (2.7-18.6 GBq) based on whole-body/-blood clearance (WB/BC) dosimetry at Memorial Sloan Kettering Cancer Center (MSKCC, n = 121). The primary endpoint was to compare overall survival (OS) in the 2 groups of patients by log-rank test. Results: Patients received a median cumulative activity of 14.8 GBq at GR and 24.2 GBq at MSKCC ( P < 0.0001). The median follow-up after the diagnosis of metastases was 7.2 y (0.4-31 y). Five-year OS was 86.8% and 78.8% for patients treated at GR and at MSKCC, respectively ( P < 0.01). However, there was no statistical difference in OS after correction for sex, age at the diagnosis of distant metastases, metastases site, and metastases extension between the 2 centers ( P = 0.16). OS at 5 y was 96% and 96% for patients younger than 40 y with micrometastases, 70% and 65% for patients older than 40 y with macrometastases or multiple metastases, and 92% and 87% for younger patients with macrometastases or older patients with micrometastases treated at GR and MSKCC, respectively ( P = not significant). Conclusion: Routine use of WB/BC dosimetry without lesional dosimetry provided no OS advantage when compared with empiric fixed RAI activity in the management of thyroid cancer patients with RAI-avid distant metastases., (© 2017 by the Society of Nuclear Medicine and Molecular Imaging.)

Purpose: In patients with metastatic differentiated thyroid carcinoma (DTC), fluorodeoxyglucose (FDG) uptake as well as age, tumor size and radioactive iodine (RAI) uptake are prognostic factors for survival. High FDG uptake is a poor prognostic factor and lesions with high FDG uptake are often considered aggressive, but the predictive value of FDG uptake for morphological progression is unknown. The principal aim of this retrospective single center study was to determine whether the intensity of FDG uptake was correlated on a per lesion analysis with tumor growth rate (TGR) expressed as the percentage of increase in tumor size during 1 year (1-year TGR)., Methods: Fifty five patients with DTC were included between July 2012 and May 2014 with the following criteria: (i) at least one distant metastasis measuring ≥ 1 cm in diameter on CT scan (ii) evaluation by FDG-positron emission tomography/computed tomography (PET/CT) performed at our center (iii) at least one CT or another FDG-PET/CT performed 3 to 12 months after the reference FDG-PET/CT in the absence of systemic or local treatment between the two imaging procedures., Results: One hundred and fifty-six metastatic lesions located in lungs (63), neck lymph nodes (28), chest lymph nodes (42), bone (11), liver (2) and other sites (12) were studied. The median size was 16 mm, median SUVmax/lesion: 8.7; median metabolic tumor volume/lesion (Metab.TV/lesion): 3.7 cm 3 . The median 1-year TGR was 40.68 %. SUVmax and Metab.TV/lesion were not correlated to their 1-year TGR (p = 0.38 and p = 0.74 respectively). Among single patients with multiple lesions, the lesions with the highest SUVmax/lesion or the highest Metab.TV/lesion did not disclose the higher 1-year TGR., Conclusion: The intensity of FDG uptake on a per lesion analysis is not correlated to its 1-year TGR and cannot be used as a surrogate marker of tumour progression.

Background: Persistent/recurrent disease in the neck is frequent in patients with differentiated thyroid cancer (DTC)., Objective: Assess efficacy, safety, and prognostic factors of first neck reoperation in DTC., Methods: Retrospective study of consecutive patients undergoing neck reoperation for recurrent/persistent DTC in a referral cancer center. Response after reoperation was defined according to the 2015 American Thyroid Association guidelines., Findings: One hundred sixty-one DTC patients were enrolled (64% females, median age 35 years, 96% papillary DTC). Initial stage was pT3 in 43% and pT4 in 10%, pN1 in 74%. Aggressive histology was present in 25% of the patients, in both primary and persistent/recurrent tumor. Four patients had no malignancy in the reoperative specimen, and 1 patient died due to postoperative hematoma and was excluded from further analysis. Following reoperation, 15 patients (10%) had persistent structural disease, 16 (10%) had biochemical incomplete response, 26 (17%) had indeterminate response, and 99 (63%) had complete response (CR), among whom 24 relapsed later. After a median follow-up of 5 years, only 83 patients (53%) had CR without the need for further treatments. The rate of permanent complications was: hypoparathyroidism 2%, laryngeal nerve palsy 0.6%, other 6%. Age ≥45 years, aggressive histology, and lymph node ratio ≥0.6 at initial surgery were independent risk factors for incomplete response after reoperation. Male sex, aggressive histology, and ≥10 metastases at reoperation were independent risk factors of secondary relapse following CR achieved with reoperation., Conclusion: A careful risk-benefit analysis should guide surgical decision, particularly in patients with risk factors for incomplete response., (Copyright © 2017 by the Endocrine Society)

The clinical and epidemiological profiles of differentiated thyroid cancers (DTCs) have changed in the last three decades. Today's DTCs are more likely to be small, localized, asymptomatic papillary forms. Current practice is, though, moving toward more conservative approaches (e.g. lobectomy instead of total thyroidectomy, selective use of radioiodine). This evolution has been paralleled and partly driven by rapid technological advances in the field of diagnostic imaging. The challenge of contemporary DTCs follow-up is to tailor a risk-of-recurrence-based management, taking into account the dynamic nature of these risks, which evolve over time, spontaneously and in response to treatments. This review provides a closer look at the evolving evidence-based views on the use and utility of imaging technology in the post-treatment staging and the short- and long-term surveillance of patients with DTCs. The studies considered range from cervical US with Doppler flow analysis to an expanding palette of increasingly sophisticated second-line studies (cross-sectional, functional, combined-modality approaches), which can be used to detect disease that has spread beyond the neck and, in some cases, shed light on its probable outcome., (© 2016 European Society of Endocrinology.)

Aim: To assess the interest of (18)F-fluorodeoxyglucose positron emission tomography ((18)F-FDG PET/CT) to evaluate the tumor response after radiotherapy (RT) in anaplastic thyroid cancer (ATC) patients., Methods and Materials: 92 patients were treated for ATC at our institution from 1987 to 2012, out of which 64 (70%) received an aggressive multimodal treatment and 28 (30%) a palliative treatment. In the multimodal treatment group, curative-intended surgery, chemotherapy, and RT were delivered in 35 (55%), 59 (92%), and 56 (88%) patients. The maximum standardized uptake value (SUVmax) was determined in tumor (T), nodes (N) and metastases (M) in each available (18)F-FDG PET/CT., Results: The median follow-up was 3.2years. The 1-year actuarial overall survival (OS) was 18% (median: 5.2months) in the entire population and 27% (median: 7months) in the multimodal treatment group. In the multivariate analysis, RT, surgery, and pre-RT chemotherapy independently predicted for OS, with HRs respectively of 0.1, 0.3, and 0.5. Quantification of FDG uptake with SUVmax was assessable in 26 (40%), 19 (30%), and 25 (39%) of (18)F-FDG PET/CT performed initially (prior to any treatment), prior to RT, and after RT, respectively. Mean SUVmax significantly decreased in T (p<0.001), but not in N (p=0.1) and M (p=0.3) during the assessment period, which might be related to the local effect of RT. Comparing pre- and post-RT (18)F-FDG PET/CT, the T mean relative SUVmax decrease was lower (23±54%) in the 4 patients that had a local relapse (LR) as compared with others in the 12 others patients (62±33%; p=0.3). A relative SUVmax decrease inferior to 20% significantly predicted for LR (p=0.02)., Conclusion: The prognosis of ATC patients remains dismal despite an aggressive multimodal treatment. Although our results were not significant, (18)F-FDG PET/CT could potentially serve as a surrogate marker of treatment response in ATC., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Background: Aggressive histopathologic subtypes of differentiated thyroid cancer (DTC) are fluorodeoxyglucose (FDG)-avid tumors and are at high risk for persistent/recurrent disease. In these patients, fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) is performed in cases of suspicion of recurrence based on thyroglobulin (Tg) levels or thyroglobulin antibodies (TgAb). The goals of this study were to evaluate the sensitivity of systematic postoperative FDG-PET/CT and to identify risk factors for abnormal FDG-PET/CT., Methods: Single-center retrospective study of 38 consecutive patients (16 males, 22 females; mean age, 57 years) with aggressive histology DTC, without known persistent disease at the time of postoperative radioactive iodine (RAI) ablation. The most frequent aggressive histologic subtypes were tall cell papillary carcinoma (45%) and poorly differentiated carcinoma (42%)., Results: A total of 86 lesions were found in 20 (53%) patients, distributed in 33 organs. FDG-PET/CT and the postablation whole-body scan (RAI WBS) showed persistent disease in 15 and 12 patients, respectively. FDG-PET/CT was more sensitive than WBS for the detection of individual lesions (69% vs. 59%). Both imaging techniques were complementary with 41% of the lesions detected only by FDG-PET/CT and 31% only by RAI WBS. The only risk factor of abnormal FDG-PET/CT was a stimulated Tg level (Tg/TSH) measured at ablation >10 ng/mL with persistent disease showing FDG uptake in 72% of the patients with a Tg/TSH >10 ng/mL and in 10% of the patients with Tg/TSH ≤10 ng/mL., Conclusion: Postoperative FDG-PET/CT should be performed routinely in patients with aggressive histology DTC.

Purpose of Review: Radioactive iodine (RAI) is administered postoperatively to the majority of thyroid cancer patients. No available study has demonstrated any benefit in low-risk patients., Recent Findings: RAI should be used selectively in low and intermediate-risk patients, based on the surgical and pathological reports and on postoperative serum thyroglobulin level and neck ultrasonography. When used, a low activity (30 mCi) is administered following recombinant human thyrotropin stimulation. High-risk patients are treated with a high activity of RAI (100 mCi or more)., Summary: RAI is not administered in many low-risk patients who can be reliably followed up with serum thyroglobulin determination on L-thyroxine treatment and neck ultrasonography. RAI may be administered in case of abnormality, and this delay will not reduce the chance of cure.

Background: It is not clear whether the administration of radioiodine provides any benefit to patients with low-risk thyroid cancer after a complete surgical resection. The administration of the smallest possible amount of radioiodine would improve care., Methods: In our randomized, phase 3 trial, we compared two thyrotropin-stimulation methods (thyroid hormone withdrawal and use of recombinant human thyrotropin) and two radioiodine ((131)I) doses (i.e., administered activities) (1.1 GBq and 3.7 GBq) in a 2-by-2 design. Inclusion criteria were an age of 18 years or older; total thyroidectomy for differentiated thyroid carcinoma; tumor-node-metastasis (TNM) stage, ascertained on pathological examination (p) of a surgical specimen, of pT1 (with tumor diameter ≤1 cm) and N1 or Nx, pT1 (with tumor diameter >1 to 2 cm) and any N stage, or pT2N0; absence of distant metastasis; and no iodine contamination. Thyroid ablation was assessed 8 months after radioiodine administration by neck ultrasonography and measurement of recombinant human thyrotropin-stimulated thyroglobulin. Comparisons were based on an equivalence framework., Results: There were 752 patients enrolled between 2007 and 2010; 92% had papillary cancer. There were no unexpected serious adverse events. In the 684 patients with data that could be evaluated, ultrasonography of the neck was normal in 652 (95%), and the stimulated thyroglobulin level was 1.0 ng per milliliter or less in 621 of the 652 patients (95%) without detectable thyroglobulin antibodies. Thyroid ablation was complete in 631 of the 684 patients (92%). The ablation rate was equivalent between the (131)I doses and between the thyrotropin-stimulation methods., Conclusions: The use of recombinant human thyrotropin and low-dose (1.1 GBq) postoperative radioiodine ablation may be sufficient for the management of low-risk thyroid cancer. (Funded by the French National Cancer Institute [INCa] and the French Ministry of Health; ClinicalTrials.gov number, NCT00435851; INCa number, RECF0447.).