Treatment Of Metastatic Thyroid Cancer Research Articles

Ectopic thyroid cancer with a normal thyroid gland

Introduction: Ectopic thyroid tissue may appear in any location along the trajectory of the thyroglossal duct from the foramen cecum to the mediastinum, as either a lingual thyroid or a thyroglossal duct cyst. In rare cases, aberrant migration of the gland can result in lateral ectopic thyroid tissue. As for native thyroid gland, ectopic tissues are subject to malignant transformation. Case Report: A 40-year-old female patient presented with a right-sided neck swelling. She had a history of treated Hodgkin’s lymphoma at the age of 16 years. She has hypothyroidism and on thyroxine and is known to have benign small thyroid nodules for the last 7 years. The neck swelling was suspicious for papillary thyroid carcinoma upon cytological examination. She underwent surgery (total thyroidectomy with central and right lateral selective neck dissection) that confirmed the presence of papillary thyroid cancer in the neck but the thyroid gland was devoid of any cancer. The patient had post-operative radioiodine ablation. She is free of any recurrence or residual disease after one-year post-treatment. Conclusion: This case highlights the unusual presentation of thyroid carcinoma arising within an ectopic thyroid tissue in an otherwise cancer-free thyroid gland. The management of this case followed the standard treatment of metastatic thyroid cancer; however, it raises the question of whether these rare cases should receive de-escalation of standard management.

Genomic and Transcriptomic Characteristics of Metastatic Thyroid Cancers with Exceptional Responses to Radioactive Iodine Therapy.

The determinants of response or resistance to radioiodine (RAI) are unknown. We aimed to identify genomic and transcriptomic factors associated with structural responses to RAI treatment of metastatic thyroid cancer, which occur infrequently, and to test whether high MAPK pathway output was associated with RAI refractoriness. Exceptional response to RAI was defined as reduction of tumor volume based on RECIST v1.1. We performed a retrospective case-control study of genomic and transcriptomic characteristics of exceptional responders (ER; n = 8) versus nonresponders (NR; n = 16) matched by histologic type and stage at presentation on a 1:2 ratio. ER are enriched for mutations that activate MAPK through RAF dimerization (RAS, class 2 BRAF, RTK fusions), whereas NR are associated with BRAFV600E, which signals as a monomer and is unresponsive to negative feedback. ER have a lower MAPK transcriptional output and a higher thyroid differentiation score (TDS) than NR (P < 0.05). NR are enriched for 1q-gain (P < 0.05) and mutations of genes regulating mRNA splicing and the PI3K pathway. BRAFV600E tumors with 1q-gain have a lower TDS than BRAFV600E/1q-quiet tumors and transcriptomic signatures associated with metastatic propensity. ER tumors have a lower MAPK output and higher TDS than NR, whereas NR have a high frequency of BRAFV600E and 1q-gain. Molecular profiling of thyroid cancers and further functional validation of the key findings discriminating ER from NR may help predict response to RAI therapy.

OD75 - Red marrow dosimetry in 131I treatment of metastatic thyroid cancer: comparison of mathematical models

OD75 - Red marrow dosimetry in 131I treatment of metastatic thyroid cancer: comparison of mathematical models

Genomic DNA methylation analysis reveals that BLNK is a key potential gene in the regulation of autophagy-related thyroid cancer progression

The purpose of this study was to explore the relationship between autophagy and DNA methylation, and to identify key genes for autophagy-regulated thyroid cancer progression. We divided patients with thyroid cancer into high-autophagy score (AS) group and low-AS group based on their AS values. The results found that AS was associated with the distant metastasis of thyroid cancer, and adversely affected prognosis. Then, we screened 359 differently expressed genes (DEGs) with DNA methylation status consistent with gene expression change. Functional classification analysis demonstrated that the 359 DEGs consistent with DNA methylation status were significantly involved in adhesion, migration and differentiation of immune cells. To further screen the key genes in the autophagy-related thyroid cancer progression, we constructed a protein-protein interactions (PPI) network and performed prognostic analysis. B cell linker (BLNK) was identified as the key potential gene affecting autophagy-related thyroid cancer progression. Finally, we verified that BLNK promoted the proliferation of thyroid cancer cells, and BLNK expression was regulated by DNA methylation. Our research provides a new perspective for exploring the relationship between autophagy and DNA methylation during the progression of thyroid cancer, and provides a new target for the treatment of metastatic thyroid cancer.

123I Scan With Whole-Body Retention Measurement at 48 Hours for Simplified Dosimetry Before 131I Treatment of Metastatic Thyroid Cancer.

A previously published model (Atkins) allows for calculation of 131I maximum tolerated activity on the basis of 48-hour whole-body retention of 131I on a pretherapy diagnostic scan. Our practice uses iodine 123I for diagnostic imaging of metastatic thyroid cancer for staging before 131I therapy, with images typically acquired 24 hours after administration of the radiopharmaceutical. We explored the feasibility of an additional 123I whole-body scan and retention measurement at 48 hours, with application of the model to estimate maximum tolerated activity of radioiodine before 131I treatment of metastatic thyroid cancer.

Paediatric Molecular Radiotherapy: Challenges and Opportunities

The common contemporary indications for paediatric molecular radiotherapy (pMRT) are differentiated thyroid cancer and neuroblastoma. It may also have value in neuroendocrine cancers, and it is being investigated in clinical trials for other diseases. pMRT is the prototypical biomarker-driven, precision therapy, with a unique mode of delivery and mechanism of action. It is safe and well tolerated, compared with other treatments. However, its full potential has not yet been achieved, and its wider use faces a number of challenges and obstacles. Paradoxically, the success of radioactive iodine as a curative treatment for metastatic thyroid cancer has led to a ‘one size fits all’ approach and limited academic enquiry into optimisation of the conventional treatment regimen, until very recently. Second, the specialised requirements for the delivery of pMRT are available in only a very limited number of centres. This limited capacity and geographical coverage results in reduced accessibility. With few enthusiastic advocates for this treatment modality, investment in research to improve treatments and broaden indications from both industry and national and charitable research funders has historically been suboptimal. Nonetheless, there is now an increasing interest in the opportunities offered by pMRT. Increased research funding has been allocated, and technical developments that will permit innovative approaches in pMRT are available for exploration. A new portfolio of clinical trials is being assembled. These studies should help to move at least some paediatric treatments from simply palliative use into potentially curative protocols. Therapeutic strategies require modification and optimisation to achieve this. The delivery should be personalised and tailored appropriately, with a comprehensive evaluation of tumour and organ-at-risk dosimetry, in alignment with the external beam model of radiotherapy. This article gives an overview of the current status of pMRT, indicating the barriers to progress and identifying ways in which these may be overcome.

Single-cell RNA sequencing reveals the regenerative potential of thyroid follicular epithelial cells in metastatic thyroid carcinoma

Thyroid stimulating hormone deficiency is the cornerstone of treatment for metastatic thyroid cancer. Due to the loss of follicular epithelial cells in thyroid cancer, the thyroid gland degenerates to 85% of its original size. When thyroid stimulating hormone is restored, follicular epithelial cells in thyroid cancer regenerate, which is postulated to be related to stem-like cells. By single cell RNA seq, we found a group of rare thyroid follicular epithelial cells in mouse metastatic thyroid cancer, which expressed stem-like genes (CD44V6+ and CD133+) and a large number of differentiated cells (CD44V6+ and CD24+). In mouse and in organoids, the two subsets contribute equally to metastatic thyroid cancer regeneration. The analysis of human metastatic thyroid cancer revealed that the differentiated thyroid follicular epithelial cell subpopulation was similar to that of the stem like epithelial cell subpopulation, and the regeneration potential was also enhanced after thyroid stimulating hormone ablation. Accordingly, we propose that the regeneration of metastatic thyroid cancer is driven by almost all persistent thyroid follicular epithelial cells, not only by few stem-like cells.

Novel Targeted Therapies for Metastatic Thyroid Cancer-A Comprehensive Review.

The knowledge on thyroid cancer biology has grown over the past decade. Thus, diagnostic and therapeutic strategies to manage thyroid cancer are rapidly evolving. With new insights into tumor biology and cancer genetics, several novel therapies have been approved for the treatment of thyroid cancer. Tyrosine kinase inhibitors (TKIs), such as lenvatinib and sorafenib, have been successfully utilized for the treatment of radioactive iodine (RAI)-refractory metastatic differentiated thyroid cancer (DTC). In addition, pretreatment with mitogen-activated protein kinase (MAPK) inhibitors (trametinib and selumetinib) has been shown to restore RAI avidity in previously RAI-refractory DTCs. Local therapies, such as external beam radiation and radiofrequency/ethanol ablation, have also been employed for treatment of DTC. Vandetanib and cabozantinib are the two TKIs currently approved by the Food and Drug Administration (FDA) for the treatment of medullary thyroid cancer (MTC). Other novel therapies, such as peptide receptor radionuclide therapy and carcinoembryonic antigen (CEA) vaccine, have also been utilized in treating MTC. Ongoing trials on selective rearranged-during-transfection (RET) protooncogene inhibitors, such as LOXO-292 and BLU-667, have demonstrated promising results in the treatment of metastatic MTC resistant to non-selective TKIs. The FDA-approved BRAF/MEK inhibitor combination of dabrafenib and trametinib has revolutionized treatment of BRAFV600E mutation positive anaplastic thyroid cancer. Several other emerging classes of medications, such as gene fusion inhibitors and immune checkpoint inhibitors, are being actively investigated in several clinical trials. In this review, we describe the molecular landscape of thyroid cancer and novel targeted therapies and treatment combinations available for the treatment of metastatic thyroid cancer.

Managing radioiodine refractory thyroid cancer: the role of dosimetry and redifferentiation on subsequent I-131 therapy.

Poor responses to iodine-131 (I-131) therapy can relate to either low iodine uptake and retention in thyroid cancer cells or to increased radioresistance. Both mechanisms are currently termed radioactive iodine (RAI)-refractory (RAI-R) thyroid cancer but the first reflects unsuitability for I-131 therapy that can be evaluated in advance of treatment, whereas the other can only be identified post hoc. Management of both represents a considerable challenge in clinical practice as failure of I-131 therapy, the most effective treatment of metastatic thyroid cancer, is associated with a poor overall prognosis. The development of targeted therapies has shown substantial promise in the treatment of RAI-R thyroid cancer in progressive patients. Recent studies show that selective tyrosine kinase inhibitors (TKIs) targeting B-type rapidly accelerated fibrosarcoma kinase (BRAF) and mitogen-activated protein kinase (MEK) can be used as redifferentiation agents to re-induce RAI uptake, thereby (re)enabling I-131 therapy. The use of dosimetry prior- and post-TKI treatment can assist in quantifying RAI uptake and improve identification of patients that will benefit from I-131 therapy. It also potentially offers the prospect of calculating individualized therapeutic administered activities to enhance efficacy and limit toxicity. In this review, we present an overview of the regulation of RAI uptake and clinically investigated redifferentiation agents, both reimbursed and in experimental setting, that induce renewed RAI uptake. We describe the role of dosimetry in redifferentiation and subsequent I-131 therapy in RAI-R thyroid cancer, explain different dosimetry approaches and discuss limitations and considerations in the field.

87. Lesion dosimetry in metastatic thyroid cancer treated with 131I: Method and preliminary results

Purpose 131I treatment of metastatic thyroid cancer should take into account doses to metastasis for an optimized approach as highlighted by EU 2013/59 Directive. A SPECT-TC dose calculation method is proposed and verified to standardize the operating protocol; patients’ preliminary results are shown. Methods SPECT-TC was calibrated with a phantom (spheres 11.5, 5.6, 1.1 ml, cylinder 130 ml) filled with liquid 131I (13 MBq/ml). Acquisition (64views, circular-orbit, 256 × 256, Iterative SCAC) on successive days allowed partial volume effects, dead-time and detector radius (25 ÷ 33 cm) corrections to calculate the dose, whose accuracy was verified. For 8 patients after the therapeutic administration and for 2 patients also in pre-therapy phase 4 SPECT-TC (4 ÷ 6, 24, 48, 96 ÷ 144 h) were performed to calculate the dose to 30 lesions (24 bone,7 lymph node,6 pulmonary) with the MIRD spheres model. Results Calibration factors (cylinder 1.4 kcts/MBq) confirmed partial volume effects (130 ml:100%, 11 ml:75%, 5.5 ml:58%, 1.1 ml:6%) and radius dependence ( ∼ 10%). Dead-time strongly influences counts in early acquisition (up to 17 %). Mean accuracy on activity −15% [−9% ÷ −24%] and dose −13 % [−9% ÷ −18%] for volumes larger than 2.5 cc validates the dosimetric method, according to literature (MIRD24). Dose to lesions per activity unit varies among patients (mean ± 1dev.st 26 ± 38, range 0.1 ÷ 189 Gy/GBq) and within the same patient (up to +583 %) and uptake seems to decrease in following treatments: individualized dosimetry is needed. CT-based method is recommended for VOIs segmentation (mean – 4.9% compared to the isocontour threshold one). In-therapy dose values show high differences (up to −126%) compared to pre-therapy results, whose efficacy must be further investigated with more patients also in terms of optimal activity to be administered to simulate the treatment. Conclusions Lesion dosimetry of metastatic thyroid cancer treated with radioiodine is accurate with SPECT-TC and provides to the physician a fundamental tool to optimize the treatment. Download : Download high-res image (119KB) Download : Download full-size image Download : Download high-res image (118KB) Download : Download full-size image

Focal segmental glomerulosclerosis lesion associated with inhibition of tyrosine kinases by lenvatinib: a case report

BackgroundLenvatinib is a tyrosine kinase inhibitor with novel binding ability. It is considered the standard of care for metastatic thyroid cancer; moreover, whether it is indicated for other malignant tumors has been examined. Lenvatinib increases the risk of kidney injury in some patients. In comparison with sorafenib, which is a conventional tyrosine kinase inhibitor (TKI), lenvatinib results in more side effects, including hypertension and proteinuria. We describe a case of secondary focal segmental glomerulosclerosis (FSGS) that developed following treatment of metastatic thyroid cancer with lenvatinib and reviewed the mechanisms of renal impairment.Case presentationWe describe a patient with metastatic thyroid cancer who developed hypertension, nephrotic syndrome, and acute kidney injury after 3 months of lenvatinib treatment. Renal biopsy results revealed that 7 of 16 glomeruli indicated complete hyalinization, and that the glomeruli with incomplete hyalinization showed FSGS due to a vascular endothelial disorder and podocyte damage, which seemed to have been induced by lenvatinib treatment. These findings were similar to those of renal impairment treated with conventional TKIs. Although lenvatinib treatment was discontinued, up to 15 months were required to achieve remission of proteinuria, thus leading to chronic kidney disease with hyalinized lesions.ConclusionsTo the best of our knowledge, this is the first reported case of secondary FSGS by lenvatinib treatment. Renal impairment treated with TKIs is commonly associated with minimal change nephrotic syndrome/FSGS findings, and it is suggested that renal involvement with TKI is different from that with the vascular endothelial growth factor ligand. Overexpression of c-mip due to TKI causes disorders such as podocyte dysregulation and promotion of apoptosis, which cause FSGS. Lenvatinib may result in FSGS by a similar mechanism with another TKI and could cause irreversible renal impairment; therefore caution must be used. It is essential to monitor blood pressure, urinary findings, and the renal function.

Modeling therapeutic response to radioiodine in metastatic thyroid cancer: a proof-of-concept study for individualized medicine.

PurposeRadioiodine therapy (RAI) has traditionally been used as treatment for metastatic thyroid cancer, based on its ability to concentrate iodine. Propositions to maximize tumor response with minimizing toxicity, must recognize the infinite possibilities of empirical tests. Therefore, an approach of this study was to build a mathematical model describing tumor growth with the kinetics of thyroglobulin (Tg) concentrations over time, following RAI for metastatic thyroid cancer.Experimental DesignData from 50 patients with metastatic papillary thyroid carcinoma treated within eight French institutions, followed over 3 years after initial RAI treatments, were included in the model. A semi-mechanistic mathematical model that describes the tumor growth under RAI treatment was designed.ResultsOur model was able to separate patients who responded to RAI from those who did not, concordant with the physicians' determination of therapeutic response. The estimated tumor doubling-time ( was found to be the most informative parameter for the distinction between responders and non-responders. The model was also able to reclassify particular patients in early treatment stages.ConclusionsThe results of the model present classification criteria that could indicate whether patients will respond or not to RAI treatment, and provide the opportunity to perform personalized management plans.

Treatment and surveillance of advanced, metastatic iodine-resistant differentiated thyroid cancer.

This review will focus on the management and treatment of metastatic thyroid cancer that is radioactive iodine refractory and review the new drugs and their mechanism of actions as well as their adverse events. Until recently, there were no efficacious therapeutic modalities for these patients. With advancement in knowledge and research of the molecular aberrations and oncogenic mutations in thyroid cancer as well as further understanding the role of angiogenesis in tumor growth molecular pathogenesis, novel targeted therapies are available for these patients. Some of these drugs have successfully prolonged progression free survival and are now Food and Drug Administration approved. Additional agents are approved for the treatment of other types of cancers and are currently under investigation for differentiated thyroid cancer treatment. Differentiated thyroid cancer (papillary and follicular) is the most common endocrine malignancy. It is generally known to have an excellent prognosis and patients are usually cured with the conventional primary treatments including surgery, radioactive iodine, and thyroid stimulating hormone suppression. A minor proportion of patients do not fully recover mainly because they develop radioactive iodine-resistant disease. These patients have few treatment options, which we aimed to describe here.

Dosimetry of lesions in radioiodine therapy of metastatic throid cancer: SPECT-TC calibration, verification and preliminary patient results

Introduction 131 I is used in treatment of metastatic thyroid cancer. Higher activity seems to improve the outcome compared to multiple lower treatments. Patient-specific dosimetry avoids adverse effects and allows appropriate metastasis irradiation. SPECT-TC is more accurate to estimate activity than planar methods. Purpose To define quantitative SPECT-TC lesion dosimetry protocol. Materials and methods Three hollow spheres (11.5, 5.6 and 1.1 ml) and a cylinder (130 ml), filled with liquid 131 I (13 MBq/ml) and placed into a water phantom, were acquired (SPECT-TC SiemensIntevo, 64views, 20s/view, circular-orbit, 128 × 128 and 256 × 256) on successive days (dead time 26 ÷ 0.5%). Images were Iterative (Flash3D) scatter-attenuation corrected. Detectors counts-rates and dead-time were noted. Counts/activity were evaluated on volumes segmented with TC and threshold-method. Partial volume effects, radius dependence (25-33cm) and dead-time were evaluated; calibration’s verification and a first patient dosimetry was also reported. Results Calibration factors (cylinder:25.4, smallest sphere:1.4 kcts/MBq) confirmed partial volume effects. Volume recovery coefficients (130 ml–100%, 11 ml–75%, 5.5ml-58%, 1.1 ml–6%) showed radius dependence (within 4.5 % for cylinder; up to 43% for the smallest sphere). The dead-time versus cts/MBq showed a linear dependence (r 2 = 0.99) that allowed the relative correction. According to literature (MIRD24), calibration’s verification showed an accuracy within ± 11 % (except for the smallest volume up to 36 %). Similar results were found for all segmentation methods but the CT-based was the most accurate one. This calibration was applied to a patient lung lesion (56 Gy). Conclusion SPECT-TC represents the more reliable system for lesion dosimetry, allowing accurate volumes and dead-time correction.

Thyroid Cancer—Risks and Causes

The incidence of thyroid cancer has almost doubled in recent years and over 60,000 people will be diagnosed in the US in 2015. While the prognosis for most such patients is excellent, a significant proportion die of thyroid cancer from local tumor progression and above all from metastases. Here we review the different types of thyroid cancers and their molecular changes with a special emphasis on the currently known susceptibility and precipitating factors. With the recent clinical introduction of tyrosine kinase inhibitors for the treatment of metastatic thyroid cancer it is clear that a simple cure is not at hand and further understanding of the molecular mechanisms of these tumors is urgently needed.

Phase II study of everolimus and sorafenib for the treatment of metastatic thyroid cancer.

6024 Background: Everolimus is an oral inhibitor of the mammalian target of rapamycin (mTOR). Unpublished work from the Fagin lab shows that mTORC1 is also required for the growth promoting effects of the oncoproteins RET/PTC, RAS and BRAF in rat thyroid PCCL3 cells. Further work shows synergy of mTORC inhibitors with RET kinase inhibitors in medullary thyroid cancer cell lines. Sorafenib is an oral kinase inhibitor with in vitro activity against multiple targets, including RAF, RET, VEGFR1, and VEGFR2 that is compendium approved for the treatment of radioactive iodine-refractory (RAIR) and medullary (MTC) thyroid cancer. Methods: The study was a single institution, two-stage phase II design. Primary objective was response rate initiated on 9/21/2010. Eligible patients (pts) had progressive, RAIR/fluorodeoxyglucose (18-F)-avid, recurrent/metastatic, non-anaplastic, thyroid cancer; RECIST measurable disease; and adequate organ/marrow function. Sorafenib was given at 400 mg orally twice a day and Everolimus at 5 mg orally once daily. 41 patients were enrolled; 36 were eligible for the primary endpoint of response and 3 were evaluable for toxicity only at the data cutoff date of 1/10/13. Seventeen patients are still actively on study. Mutational analyses of tissue is ongoing. Results: Of the 41 eligible pts, demographics: female- 44% (18); median age-61 years (35-79). Grade 4-5 adverse events at least possibly related to drug: grade 4- Alanine Aminotransferase Increase (1 pt): grade 4- Hyperglycemia (1 pt): grade 4-Pancreatitis (1 pt). Histology and response data by partial response, confirmed and unconfirmed, (PR), stable disease (SD) and progression of disease (POD) are in the table below. The median time on treatment is 167 days (range 1 to 797 days) at the cutoff date of 1/10/2013. Conclusions: The combination of sorafenib and everolimus shows promising results, especially in the Hurthle cell and medullary subgroups where data from studies at Ohio State have suggested very poor response to sorafenib alone. Clinical trial information: NCT01141309. [Table: see text]

Radioiodine Treatment of Metastatic Thyroid Cancer: Relative Efficacy and Side Effect Profile of Preparation by Thyroid Hormone Withdrawal Versus Recombinant Human Thyrotropin

To effectively treat differentiated thyroid cancer (DTC) with radioiodine (RAI) it is necessary to raise serum thyrotropin (TSH) levels either endogenously by thyroid hormone withdrawal (THW) or exogenously by administration of recombinant human TSH (rhTSH). The aim of our study was to compare the relative efficacy and side effect profile of rhTSH versus THW preparation for RAI therapy of metastatic DTC. Fifty-six patients (31 women and 25 men) with RAI-avid distant metastases of DTC treated with either rhTSH-aided (n=15) or THW-aided RAI (n=41) and followed for 72±36.2 months were retrospectively analyzed. The groups were comparable in regard to mean size of target lesions (rhTSH vs. THW 6.4 vs. 4.8 cm, p=0.41), mean baseline thyroglobulin level (6995 vs. 5544 ng/mL, p=0.83), distribution of micronodular and macronodular pulmonary metastases (67% vs. 63%, p=0.54, 13% vs. 15% p=0.64, respectively), osseous (53% vs. 29%, p=0.09), brain (0% vs. 2%, p=0.73), and liver/kidney metastases (13% vs. 2%, p=0.61). Patients in the rhTSH group were older (rhTSH vs. THW mean 62 vs. 49 years, p=0.01), and received lower cumulative RAI dose (256 vs. 416 mCi, p=0.03), which was more frequently based on dosimetric calculations (80% vs. 46%, p=0.024). Responses to treatment were based on RECIST 1.1 criteria. Adjusted by age rates of complete response (CR), stable disease (SD), progressive disease (PD), and progression free survival (PFS) were not different between the groups (rhTSH vs. THW CR hazard ratio [HR] 0.97, 95% CI 0.08-11.42, p=0.982; SD HR 3.22, 95% CI 0.79-13.18, p=0.104, PD HR 0.26, 95% CI 0.52-1.26, p=0.094; PFS HR 0.41, 95% CI 0.14-1.23, p=0.112). The only independent risk factor for nonresponding to treatment and presentation with PD was age (HR 1.06, 95% CI 1.02-1.11, p=0.008). Age was also an independent factor affecting PFS (HR 1.04 for each year, 95% CI 1.02-1.07, p=0.001). Rates of leukopenia, thrombocytopenia, xerostomia, and restrictive pulmonary disease after RAI were not significantly different (rhTSH vs. THW 30% vs. 28%, p=0.61, 10% vs. 0%, p=0.37, 0% vs. 12%, p=0.20, 0% vs. 2%, p=0.73, respectively). Patients with metastatic DTC prepared with rhTSH achieve comparable benefit of RAI therapy as those treated after THW.

Radioiodine Treatment of Differentiated Thyroid Carcinoma: The Experience at Seoul National University Hospital

Radioactive iodine therapy has played an important role in the management of differentiated thyroid cancer (DTC) since specific accumulation of iodide in the thyroid gland was initially reported. The incidence of thyroid cancer is increasing in many countries including Korea. Conventional RIT has an effect on the treatment of metastatic thyroid cancer. To obtain the effects of I-131 therapy, tumors must accumulate iodide. However, about 20-30% of thyroid cancers do not accumulate iodide; they have a poor prognosis compared to DTC. For such cases, there are several methods available to increase the effects of RIT. One is by increasing the administration dose to the maximal safe dose to increase the delivery of I-131 to the tumor. Another is using retinoic acid to induce re-differentiation of cancer cells and to restore the accumulation of iodide. By such efforts, the clinical outcome of thyroid cancer can be improved. Historically, radioiodine therapy was started at the Seoul National University Hospital in 1960 when the “Radioisotope Clinic” was opened; this service has played a central role in nuclear medicine practice in Korea. In this paper, we summarized the data and experience with I-131 treatment on recurrent/metastasis of DTC at the Seoul National University Hospital.

Recombinant human thyroid-stimulating hormone as an alternative for thyroid hormone withdrawal in thyroid cancer management

The purpose of the review is to summarize the current findings of using recombinant human thyroid-stimulating hormone (rhTSH, also known as Thyrogen) as adjuvant stimulation for diagnostic monitoring, thyroid remnant ablation, and treatment of metastatic thyroid cancer. A negative Thyrogen-stimulated thyroglobulin level has a negative predictive value of up to 98.5%. Therefore, it is unnecessary to repeat a Thyrogen-stimulated thyroglobulin level in the surveillance of patients with a negative result. There are no significant differences found in the rate of recurrence or persistent disease between Thyrogen-assisted and thyroid hormone withdrawal-ablated patient groups. Studies have shown that rapid clearance of excess radioiodine from the body in the euthyroid state with Thyrogen stimulation has significantly reduced whole body radiation exposure as compared with the hypothyroid state in withdrawal patients. Thyrogen-assisted diagnosis and radioiodine ablation of thyroid remnant provide a reliable tool in the management of thyroid cancer without sacrificing patient quality of life. We believe that the use of Thyrogen for radioiodine treatment of metastatic thyroid cancer may also provide a better option due to its rapid preparation time and safety. Further prospective studies are required for the assessment of long-term outcomes.

What role for recombinant human TSH in the treatment of metastatic thyroid cancer?

The introduction into clinical practice of recombinant human thyroid-stimulating hormone (rhTSH) has marked a turning point in the management of patients with differentiated thyroid cancer. RhTSH offers a safe and reliable alternative to thyroid hormone withdrawal by avoiding both the clinical consequences of hypothyroidism, with a positive impact on quality of life and work productivity, and the potential risk of cancer growth due to a long-lasting endogenous TSH stimulation. In the follow-up of thyroid cancer patients, rhTSH stimulated thyroglobulin is now routinely proposed as it has been shown to be as sensitive as endogenously stimulated thyroglobulin for the detection of residual and metastatic cancer [1]. More recently, the use of rhTSH has been approved for the preparation of adult low-risk patients for postsurgical radioiodine ablation of thyroid remnants with 3.7 GBq I [2]. Although the activity necessary to achieve a comparable rate of ablation is probably higher than that required under hypothyroidism [3, 4], the use of rhTSH is associated with a lower whole-body radiation exposure [5] and allows a shorter hospitalization length, which partially compensates for its cost [6]. The use of rhTSH in the treatment of metastatic thyroid cancer is much more controversial. Although rhTSH has not been formally approved so far for this indication, it has been used off-label since the 1990s to treat patients in which thyroid hormones could not be stopped [7]. This includes patients unable to raise an adequate endogenous TSH response, either because of hypopituitarism or continued production of thyroxine by a thyroid remnant or metastatic tumour, and patients in poor condition due to advanced disease. The results obtained in some patients are encouraging. One may raise the question whether a wider use of rhTSH can be advovated in the therapeutic setting. In our opinion, both clinical and biological data from the literature argue against a more liberal use of rhTSH for the therapy of metastatic thyroid cancer. First, tumour cells of thyroid cancer have a reduced expression of most thyroid-specific genes, including the TSH receptor and the Na/I symporter (NIS) gene [8]. Although the standard two injections protocol of rhTSH provides a high plasma TSH peak, roughly in the range 100–150 mIU/L 24 h after the second injection [9], the concentration increase is short-lived [10]. In order to improve the number of NIS and TSH receptors, and thus enhance the iodine-trapping ability of the cells, a high and prolonged period of TSH stimulation elevation is desirable [11]. Indeed, a I whole-body scan under hypothyroidism is more sensitive than the same scan after rhTSH administration [12]. It should be remembered that a posttherapeutic scan of good quality is an invaluable tool to discover unsuspected metastases and to assess the efficacy of repeated I treatment in metastatic patients [13]. Second, published experience shows that rhTSH stimulates the uptake of radioiodine in metastatic lesions [7]. However, prospective randomized studies comparing the relative efficacy of rhTSH-aided metastatic cancer treatEur J Nucl Med Mol Imaging (2009) 36:883–885 DOI 10.1007/s00259-008-1046-0