Peptide receptor radionuclide therapy (PRRT) has emerged as one of the most pivotal modalities of treatment for neuroendocrine tumors (NETs). PRRT is a form of targeted therapy in which a radiolabeled peptide is used as a vector to deliver cytotoxic doses of radiation to those cancer cells which abundantly express receptors for that particular peptide (1). To date, several forms of radiolabeled peptides have been utilized for diagnostic purposes based on tumor receptor expression profiles, including somatostatin, cholecystokinin (CCK), neuropeptide-Y, gastrin, glucagon-like peptide-1, and others (2). However, the vast majority of PRRTs are radionuclides tagged to somatostatin analogs (SSAs), which target somatostatin receptors (SSTRs). While PRRT has been vastly utilized in the treatment of NETs, one of the actively investigated fields is the utility of PRRT in the treatment of thyroid cancer. In this review, we discuss the current standard-of-care for the management of various forms of thyroid cancer and then, discuss the utility of PRRT in oncology, along with the current evidence of SSA-based diagnostic imaging and PRRT in thyroid cancer. We also discuss the potential applicability of theranostics and future directions in the utility of PRRT as a crucial form of targeted therapy in thyroid cancer.

The yearly incidence of thyroid cancer has nearly tripled from 4.9 per 100,000 individuals in 1975 to 14.3 per 100,000 individuals in 2009 (3). Differentiated thyroid cancer (DTC), comprised of papillary thyroid cancer (PTC), and follicular thyroid cancer (FTC) along with the Hürthle cell subtype of thyroid cancer (HTC), constitutes over 90% of all thyroid cancers (3). Medullary thyroid cancer (MTC) and anaplastic thyroid cancer (ATC) are much rarer but carry a higher mortality risk compared to DTC (4, 5).

The conventional treatment for DTC is thyroidectomy (hemi- or total thyroidectomy depending on the extent of the disease) with or without central and/or lateral lymph node dissection. Following surgery, radioactive iodine (RAI) therapy with iodine-131 (¹³¹I) is generally considered for those DTCs that have an intermediate-to-high risk for structural disease recurrence (3). For local recurrence and for distant metastases, repeat surgery and/or RAI therapy remains the preferred modality of treatment, and most RAI-avid DTCs have a favorable prognosis despite the presence of metastatic disease (3). However, up to 22% of DTCs may become RAI-refractory due to their inability to concentrate iodine into the tumor cells, and certain DTC subtypes such as tall-cell and diffuse sclerosing variants of PTC, insular variant of FTC, HTC, and poorly differentiated thyroid cancers (PDTCs) have a propensity to be RAI-refractory (3). In these circumstances, RAI is not effective, and diagnostic imaging is performed using 18-fluorodeoxyglucose positron emission tomography computed tomography (¹⁸FDG-PET/CT). In general, the more differentiated forms of DTC tend to retain iodine-concentrating capacity, are metabolically less active, more RAI-avid, and less ¹⁸FDG-PET-avid, while the more dedifferentiated forms are hypermetabolic, less RAI-avid, and more ¹⁸FDG-PET-avid (6). Local treatment options for RAI-refractory DTCs include external beam radiation, radiofrequency ablation or cryoablation. Molecular characterization of DTCs (7), and the advent of widespread molecular testing has allowed for identification of several potential targets for therapy. The tyrosine kinase inhibitors (TKIs) lenvatinib and sorafenib have been approved by the Food and Drug Administration (FDA) in the United States for the treatment of progressive, RAI-refractory metastatic DTC (8, 9). Other systemic therapies such as proto-oncogene serine/threonine-protein kinase (BRAF) inhibitors (dabrafenib), mammalian target of rapamycin (mTOR) inhibitors (everolimus), neurotrophic receptor tyrosine kinase (NTRK) inhibitors and immune checkpoint inhibitors (ICIs) are being evaluated in several clinical trials (10, 11). Recently, re-differentiation and restoration of iodine-concentrating capacity within RAI-refractory tumors by using mitogen-activated protein kinase kinase (MEK) inhibitors (trametinib and selumetinib) is being actively investigated as another promising modality of therapy (12, 13). Selumetinib has been granted an orphan drug designation by the FDA as an agent re-inducing RAI uptake in advanced DTC. Certain forms of DTCs such as HTCs, and PDTCs are rare and data on the utility of targeted therapy in these thyroid cancer subtypes is limited, although there is recent data emerging on long-term remission noted in PDTCs with the use of combination of lenvatinib (TKI) and pembrolizumab (ICI) (14, 15).

MTC is considered as a type of NET and is derived from the parafollicular C-cells (4). The prevalence of MTC is 1% – 2% in the United States (4). MTC can be sporadic or can manifest as a part of multiple endocrine neoplasia 2A and 2B. As the C-cells do not have the ability to concentrate iodine, MTCs are RAI-refractory, and the major functional imaging of utility is the ¹⁸FDG-PET/CT (4). The conventional treatment for MTC is thyroidectomy and lymph node dissection (4). Other treatments include external beam radiation for recurrent disease in the neck, surgical resection, or chemoembolization of hepatic metastases, and systemic therapy for progressive, metastatic MTC (4). Initially, two TKIs, vandetanib and cabozantinib, demonstrated efficacy in improving progression-free survival (PFS) in MTC and are now approved by the FDA for the treatment of progressive metastatic MTC (16, 17). Recently, two selective rearranged during transfection (RET) inhibitors, selpercatinib and pralsetinib have been approved for the treatment of progressive metastatic MTC, and these agents harbor better adverse event (AE) profiles (18, 19). Several other targeted therapies, including ICIs and carcinoembryonic antigen (CEA) vaccine are also being investigated for the treatment of this condition (11).

ATC is the most aggressive form of thyroid cancer, with a prevalence of 1.7% in the United States and a median prevalence of 3.6% worldwide (5). The management of ATC is more complicated due to the rapid progression and poor prognosis of the disease. For potential surgical resection of the primary tumor, several factors should be considered, including patient’s age, functional status, extent of the disease, status of airway, use of neoadjuvant or adjuvant therapy, whether the surgery is curative, palliative, or for prevention of complications such as obstruction of trachea and/or esophagus, and the goals of care of the patients, with timely involvement of palliative care (5). Neoadjuvant or adjuvant chemoradiation should be implemented as soon as possible after careful consideration of risks and benefits (5). Some of the available chemotherapy regimens include paclitaxel/carboplatin and docetaxel/doxorubicin, and their use is recommended in patients treated with definitive-intention radiation (5). In patients who have undergone R0 (negative microscopic and gross tumor margin) or R1 (negative gross tumor margin) surgical resection, or in patients with R2 resection (positive gross tumor margin/debulking procedure) with good performance status, intensity-modulated radiation with systemic therapy is recommended (5). However, the overall survival (OS), and disease-free survival is not different among R0, R1, and R2 statuses (20). In BRAF V600E-mutated ATCs, a combination of BRAF and MEK inhibitors can be utilized. The BRAF/MEK inhibitor combination of dabrafenib and trametinib is approved by the FDA for the treatment of BRAF V600E-mutated ATCs based on the substantial response rate observed in a phase II, open label trial (5, 21). Anaplastic lymphoma kinase (ALK) inhibitors, NTRK inhibitors, mTOR inhibitors, ICIs and TKIs (particularly the combination of lenvatinib and pembrolizumab) are some of the other targeted therapies with potential utility in ATC (5, 15, 22, 23).

Despite the availability of several local and systemic treatment options for thyroid cancers, metastatic/inoperable forms of RAI-refractory DTCs, HTCs, PDTCs, and MTCs continue to pose a challenge for optimal management. This is either due to suboptimal and variable response to treatment, or due to severe or unacceptable AEs or toxicities associated with several of these systemic therapies. Some of the common AEs associated with TKIs used for thyroid cancer include nausea, diarrhea, anorexia, fatigue, mucositis, hypertension, cardiac failure, rash, palmar-plantar erythrodysesthesia, skin pigmentary changes, alopecia, and aerodigestive fistula formation (24–27). The AE profile of selective RET inhibitors is similar to that of TKIs, with common AEs observed being neutropenia, hepatic transaminase elevation, constipation, diarrhea, hypertension, and rash (28). Some of the BRAF and MEK inhibitor-associated AEs include hypertension, reduced cardiac ejection fraction, cardiomyopathy, fever, diarrhea, rash, and ocular AEs such as central serous retinopathy (29–31). Therefore, there is a need for a systemic therapy that is not only efficacious, but also has lower number of AEs. PRRT can potentially serve as a systemic targeted therapy in thyroid cancer due to its better safety profile and high treatment efficacy demonstrated in several other forms of tumors (32–35).

Somatostatin, also known as somatotropin release inhibiting factor (SRIF) is a cyclic peptide hormone that has several complex endocrine, paracrine, and modulatory effects across different organ systems, including inhibition of secretion of various hormones and enzymes and cell proliferation, and also functions as a neurotransmitter and as an immunomodulator (36–39). Somatostatin was initially isolated from ovine hypothalamus as a peptide capable of inhibiting the release of growth hormone (40). Further studies have identified the presence of somatostatin in almost every tissue of the body (36, 41, 42). The two active forms of somatostatin are SRIF-14, which contains 14 amino acids and SRIF-28, which has 24 amino acids (43). Somatostatin is known to inhibit the secretion of not only growth hormone, but also of prolactin, thyroid stimulating hormone, adrenocorticotropic hormone, insulin, glucagon, and gastrointestinal hormones such as CCK, gastrin, ghrelin, secretin, and vasoactive intestinal polypeptide (38, 41, 44). Somatostatin also inhibits gastrointestinal exocrine function, including production of gastric, pancreatic, and intestinal digestive fluids and enzymes (38). Therefore, it has been recommended for routine use in patients undergoing pancreatic surgeries (45, 46).

SSTRs are a family of seven-subunit transmembrane G protein-coupled receptors, with five distinct subtypes being identified in humans, namely SSTR 1, 2, 3, 4, and 5 (37). The SSTR genes for each subtype are located on different chromosomes, and SSTR2 has two splice variants (SSTR2A and SSTR2B) (38). These SSTRs are vastly and variably expressed in different normal tissues as well as in various benign and malignant tumors in humans, but several forms of tumors seem to predominantly express SSTR2 and sometimes SSTR1, 3 or 5, while SSTR4 expression is rare (38, 39, 47, 48).

SRIF-14 and SRIF-28 bind to all five subtypes of SSTRs with nanomolar affinity (38). Furthermore, based on structural homology, the SSTRs are classified into two sub-groups, the SRIF1, which includes SSTRs 2, 3, and 5, and SRIF2, which includes SSTRs 1 and 4 (38). The synthetic SSAs such as octreotide and seglitide demonstrate binding affinity to SRIF1 receptors, with high affinity to SSTR2 and intermediate affinity to SSTR 1 and 5, while no such binding affinity is demonstrated towards SRIF2 receptors (49). Activation of all SSTR subtypes decreases adenylyl cyclase activity, and promotes variable effects on the activities of phospholipase C, mitogen-activated protein kinase, calcium and potassium channels, and phosphotyrosine phosphatase (38).

Radiolabeled SSAs have emerged as some of the most widely used theranostic agents. Theranostics can be defined as the utilization of materials that can serve both as modalities of diagnostic imaging and as treatment (50). By combining diagnostics and therapeutics, theranostic agents harbor the advantage of sharing the same biodistribution and receptor selectivity that overcomes the potential disparity that may be encountered with using two different agents for imaging and treatment. The radionuclides tagged with the SSAs may serve a diagnostic or therapeutic purpose based on the type of the emitted radiation. Diagnostic imaging can be achieved by utilizing SSAs tagged with positron emitters such as gallium-68 (⁶⁸Ga), copper-64 (⁶⁴Cu) or fluorine-18 (¹⁸F) which can be imaged using positron (β+) emission tomography (PET), or with γ-emitters such as indium-111 (¹¹¹In) or technetium-99 (⁹⁹Tc) which can be imaged using single photon emission computed tomography (SPECT) (50). SSAs tagged with β-emitters such as lutetium-177 (¹⁷⁷Lu) and yttrium-90 (⁹⁰Y) or α-emitters such as lead-212 (²¹²Pb), bismuth-213 (²¹³Bi), and actinium-225 (²²⁵Ac) serve as therapeutic agents (PRRT) by destroying the targeted tumor cells (50). These radionuclides are chelated within various chelators such as DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,20-tetra-acetic acid), DTPA (diethylenetriamine penta-acetic acid), or NODAGA (1,4,7-triazacyclononane,1-glutaric acid-4,7-acetic acid) and are ‘tagged’ to the SSAs. Earlier forms of PRRT comprised of conventional octreotide as the SSA. Later developments, such as modification of octreotide with insertion of tyrosine in the 3^rd position (Tyr³-OC or TOC), or replacing the c-terminal amino alcohol, threoninol, with threonine (TATE) improves the SSA’s binding affinity to SSTR2 subtype (51). Some of the common chelator-SSA combinations include [DOTA⁰,Tyr³]octreotate (DOTATATE), [DOTA⁰,Tyr³]octreotide (DOTATOC), and [DOTA⁰-1-NaI³]octreotide (DOTA-NOC) (35). The individual components of a radiolabeled SSA analog have been delineated in Figure 1. So far, ¹⁷⁷Lu-SSAs, especially ¹⁷⁷Lu-DOTATATE has been the most commonly utilized form of PRRT. Certain radiolabeled SSAs such as ¹¹¹In-DTPA-octreotide (¹¹¹In-pentetreotide) may not be as effective for PRRT when compared to ¹⁷⁷Lu- or ⁹⁰Y-based SSAs as the latter two radionuclides are β-emitters which are long-range electron emitters with better cytolytic potential and irradiation of the environment neighboring the tumor, while ¹¹¹In is an Auger electron emitter which has short-range low-energy electron emission (51).

SSTRs are vastly overexpressed particularly in NETs; tumors that arise from neuroendocrine cells and/or neural crest cells (52). These cells are present in several organs, including the bronchi, pancreas, and the gastrointestinal tract. Based on the site of origin, NETs can be pancreatic NETs (PNETs), gastroenteropancreatic NETs (GEP-NETs), carcinoids, small cell lung cancer, or large cell neuroendocrine carcinoma (53). Other tumors of neuroendocrine origin include pheochromocytoma and paraganglioma (PPGL), MTC, neuroblastoma, meningioma, and Merkel cell carcinoma (53). In a landmark phase 3 clinical trial (NETTER-1), ¹⁷⁷Lu-DOTATATE therapy in addition to long-acting repeatable (LAR) octreotide in patients with SSTR+ well-differentiated, metastatic midgut NETs resulted in substantially longer PFS compared to treatment with LAR octreotide alone (33). Based on the data from the NETTER-1 trial, the United States FDA approved ¹⁷⁷Lu-DOTATATE in January 2018 for the treatment of SSTR+ GEP-NETs. The treatment was also approved in Europe based on the data from NETTER-1, as well as based on safety and efficacy data from the phase I/II ERASMUS study (34). In addition, PRRT has been effective in treating several other types of NETs, including PPGL (32, 54–60). The safety profile of PRRT is favorable and the treatment is generally well-tolerated. The most common AEs include nausea (65% all grades and 5% grades 3 and 4 in NETTER-1) and vomiting (53% all grades and 2% grades 3 and 4 in NETTER-1) which is mainly attributed to the renoprotective amino acid infusion that is concurrently administered with PRRT (61). This is managed with pre-infusion anti-emetic administration. Hematologic dysfunction, including transient myelosuppression, cytopenia (anemia: 81%, thrombocytopenia: 53%, neutropenia: 26% per NETTER-1 trial data, all grade 1 or 2), myelodysplastic syndrome (2.7% in NETTER-1, and 2% [median time to development: 28 months] in ERASMUS), and leukemia (0.5% [median time to development: 55 months] in ERASMUS) have been observed. Renal toxicity is of concern and <1% of patients in NETTER-1 trial developed renal failure, and this AE can be potentially prevented with amino acid infusion pre- and post-¹⁷⁷Lu-DOTATATE administration. Other potential AEs include abdominal pain, constipation, diarrhea, hepatic dysfunction, hyperglycemia, electrolyte disturbances, and neurohormonal crises in cases of NETs producing biologically active products (33, 34). The principle of PRRT and the mechanism of action of radiolabeled SSAs has been illustrated in Figure 2.

Large-scale studies on PRRT in thyroid cancer are yet to commence. However, recently published systematic reviews and meta-analyses have allowed for evaluation of currently available data on the utility of PRRT in thyroid cancers. A meta-analysis by Lee et al. evaluated 11 published articles on DTC and/or MTC for efficacy and outcomes with various PRRTs (123). The objective response rate (ORR) in MTC was 8.5% (95% CI, 1.9% – 19.2%; i² = 53.5%) and the disease control rate (DCR) was 60% (95% CI, 49.6%–69.8%; i² = 28.7%), while for DTC, the ORR and DCR rates were 15.6% (95% CI, 7.80%–26.74%; i² = 0%), and 53.9% (95% CI: 41.13%–66.39%; i² = 0%), respectively. Proportion of serious/severe AEs (SAEs) was 2.8% (95% CI, 0.5%–8.3%) in MTC, and 2.82% (95% CI: 0.03%–17.61%) in DTC. In comparison, SAE frequency in other established systemic therapies for thyroid cancer have ranged from 0.4% to as high as 47% (Table 2), which further highlights the relatively better safety profile of PRRT. Also, ¹⁷⁷Lu-based PRRT was associated with better ORR and DCR outcomes when compared to ⁹⁰Y-based PRRT. In a systematic-review conducted by Maghsoomi et al. (124), on 41 studies related to PRRT in thyroid cancer (157 patients with RAI-refractory DTC and 220 patients with MTC), biochemical response was noted in 25.3% of DTC and 37.2% of MTC patients, and CR/PR were noted in 10.5% of DTC and 10.6% of MTC patients. In patients with advanced disease, 46 deaths out of 95 patients were noted in DTC and 63 deaths out of 144 patients were noted in MTC. While major AEs were noted with ⁹⁰Y-based PRRT, the AEs with ¹⁷⁷Lu- or ¹¹¹In-based PRRTs were mild or transient. In comparison, in the NETTER-1 trial, the ORR was 18% (95% CI: 10% - 25%; 18/101 patients in the ¹⁷⁷Lu-DOTATATE arm), while the frequency of SAEs was 9% in the ¹⁷⁷Lu-DOTATATE arm (33). Among the TKIs, the ORRs have been between 12.2% - 64.8% for DTC, and 28% - 45% for MTC, and the SAE frequency is up to 30.3% in DTC and up to 15.9% in MTC (8, 9, 16, 17). With selective RET inhibitors, the ORR has been 60% - 73% for MTC and up to 79% - 89% in RET-fusion thyroid cancers, with SAEs up to 28% - 47% (18, 19). Although these are not head-to-head comparisons, PRRT for thyroid cancer seems to have comparable ORRs to PRRT in NETs, and while the ORRs are better with TKIs or with selective RET inhibitors, PRRT seems to have a better safety profile compared to these systemic therapies. A comparison of outcomes among the meta-analysis findings in PRRT and thyroid cancer, the various systemic therapies for thyroid cancer, and PRRT in NETs is provided in Table 2.

Targeted therapy for thyroid cancer with PRRT is a continuously and rapidly evolving field, with several radiolabeled SSAs being investigated for their potential theranostic utility in various clinical trials for NETs. Nevertheless, the field of theranostics and PRRT in thyroid cancer is relatively young and has several areas that need further research. One such area includes further optimization of diagnostic radiolabeled ligand-based imaging for better visual delineation of thyroid tumors. As most PRRTs utilize SSAs that bind to SSTR2, treatment of thyroid cancers that express other types of SSTRs would not be feasible with most of the currently available PRRTs. Particularly DTCs may demonstrate varied SSTR subtype expressions as opposed to NETs, which commonly express SSTR2 (51). While several studies have demonstrated SSTR2 positivity in thyroid cancers, other studies have demonstrated a relative abundance of other SSTR subtypes, such as SSTR5, in these tumors (62, 66, 109, 125). These findings highlight the importance of developing PRRTs based on SSAs that could target SSTRs apart from the SSTR2 subtype. For instance, ¹¹¹In-DOTA-NOC has increased affinity towards SSTR3 and 5, along with a high affinity to SSTR2, thus potentially allowing for further optimization of SSA-based tumor imaging (51, 126). In this manner, development of the corresponding ¹⁷⁷Lu-DOTA-NOC or α-emitter-DOTA-NOC PRRTs may potentially be more efficacious in treating thyroid cancers.

A dosimetry-based approach to the diagnostic evaluation of thyroid cancers using radiolabeled SSAs allows for better identification of tumors that are likely to respond to the PRRT. The SUV_max values on 68Ga-DOTATOC imaging have been shown to correlate with SSTR2 mRNA expression in human tissues (67), and on the contrary, SUV_max correlates negatively with higher Ki-67 index (suggestive of more aggressive, undifferentiated tumor) among GEP-NETs (127). More dosimetric studies are required to further characterize the potential of thyroid cancers that can be targeted by PRRT. Individualized dosimetry-based approach focused on predicting the tumoricidal effects of certain tumor-absorbed dose thresholds has been proven effective in other types of cancers such as hepatocellular carcinoma (128). While β emitters are currently widely used as components of PRRT for NETs and thyroid cancer, α emitter-based SSAs also hold potential to serve as alternative forms of PRRT. As opposed to β emitters, which have a longer penetration range and a potential for damaging normal surrounding tissue, α emitters have a shorter penetration range leading to lesser normal tissue damage and have a higher energy and high linear energy transfer, leading to higher cytotoxicity (129, 130). More data on clinical utility of' α emitter-based PRRT should be available in the upcoming years. Another interesting area for further research is exploring methods to upregulate the expression of SSTRs on the cell surface. Preliminary in vitro and in vivo animal model experiments using epigenetic modifier drugs have resulted in successful upregulation of SSTR2 at transcriptional and functional levels (131). Further studies in humans are necessary to evaluate the safety and efficacy of SSTR-upregulator molecules. Literature on the association between PRRT and the molecular signatures of thyroid cancer (for instance, sporadic thyroid cancers versus thyroid cancers with germline pathogenic variants) is currently lacking and this area holds potential as another interesting avenue for future studies.

Apart from trying alternate radionuclides and chelators, modifications of the SSA or the peptide component of a radiolabeled SSA can also allow for improvement in the pharmacokinetics, and in turn potentially improve the diagnostic and therapeutic performance. Recently, Evans Blue (EB) analog has been conjugated with DOTATATE to develop DOTA-EB-TATE, which reversibly binds to the circulating albumin and improves the half-life of the molecule (132). ⁹⁰Y-DOTA-EB-TATE has demonstrated better tumor response and survival rates compared to DOTATATE in mouse models (132). Our group also demonstrated that ⁹⁰Y-DOTA-EB-TATE exhibits the highest tumor uptake in mouse xenograft models, irrespective of the type of thyroid cancer cell line xenograft, when compared to ⁶⁸Ga-DOTATATE and ⁶⁸Ga-DOTA-JR11 (70). Moreover, we also demonstrated superior tumor volume reduction and disease-specific survival in the SSTR2+ thyroid cancer xenograft mouse models with the use of ¹⁷⁷Lu-DOTA-EB-TATE when compared to ¹⁷⁷Lu-DOTA-TATE and¹⁷⁷Lu-DOTA-JR11 (70). Therefore, EB-TATE-based SSA imaging and PRRT holds potential to improve theranostics in thyroid cancer.

Currently, clinical trials on PRRT or SSA-based imaging in thyroid cancers are sparse. For instance, one trial (NCT04106843) had to be withdrawn due to lack of registration of participants. There is one study (NCT04927416) that is currently recruiting patients for further characterization of metastatic RAI-refractory DTCs, HTCs, and MTCs using ⁶⁸Ga-DOTATATE PET/CT. Another randomized cross-over study utilizing ¹⁷⁷Lu-PP-F11N, a CCK2 receptor analog with or without sacubitril for treatment of metastatic MTC (NCT03647657) has been completed, and the results are awaited, while another combined pilot and phase I clinical trial (NCT02088645) is currently recruiting advanced MTC patients for theranostics with ¹⁷⁷Lu-PP-F11N.

In conclusion, PRRT is a rapidly evolving field, and holds great potential as a theranostic tool in the management of metastatic RAI-refractory thyroid cancers. Current literature has provided substantial evidence for the efficacy and the safety profile of PRRT. Certain forms of thyroid cancers, such as HTCs and MTCs could be potentially treated better with PRRT as opposed to other forms of systemic therapies. The efficacy of PRRT may also depend on the tumor characteristics observed on the diagnostic radiolabeled-SSA imaging, and the molecular landscape of the various thyroid cancers. Large-scale, randomized controlled trials are necessary to further delineate the functional and molecular characteristics of the tumors that do and do not respond to PRRT and to perform head-to-head comparisons with other commonly used systemic therapies for the management of RAI-refractory thyroid cancers.

SG prepared the manuscript. CK reviewed the manuscript and provided suggestions to improve the manuscript. JK-G conceptualized the manuscript, reviewed the manuscript, and provided suggestions to improve the manuscript. All authors were involved in the revision of the manuscript. All authors contributed to the article and approved the submitted version.

This work was funded by the intramural program of the National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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