The 5-year disease-specific survival in DTC patients is excellent in those with localized and regional disease (above 98%). However, it is significantly lower in patients with distant metastases (approximately 50%) ^[1]. Radioiodine therapy is the cornerstone of metastatic DTC, which accounts for 10% of patients. Half of the metastatic patients achieve complete or partial remission or have stable disease over a long period following radioiodine therapy. Unfortunately, in the remaining patients, the disease progresses despite the therapy ^[2]. Post-therapeutic radioiodine whole-body imaging is crucial for staging and evaluating radioiodine avidity in recurrent or metastatic disease ^[3]. Approximately 70% of patients with metastatic disease demonstrate radioiodine uptake, whereas the remaining develop non-radioiodine-avid metastases or have progressive disease despite radioiodine treatment ^[3].

There is increasing evidence that treatment response in advanced and metastatic disease is related to tumor-absorbed doses, leading to the need for personalized therapy. Beyond iodine-131 (¹³¹I) uptake, several other factors, such as the molecular pathogenesis and mechanisms of DTC, specific patients’ characteristics, and disease presentation, should be taken into account and considered on an individual basis ^[4].

Imaging has a crucial role in the diagnostics, therapeutic approaches, and monitoring of radioiodine-refractory (RAI-R) DTC patients. Computed tomography (CT) and magnetic resonance imaging (MRI) are anatomical imaging modalities that may be used for the detection of residual or recurrent disease in patients with high serum thyroglobulin (Tg) ^[1]. Nuclear medicine functional imaging, i.e., single photon emission computed tomography (SPECT) and positron emission tomography (PET), in combination with CT or MRI, besides anatomical, provides the evaluation and quantification of DTC lesions at the molecular level.

2. Radioiodine-Refractory Differentiated Thyroid Cancer: Definition and Criteria

Among DTC patients, about 30% have or will develop metastatic disease at loco-regional lymph nodes (5-year survival rate > 90%) or, more rarely, in distant organs (mainly lungs and bones) with a significantly worse prognosis (5-year survival approx. 55%). Additionally, an increase in the overall mortality rate of DTC patients has been observed lately, probably due to an increased incidence of metastatic DTC patients ^[5]. Luckily, many patients with advanced DTC still exhibit ¹³¹I avidity, and therefore approximately 40% will achieve remission after ¹³¹I treatment ^[6][7][8][9]. Consequently, repeated courses of ¹³¹I therapy, in addition to TSH suppression, are the standard of care to manage metastasized DTC when the disease remains iodine-avid ^[10][11]. Unfortunately, ¹³¹I therapy becomes ineffective in a fraction of patients and should be stopped when a patient no longer responds to treatment. However, considering that RAI-R DTC patients still have limited therapeutic options, premature stopping of ¹³¹I therapy (i.e., when still able to obtain disease stabilization and symptom relief) should be avoided. The correct identification of RAI-R disease remains controversial (Table 1). Currently, different criteria to define an RAI-R disease are reported in the literature. In 2014, an international expert panel proposed stopping ¹³¹I therapy when “at least one lesion becomes ¹³¹I negative and continues to grow” ^[2]. Sacks and colleagues supported stopping ¹³¹I therapy when diagnostic scintigraphy (i.e., low ¹³¹I or ¹²³I activity administered) is negative in the presence of structural disease, in the case of a positive [¹⁸F]FDG PET scan or cumulative administered activities of >18.5–22 GBq ¹³¹I ^[12]. Legend: WBS—whole body scan; GBq—Gigabecquerel; [¹⁸F]FDG—2-[¹⁸F]fluoro-2-deoxy-D-glucose; PET/CT—positron emission tomography/computed tomography. Finally, the American Thyroid Association 2015 Guidelines propose criteria summarized in Recommendation 91. “Radioiodine-refractory, structurally evident DTC is classified in patients with appropriate TSH stimulation and iodine preparation in four basic ways: (i) the malignant/metastatic tissue does not ever concentrate RAI (no uptake outside the thyroid bed at the first therapeutic WBS); (ii) the tumor tissue loses the ability to concentrate RAI after previous evidence of RAI-avid disease (in the absence of stable iodine contamination); (iii) RAI is concentrated in some lesions but not in others; and (iv) metastatic disease progresses despite significant concentration of RAI” ^[3]. Furthermore, the BRAFV600E gene mutation seems to exhibit more aggressive tumor behavior and is more often associated with RAI-R disease; it also carries an increased risk of recurrence and a higher disease-specific mortality ^[13]. However, as discussed by Giovanella and van Nostrand, any classification is only conditionally appropriate for managing individualized patient care ^[11]. Notably, the absence of visualization of malignant tissues on a diagnostic and/or post-therapy whole-body scintigraphy greatly increases the likelihood that DTC metastases are RAI-R. However, a careful standardization of imaging in terms of preparation, prescribed activity, and imaging technique is pivotal to avoiding false-negative results and, consequently, an inappropriate discontinuation of (still active) ¹³¹I therapy ^[14][15]. After assessment of multiple factors and aiming to personalize the patient’s care, at the time that a patient is declared RAI-R, ¹³¹I therapy is discontinued and alternative therapies are considered. A careful staging of RAI-R disease is integral to deciding on further therapeutic strategies, monitoring treatment efficacy, and detecting progressive disease. In addition to conventional cross-sectional imaging (i.e., CT, MRI), various positron-emitting radiopharmaceuticals enable the use of PET in combination with CT (PET/CT) or MR (PET/MR) to characterize different biological and molecular characteristics of RAI-R disease. This is highly relevant to personalizing the management of RAI-R disease, and, in addition, some radiopharmaceuticals open the door to theranostics applications by using companion beta- or alpha-emitting radiopharmaceuticals.

3. Radiopharmaceuticals Used for Radioiodine-Refractory Differentiated Thyroid Cancer Imaging and Therapy

3.1. [

¹⁸

F]FDG

[¹⁸F]FDG is, besides radioiodine, the most commonly employed molecular imaging tracer in RAI-R DTC. It is considered especially appropriate in DTC patients with elevated serum Tg and negative radioiodine whole-body imaging ^[16], and its sensitivity depends on tumor differentiation, which has a superior detection rate in DTC patients with aggressive histopathology/biological behavior. [¹⁸F]FDG, as a glucose analogue, is transported into the cells across the glucose transporter (GLUT) protein and phosphorylated by hexokinase into [¹⁸F]FDG-6-phosphate, which is not metabolized but trapped within the cell (Figure 1). Cancer cells have a higher concentration of membranous GLUT proteins, such as GLUT1 and GLUT3, and more enzymes involved in the glycolytic pathway, which is even more pronounced in undifferentiated cancer cells. Therefore [¹⁸F]FDG is more intensely accumulated in cancer cells as compared to normal cells ^[17]. In undifferentiated DTC cells, iodine accumulation is decreased or lost, but GLUT proteins are upregulated, and consequently, [¹⁸F]FDG uptake is higher ^[18]. Regarding the optimal preparation protocol for [¹⁸F]FDG imaging on levothyroxine vs. after stimulation with recombinant human thyrotropin (rhTSH), there is still an academic discussion ongoing. Leboulleux and colleagues performed a prospective study with 63 DTC patients (52 with papillary thyroid cancer and 11 with follicular thyroid cancer). All patients underwent both basal and rhTSH-stimulated (24 and 48 h before tracer administration) [¹⁸F]FDG PET/CT. The colleagues found that the per-patient sensitivity was not different between basal and rhTSH-stimulated imaging studies ^[19]. On the other hand, the use of rhTSH significantly increased the per-lesion sensitivity (i.e., the number of detected lesions). However, this resulted in a change of treatment plan in only 6% of the cases.

3.2. PSMA-Targeting Radiopharmaceuticals

Prostate-specific membrane antigen (PSMA) is a transmembrane glycoprotein type II encoded by the Folate Hydrolase 1 gene ^[20] expressed in prostate cancer but also on the membrane of neovascular endothelial cells of various solid tumors, such as thyroid, head, bladder, lung, breast, gynecologic, gastric, and colorectal cancers ^[21] (Figure 1). Immunohistochemical studies have demonstrated that high PSMA expression in the neovasculature of thyroid cancer positively correlates with a more clinically aggressive course of the disease. Moreover, it was shown that DTC patients with lesions of moderate and strong PSMA expression have a higher risk of developing radioiodine-refractory disease or a higher risk of disease-specific mortality ^[22][23] (Figure 2). This finding opens the door for the use of PSMA-targeting tracers for diagnostic but also therapeutic purposes. PSMA-targeting tracers are usually labeled with ⁶⁸Ga and ¹⁸F. From a technical point of view, PET performs better with ¹⁸F as compared to ⁶⁸Ga due to the shorter positron range, lower maximum β⁺energy, and higher positron yield, which leads to better spatial resolution ^[24]. ⁶⁸Ga has an 88% abundance of positron emission and a higher maximum energy than ¹⁸F, which gives more noise to images and leads to a lower resolution ^[25]. Other major advantages of ¹⁸F over ⁶⁸Ga-labeled PSMA tracers are the longer physical half-life of ¹⁸F and its higher availability. In the end, it leads to fewer technical challenges. However, due to defluorination, ¹⁸F-labeled PSMA compounds have higher bone uptake ^[26][27]. A recent multicenter study that enrolled 348 prostate cancer patients demonstrated unspecific bone uptake of [¹⁸F]F-PSMA-1007 in 217 (51.4%) patients, of which in 80 (44.7%) patients it was crucial for further therapeutic approaches and was considered clinically important ^[28]. Similar results were found in a recent retrospective study that included 214 patients. Ninety-four (43.9%) patients had at least one non-specific bone lesion. An SUVmax cut-off of 7.2 was set to distinguish between benign and metastatic lesions ^[29]. Besides PET tracers, there are also more affordable ^99mTc-labeled PSMA SPECT tracers. However, they have lower sensitivity due to the lower performance of SPECT compared to PET technology. Still, a very recent Australian study demonstrated that [^99mTc]Tc-PSMA SPECT/CT with an improved reconstruction algorithm has a diagnostic performance similar to [⁶⁸Ga]Ga-PSMA PET/CT in a daily clinical setting ^[30]. The literature data in the setting of radioiodine-refractory DTC are limited. Currently, the limited use of PSMA-targeting radiopharmaceuticals does not significantly affect further patient management. Prospective multicentric studies are needed to evaluate its potential role in RAI-R DTC patients.

3.3. Somatostatin Receptor-Targeting Radiopharmaceuticals

Somatostatin receptor-targeting radiopharmaceuticals are used for imaging tumors with high expression of somatostatin receptors (SSTR) (Figure 1). Most commonly, somatostatin analogs are labeled with ⁶⁸Ga, such as [⁶⁸Ga]Ga-DOTA-TATE, [⁶⁸Ga]Ga-DOTA-NOC, and [⁶⁸Ga]Ga-DOTA-TOC. They have different binding affinities for different SSTR subtypes. [⁶⁸Ga]Ga-DOTA-TATE has a quite selective and very high affinity for SSTR 2, [⁶⁸Ga]Ga-DOTA-NOC binds SSTR 2 and 3, while [⁶⁸Ga]Ga-DOTA-TOC has an affinity for SSTR 2 and SSTR 5 ^[31]. DTC cells may exhibit high expression of SSTR 2, 3, and 5 ^[32][33] (Figure 3). Therefore, radiolabeled somatostatin analogs may detect DTC recurrence or metastases, which are especially noted in patients with RAI-refractory disease. Ocak and colleagues enrolled 13 patients with RAI-refractory DTC (nine with papillary thyroid cancer, one with follicular thyroid carcinoma, and three with Hurthle cell carcinoma) to evaluate and compare the performance of [⁶⁸Ga]Ga-DOTA-TATE and [⁶⁸Ga]Ga-DOTA-NOC in the detection of RAI-R DTC lesions ^[34]. Somatostatin-positive lesions were found in eight (62%) patients. Forty-five lesions were detected with [⁶⁸Ga]Ga-DOTA-TATE and 42 with [⁶⁸Ga]Ga-DOTA-NOC. Lesion uptake was significantly higher on [⁶⁸Ga]Ga-DOTA-TATE (SUVmax 12.9 ± 9.1) compared to [⁶⁸Ga]Ga-DOTA-NOC (SUVmax 6.3 ± 4.1), suggesting its potential advantage in RAI-R DTC imaging. Positive RAI-R DTC lesions on somatostatin receptor imaging open the possibility of treating these patients with peptide receptor radionuclide therapy (PRRT) based on the theranostic approach. The theranostic approach with radiolabeled somatostatin analogs is important in the management of metastatic SSTR-positive tumors, nowadays mostly neuroendocrine tumors. ¹⁷⁷Lu-labeled or ⁹⁰Y-labeled somatostatin analogs are the most common therapeutic radiopharmaceuticals. Despite the heterogeneous response, PRRT may be an alternative treatment option for advanced and metastatic RAI-R DTC with sufficient expression of SSTRs owing to its efficacy and promising safety profile, especially in those patients experiencing progression under the standard treatment options, i.e., tyrosine kinase inhibitors.

3.4. Fibroblast Activation Protein—Targeting Radiopharmaceuticals

Fibroblast activation protein (FAP) expression is very low in normal human fibroblasts. However, cancer-related fibroblasts are characterized by high expression of FAP (Figure 1) since they carry both exopeptidase and endopeptidase activity ^[17]. A large fraction of the total mass in various tumors is made of tumor fibroblasts and extracellular fibrosis, while on many occasions less than 10% of tumor cells are involved ^[35]. Thus, radiolabeled fibroblast activation protein inhibitors (FAPIs) are suitable for tumor imaging. Chen et al. recently conducted a study to evaluate the performance of [⁶⁸Ga]Ga-DOTA-FAPI-04 PET/CT in the detection of RAI-R DTC lesions ^[36]. They enrolled 24 RAI-R DTC patients and demonstrated that 21 (87.5%) patients have FAPI-positive lesions, with a mean SUVmax of 4.25 and a growth rate of 6.51%. SUVmax was positively correlated with the lesions’ growth rates. In certain cases, [⁶⁸Ga]Ga-DOTA-labeled FAPI radiopharmaceuticals showed better detection of metastatic RAI-R DTC lesions compared to [¹⁸F]FDG, also due to a better target-to-background ratio ^[37]. Detectable strong expression of FAP opens an opportunity for new therapeutic options in RAI-R DTC patients. Like PSMA labeling, several attempts have been made for ¹⁸F labeling of FAPI ligands to overcome ⁶⁸Ga limitations as stated above (e.g., longer positron range, higher maximum ⁺energy, lower positron yield, higher costs, etc.), with [¹⁸F]FAPI-74 being the most promising candidate. Studies are currently ongoing, e.g., for the diagnostic comparison of [¹⁸F]FDG with [¹⁸F]FAPI-74 in patients with TENIS syndrome (EudraCT Number: 2022-001997-70; Figure 4).