Can 99Tcm-3PRGD2(ανβ3) and 18F-FDG dual-tracer molecular imaging change the therapeutic strategy for progressive refractory differentiated thyroid cancer: Case report

Rationale: The management of radioiodine refractory differentiated thyroid cancer (RAIR-DTC) represents a major challenge in thyroid cancer. The American Thyroid Association guidelines recommend the use of tyrosine kinase inhibitors (TKIs) for RAIR-DTC that does not respond to conventional treatment. Currently, imaging modalities that predict the response to TKI treatment based on morphological and functional features are lacking. we report a case of a patient with progressive RAIR lung metastases who underwent 2-deoxy-2-[18F]fluoro-D-glucose and 99technetiumm-three polyethylene glycol spacers-arginine-glycine-aspartic acid (99Tcm-3PRGD2) dual-tracer imaging and investigate the value of this imaging strategy for determining subsequent therapeutic schedules. Patient concerns: A 52-year-old man with advanced RAIR-DTC and progressive lung metastasis. After TKI treatment [sorafenib] lost its clinical benefits, the patient’s therapeutic response was evaluated as progressive disease. 2-deoxy-2-[18F]fluoro-D-glucose PET/CT and 99Tcm-3PRGD2 SPECT/CT were performed. There were multiple FDG-positive lesions in the lung. However, 99Tcm-3PRGD2 SPECT/CT showed only 1 lesion in the right middle pulmonary lobe with arginine-glycine-aspartic positivity. Diagnosis: RAIR-DTC. Interventions: Radiofrequency ablation was performed for only the lesion with RDG and FDG positivity. Outcomes: The patient quickly achieved partial response. Lessons: This case indicates that for progressive RAIR metastases, patients can benefit more from prioritizing treatment for lesions that are both arginine-glycine-aspartic and FDG positive.


Introduction
Thyroid cancer (TC) is one of the most common malignant tumors of the head and neck. Differentiated TC (DTC) originates from the thyroid follicular epithelium and accounts for more than 95% of TC cases. [1] However, 1% to 23% of DTC patients develop distant metastases, of which 30% progress to radioactive iodine-refractory TC (RAIR-DTC). [2,3] The 10-year survival rate of RAIR-DTC is less than 10%. [4] Thus, theranostics for RAIR-DTC have become a clinical focus. In recent years, a variety of tyrosine kinase inhibitors (TKIs) have emerged and have been confirmed to prolong the progression-free survival This case report does not contain any personal identifier of the patient. It only includes radiological and pathological imaging, which does not contain any identifications. A written informed consent of patient information, images and publication was signed by the patient.
of patients with RAIR-DTC. [1,4] Ultrasound and computed tomography (CT) are commonly used in clinical trials to evaluate treatment response according to the Response Evaluation Criteria in Solid Tumors, relying on changes in tumor size. [5] However, changes in metabolic function often precede changes in morphology. Anatomic changes often fail to evaluate the response to treatment in a timely manner, particularly for TKI therapy. Therefore, we report the case of a patient with progressive RAIR lung metastases who underwent 2-deoxy-2-[ 18 F] fluoro-D-glucose ( 18 F-FDG) and 99technetiumm-three polyethylene glycol spacers-arginine-glycine-aspartic acid ( 99 Tc m -3PRGD 2 ) dual-tracer imaging and investigate the value of this imaging strategy for determining subsequent therapeutic schedules. Our case report encourages further exploration of 18 F-FDG and 99 Tc m -3PRGD 2 dual-tracer imaging for evaluating the response to TKI treatment in a timely manner.

Patient information
A 52-year-old man with RAIR-DTC and progressive lung metastasis received oral sorafenib 0.4 g twice daily. He had been smoking for about 40 years and drinking alcohol for about 20 years. The rest of his past medical history was unremarkable.

Clinical findings
In the last year, the patient's serum Tg (sTg) level and number of pulmonary lesions gradually increased, and he developed  hemoptysis ( Fig. 1). Because most lung lesions were <1 cm, therapeutic response was evaluated by combining Response Evaluation Criteria in Solid Tumors 1.1 criteria with changes in sTg levels. Changes in sTg levels were used to evaluate treatment response {[partial response, PR]: sTg decreased by more than 30% from baseline; [progressive disease, PD]: sTg increased by more than 25% from baseline; [SD]: change between PR and PD (−30% ~ +25%)}. His therapeutic response was evaluated as PD.

Diagnostic assessment
The sTg value with thyroid stimulating hormone inhibition was 17.2 ng/mL before PET/CT examination. He underwent both 18 F-FDG PET/CT and 99 Tc m -3PRGD 2 SPECT/CT with an interval of 2 days. He did not receive any antineoplastic therapy between the 2 scans. The 18 F-FDG PET/CT showed multiple lesions with increased FDG uptake in the lung. Multiple lesions with moderate to intense hypermetabolism (average standard uptake value [SUV]: 5.4, SUV max : 4.3-10.5, maximum diameter of lesions: 0.5-1.8 cm) were detected on the axial 18 F-FDG lung images (Fig. 2). 99 Tc m -3PRGD 2 SPECT/CT showed only 1 lesion with arginine-glycine-aspartic (RGD) uptake. There was moderate RGD uptake (SUV max : 3.8, maximum diameter of lesion: 1.8 cm) in the middle lobe of the right lung (Fig. 3A-C and G). We found that the dimension doubling rate of RGD-positive lesion was significantly higher than that of RGD-negative lesion.

Follow-up and outcomes
The 99 Tc m -3PRGD 2 scan showed no RGD uptake in the right middle pulmonary lobe (Fig. 3D-F and H). His sTg level decreased by 83.7% (the Tg value was 2.8 ng/mL, and the thyroid stimulating hormone value was <0.01 mIU/L). Moreover, chest CT and sTg tests were routinely performed every 3 months to assess changes in the lung lesions, and therapeutic response was evaluated as PR at follow-up (>12 months) (Fig. 4). The patient's hemoptysis disappeared.

Discussion
Integrin α v β 3 has been found to be a key factor in tumor angiogenesis that is necessary for tumor growth. Integrin α v β 3 is also important in regulating the potential of cancer cells to metastasize, influencing cell motility by interacting with fibronectin, and enhancing the survival of cancer cells in circulation by increasing their resistance to isolation-inducing cell death. [6] RGD is a small peptide containing arginine, glycine and aspartic acid. RGD has a ligand-receptor relationship with the integrin ανβ3 receptor and has high selectivity and affinity. [7] The study by Zhao et al [8] used 99 Tc m -RGD SPECT/CT to show that the integrin receptor reflected tumor neovasculature and that angiogenesis was active in RAIR-DTC lesions. Studies have reported that the expression of vascular endothelial growth factor is higher in TC tissue than in normal thyroid tissue. [9][10][11] These results provide a theoretical basis for the application of TKIs in RAIR-DTC. 99 Tc m -3PRGD 2 is a novel radiotracer based on RGD that targets the integrin α v β 3 receptor and can be used for the localization and growth evaluation of RAIR metastases. [8,[12][13][14] Compared with 18 F/ 68 Ga-labeled tracers, 99 Tc m -3PRGD 2 is a single-photon tracer that has good physical properties, is economical, and has wide availability.
The management of RAIR-DTC metastases has always been a challenge, especially in patients with multiple metastases that cannot be completely removed surgically. The currently available options are limited. [15,16] The treatment options include external beam radiation therapy, chemotherapeutic drugs such as cisplatin, doxorubicin and taxanes, and TKIs such as apatinib and sorafenib. In this case, the 99 Tc m -3PRGD 2 scan showed increased uptake as long as the lesion had weak α v β 3 receptor expression, demonstrating the high sensitivity of 99 Tc m -3PRGD 2 . Despite the progressive RAIR metastases, the therapeutic response was evaluated as PD after TKI treatment. Our 18 F-FDG and 99 Tc m -3PRGD 2 dual-tracer imaging revealed the following: if the lesion is FDG positive but RGD negative, although active glycolysis may still occur in the tumor, the proliferation ability of the vascular endothelial cells in RAIR metastasis may be inhibited, and these RAIR metastases can continue to be effectively treated by maintaining the initial KTI treatment regimen; continuation of the original TKI regimen was effective in these lesions. If the lesion is both FDG and RGD positive, the current TKI treatment regimen cannot repress tumor growth, and it is essential to revise the therapeutic strategy, such as to RFA, 125 I-seed brachytherapy, or another TKI drug. Patient prognosis might improve by prioritizing treatment for this kind of lesion.

Conclusion
Combined multimodal imaging with 99 Tc m -3PRGD 2 SPECT/CT and 18 F-FDG PET/CT may play some role in the management of RAIR-DTC metastases and guide subsequent therapy.