Introduction
The incidence of thyroid cancer continuously increased over the past three decades [
1]. Differentiated thyroid cancer (DTC) accounts for more than 90% of all thyroid cancers, and prognosis in the majority of DTC patients is excellent. However, increasing cases, especially those with high-risk DTC, have been reported to develop local recurrence or metastatic disease after initial surgery and radioactive iodine (RAI) ablation [
2]. Two-thirds of these patients will never be cured with RAI therapy and become RAI-refractory (RAIR), with a 3-year survival rate of less than 50% [
3]. Early identification of the propensity for disease progression after initial therapy in high-risk DTC patients can assist physicians to develop prompt and individualized treatment plans.
The routine evaluation of DTC patients includes the measurement of serum thyroglobulin (Tg),
131I scintigraphy, ultrasound, and computed tomography (CT). Due to positive thyroglobulin antibody (TgAb) or undifferentiated lesions that do not secrete Tg, serum Tg may not be a reliable predictor in some patients.
131I scintigraphy also often fail to detect lesions with impaired ability to concentrate iodine. CT and ultrasound provide only anatomic data, which may lag behind functional changes. Hence,
18F-fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) is gradually being used to localize lesions in patients with suspected RAIR-DTC. However, due to the common co-existence of iodine-sensitive and -refractory disease in high-risk DTC, the relatively low glucose metabolism in the lesions with heterogeneous cells are likely to be missed on FDG PET/CT [
4]. Moreover, enhanced glucose uptake in inflammatory tissues, such as reactive lymph nodes, reduces the specificity of
18F-FDG PET/CT [
5,
6]. A more effective imaging method is needed for early detection of advanced diseases in high-risk DTC patients.
Integrin α
vβ
3, which is significantly upregulated on several tumor cells and activated endothelial cells, plays essential roles in neoangiogenesis and tumor progression as a member of the arginine-glycine-aspartate (RGD)-binding subfamily [
7]. Unlike
18F-FDG PET/CT, which is a diagnosis-only modality, RGD imaging provides not only a specific method for visualizing tumor angiogenesis but also therapeutic implications for antiangiogenetic and anti-α
vβ
3 drugs [
8‐
10].
99mTc-PEG
4-E[PEG
4-c(RGDfK)]
2 (
99mTc-3PRGD
2), a novel RGD peptide tracer, is specifically designed to recognize integrin α
vβ
3.
99mTc-3PRGD
2 has been used to trace primary or metastatic lesions in patients with various tumors, including lung, breast, esophageal and thyroid cancers [
11‐
14]. Our previous studies have validated
99mTc-3PRGD2 was a valuable probe for the detection of recurrent lesions with negative radioiodine whole-body scintigraphy (WBS) [
15]. In addition, integrin α
vβ
3 has been reported to interact with the vascular endothelial growth factor receptor-2 (VEGFR-2) and platelet-derived growth factor receptor (PDGFR) [
16,
17]. The cross-talk between integrin α
vβ
3 and VEGFR-2/PDGFR is crucial for endothelial cell activation and angiogenesis. In vivo studies demonstrated that
99mTc-3PRGD
2 imaging was a noninvasive tool to predict and evaluate the response to therapy with antiangiogenic agents in breast cancer [
8].
In the present study, for the first time, we analyze the utility of 99mTc-3PRGD2 single photon emission computed tomography/computed tomography (SPECT/CT) for the prognostication of therapeutic effect and disease progression in patients with high-risk DTC after initial RAI ablation.
Discussion
Thyroid cancer is clinically heterogeneous, varying from indolent to aggressively proliferative disease. Patients with high-risk DTC, which often represents less well-differentiated disease, have a lower chance of response to RAI therapy than low-risk patients [
23]. More sensitive imaging modalities for identification of aggressive status is critical to the prognosis of high-risk DTC patients. RGD-peptide based SPECT/CT is a neo-angiogenesis imaging modality which has high affinity and specificity towards integrin α
vβ
3. Xu et al. reported that
99mTc-Galacto-RGD
2 SPECT/CT had higher sensitivity than
131I WBS and morphological imaging in the detection of lymphatic and bone metastasis in DTC patients [
7]. The overall sensitivity and specificity of
99mTc-Galacto-RGD
2 SPECT/CT were 92.86 and 86.36%, respectively, in the detection of metastatic DTC diseases. In our previous study,
99mTc-3PRGD
2 SPECT/CT showed high sensitivity in the detection of recurrence among DTC patients with Tg elevation but negative iodine scintigraphy (TENIS), and the sensitivity was improved to 100% in patients with TSH-stimulated Tg > 30 ng/mL [
15]. However, there are few studies on the ability of RGD-based imaging to predict the prognosis after initial surgery and RAI in DTC patients. In this study, we found that
99mTc-3PRGD
2 avidity was an effective predictor for non-remission in high-risk DTC. The present study also found that
99mTc-3PRGD
2 avidity was associated with poor prognosis in patients with high-risk DTC.
99mTc-3PRGD
2 avidity was significantly correlated with PFS in multivariate analysis, which indicated
99mTc-3PRGD
2 avidity as an independent risk indicator for PFS in high-risk DTC.
In this study, about three-fourth of all patients (75.8%) had
99mTc-3PRGD
2-positive lesions at initial diagnosis before RAI treatment. Of the 25 patients with
99mTc-3PRGD
2-positive lesions, about two-third of patients (64.0%) had no
131I uptake in the lesions on
131I post therapy WBS, which would have been missed by standard RAI alone. Matching iodine- and
99mTc-3PRGD
2-positive lesions were observed in 9 patients. Survival analysis indicated that the presence of
99mTc-3PRGD
2 uptake in tumor lesions and the absence of
131I uptake in these lesions were significantly related to a worse PFS after initial RAI ablation. The role of
99mTc-3PRGD
2 SPECT/CT in therapy management of high-risk DTC was further observed in 14
99mTc-3PRGD
2-positive patients having progressive disease after initial surgery and RAI. We found that additional surgery or MKIs therapy might lead to a higher rate of remission than repeated RAI in patients with
99mTc-3PRGD
2-positive lesions. Our results strongly suggested a linking between
99mTc-3PRGD
2 avidity and radioiodine refractory disease. This finding is consistent with prior studies by Zhao et al., which showed that RAIR metastatic lesions can be traced using
99mTc-3PRGD
2 SPECT imaging [
14].
Nowadays,
18F-FDG PET/CT is the main method recommended by the ATA guidelines for the detection of RAIR-DTC. Many studies have demonstrated its utility in the detection of structural disease in RAIR-DTC patients with increasing sensitivity at higher levels of serum Tg, and changes of intermediate or high-risk patient management [
24‐
26]. However, there are still some RAIR-DTC patients who have a negative
18F-FDG PET/CT, which drives the need for alternative imaging modalities. The PET or SPECT imaging of integrin α
vβ
3 has recently been evaluated in refractory DTC, and some studies found that RGD-based imaging has better diagnostic performance than
18F-FDG [
4,
27]. For instance, Parihar et al. reported
68Ga-DOTA-RGD
2 PET/CT had higher specificity and overall accuracy than
18F-FDG PET/CT in detection of lesions in RAIR-DTC patients [
4]. They noted that
68Ga-DOTA-RGD
2 PET/CT and
18F-FDG PET/CT showed a similar sensitivity of 82.3%, however
68Ga-DOTA-RGD
2 PET/CT had a higher specificity of 100% compared to 50% on
18F-FDG PET/CT. Our study indicated that compared with repeated RAI, additional surgery or targeted therapy with MKIs could lead to a higher rate of complete or partial remission in
99mTc-3PRGD
2-positive patients, suggesting
99mTc-3PRGD
2 scan could be able to guide the adjustments in management after the initial surgery and RAI ablation. Considering that the association of
99mTc-3PRGD
2 avidity with unfavorable prognosis, patients with a positive
99mTc-3PRGD
2 scan should be asked for a closer follow-up to detect recurrent or metastatic diseases in a timely manner. Therefore,
99mTc-3PRGD
2 SPECT/CT is a valuable diagnostic method for high-risk DTC patients and an effectively complementary modality for
18F-FDG PET/CT in refractory DTC.
In our study, further survival analysis revealed a trend towards worse PFS in patients with higher than median values for T/B ratio and SUV
max. Recent studies reported the T/B ratios of
99mTc-3PRGD
2 in metastatic DTC lesions were positively correlated with growth rates of these lesions [
14] and patients’ clinical stages [
7]. Another study demonstrated that the SUV
max of RAIR-DTC lesions on
68Ga-DOTA-RGD
2 PET/CT had a strong positive correlation with serum TSH-stimulated Tg levels, which reflecting the disease burden [
4]. Hence, the parameters of RGD uptake could be used as potential imaging biomarkers for tumor burden and biologic aggressiveness. We did not detect a lineal correlation between Tg levels and
99mTc-3PRGD
2 uptake in this study. The possible reason is that the serum Tg was tested before initial RAI treatment, so that Tg was partly secreted by residual thyroid tissue, which could not reflect the real burden of recurrent or metastatic diseases.
In this study, the DTC patients with positive
99mTc-3PRGD
2 lesions all received full TSH suppression of less than 0.1 mIU/l with levothyroxine, but still had a high rate of disease progression. Thyroid hormone has been reported to increase tumor growth in various types of cancer, including hepatocellular, colorectal, and lung cancers [
28‐
30]. A retrospective study followed 867 patients with intermediate- and high-risk DTC for a median of 7 years, documenting that patients with suppressed TSH levels were associated with worse 3-year overall survival [
31]. The widespread use of TSH-suppressive therapy has recently been questioned, and individualized treatment based on each patient’s characteristics has been proposed. More recently, it was reported that integrin α
vβ
3 has a high affinity binding site for thyroxine [
32]. Thyroxine has been suggested to promote proliferation and angiogenesis in multiple cancer types via binding with integrin α
vβ
3 [
33,
34]. Therefore, TSH suppressive doses of levothyroxine in DTC patients with tumoral integrin α
vβ
3 expression may have to be reconsidered, and integrin α
vβ
3-targeting
99mTc-3PRGD
2 SPECT/CT could theoretically be utilized to identify these patients. Further mechanistic and clinical studies are needed to test this hypothesis.
There are still some limitations in this study. First, the follow-up was relatively short. Further studies with larger cohort of patients and longer follow-up period are required to validate our findings. Second, only 1 patient in this study underwent 18F-FDG PET/CT at 4 months after RAI ablation. A right cervical lymph node metastasis was visualized on both 18F-FDG PET/CT and 99mTc-3PRGD2 SPECT/CT images, which was pathologically validated by fine needle aspiration biopsy. Future prospective research including parallel 18F-FDG PET/CT and 99mTc-3PRGD2 SPECT/CT examinations is needed to clarify the effect of FDG PET/CT results on prognostic significance of 99mTc-3PRGD2 SPECT/CT and compare the diagnostic and prognostic values of the 2 imaging modalities. Third, further experiments are indispensable to determine the underlying mechanism of integrin αvβ3 promoting DTC.
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