Apatinib is an orally anti-angiogenic TKI targeting VEGFR2 and PDGFR β [
6] and has been approved by the National Medical Products Administration (NMPA) for advanced gastric cancer as third-line systemic therapy [
10]. Recently, apatinib has been shown to be a promising treatment option for progressive locally advanced or metastatic RAIR-DTC [
7,
8]. Here, we reported the beneficial antitumour effects of apatinib alone or in combination with RAI therapy on progressive dmDTC. To the best of our knowledge, this is the first investigation into the neoadjuvant therapy effects of apatinib and the combination therapy with RAI on progressive dmDTC. Our results suggested that apatinib induced significant decrease in tumour size in patients with aggressive dmDTC. Apatinib alone has antitumour effect, and beneficial synergistic and complementary effects were shown when apatinib combined with RAI therapy in the treatment of dmDTC.
Patients with dmDTC usually have an unfavorable prognosis, because some of dmDTC are RAIR-DTC [
2,
3]. Furthermore, in our present study, all patients had FTC. Previous studies [
11,
12] demonstrate that patients with aggressive variants of FTC have an unfavorable prognosis and exhibit lymph node or distant metastases. In many cases, these aggressive variants of thyroid carcinoma require more aggressive or innovative forms of clinical management. TKIs such as lenvatinib and sorafenib have been approved by FDA and European Medicine Agency (EMA) for progressive, metastatic RAIR-DTC [
4,
5]. However, the therapy options for RAIR-DTC patients in China are still very limited due to limited availability of lenvatinib and sorafenib. TKI has been reported as a successful neoadjuvant for total thyroidectomy to reduce tumor burden [
13] and enhance RAI sensitivity of thyroid cancer including an increased sodium/iodide symporter expression [
14].
18F-FDG PET/CT has been widely used in the diagnosis of dmDTC and
18F-FDG-avid lesions are usually more aggressive with poor prognosis [
15,
16]. Previous studies have shown less effective of high-dose RAI therapy in patients with FDG-avid DTC than in patients with non-FDG-avid DTC [
16] and there is an inverse relationship between RAI and
18F-FDG accumulation in DTC cells [
17]. In our present study, all patients have
18F-FDG-avid dmDTC lesions suggesting aggressive diseases and less effective RAI therapy. We therefore explore the use of neoadjuvant treatment with apatinib prior to RAI therapy for evaluation of effect of apatinib on tumour progression and possible improvement of following RAI treatment results. Our present study demonstrated interestingly the effective treatment of apatinib alone on progressive dmDTC as shown in cases 1, 2, 3 and 4. Further decreases in tumour size and SUVmax, as well as serum Tg level, were found in combination with apatinib and RAI therapy in cases 1, 2 and 3. This might be explained by the synergistic antitumour effects of combination therapy with apatinib and RAI, since TKI has been reported to be able to enhance the RAI sensitivity of thyroid cancer due to the enhancement of sodium iodide symporter (NIS) function [
14]. However, it could be also possible that this effect was only due to the longer duration of apatinib therapy. In case 4 the patient was effectively treated by apatinib, however, RAI therapy showed no effect on the dmDTC, since all metastatic lesions, in this case, were negative in post-therapeutic
131I scan, these metastatic lesions may be defined as RAIR-DTC. The reasons why the patient in case 5 showed no response to apatinib remain unclear. In contrast to other four patients with FTC in cases 1 to 4, this patient had both FTC and PTC. It is well known that DTC may have heterogeneous response to TKIs [
18]. Apatinib suppresses tumour progression via blocking the VEGFR2 cascade in malignant cells [
6]. Unfortunately, the tumour tissue VEGFR2 status, in this case, was unknown. We can only speculate that the tumour progression in this case might be through other molecular pathways rather than VEGFR2 pathway. Fortunately, this patient had response to RAI therapy leading to stable disease (SD) after RAI therapy. It might be possible that the positive effect of RAI on the metastatic lesions in case 5 might be partly due to the apatinib therapy since TKI may enhance the RAI sensitivity of thyroid cancer [
14]. Our results may have implication for the complementary effect of combination therapy with apatinib and RAI as shown in cases 4 and 5.
Despite the small number of patients, our results demonstrated statistically significant reduction of tumour size and SUVmax under apatinib therapy indicating the clinical potential of apatinib therapy. Further significant decrease in tumour size and SUVmax demonstrated the synergistic and complementary effects of the combination of RAI with apatinib. The serum Tg levels which may indicate the tumour activity showed remarkably reduced after apatinib therapy and after the combination therapy with RAI, however, no statistical significance were observed due to the small numbers of patients.
There were some limitations in this study. Firstly, the number of investigated cases was limited. Secondly, there was no control group. The present study was a pilot study to evaluate the effects of apatinib on progressive dmDTC. More patients should be included in a randomized study to verify the results. Meanwhile, all patients are still alive.