Introduction

Antiangiogenic therapies that target vascular endothelial growth factor (VEGF) and VEGF receptor are the mainstay of treatment for patients with metastatic RCC (mRCC) [1]. Although effect of anticancer drugs in solid tumors is generally evaluated by changes in size, molecular targeted therapies may not cause significant tumor shrinkage despite efficacy at the molecular level.

(18F)-2-fluoropropionyl-labeled PEGylated dimeric arginine-glycine-aspartic acid (RGD) peptide [PEG3-E{c(RGDyk)}2] (18F-FPPRGD2) is a ligand targeting integrin αvβ3 on sprouting endothelial cells, which allows imaging tumor angiogenesis [2,3,4]. Withofs et al. showed positron emission tomography/computed tomography (PET/CT) using 18F-FPRGD2 reflects the expression of tumor associated integrin αvβ3 activity in RCC [5]. There are a few studies indicating the potential of 18F-FPPRGD2 PET/CT for evaluation of response to antiangiogenic drugs [2, 3].

In this study, we evaluated the detectability of mRCC lesions using 18F-FPPRGD2 PET/CT in comparison with 2-deoxy-2-(18F)fluoro-D-glucose (18F-FDG) PET/CT and the usefulness of 18F-FPPRGD2 PET/CT for early assessment of response to antiangiogenic therapy.

Material and methods

Patients

Seven patients (4 men and 3 women, mean age 64.1 ± 14.0 years) with mRCC were enrolled in this prospective study approved by our institutional review board. Informed consent was obtained from all individual participants included in the study. All patients had undergone both 18F-FPPRGD2 and 18F-FDG PET/CT within a month prior to starting systemic antiangiogenic therapy. Five patients had a follow-up 18F-FPPRGD2 PET/CT at 7–11 days (mean 8.4 ± 1.7 days) after initiation of therapy. Patients’ characteristics are shown in Table 1.

Table 1 Patients’ characteristics
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PET/CT protocol

PET/CT studies were performed using Discovery 600 or Discovery 690 PET/CT scanners (GE Healthcare, Waukesha, WI, USA). The details of PET/CT imaging protocols in our hospital have been described previously [3]. In brief, for 18F-FDG PET/CT, patients fasted for at least 6 h before scanning. Blood glucose levels at the time of injection were less than 150 mg/dl in all patients. 60 min after intravenous administration of 365–503 MBq (mean 421 ± 51 MBq) of 18F-FDG, non-contrast CT data for attenuation correction and anatomical localization was acquired. Thereafter, a whole-body PET scan from skull base to the mid-thighs was performed. For 18F-FPPRGD2 PET/CT, 60 min after intravenous administration of 223–374 MBq (mean 298 ± 45 MBq) of 18F-FPPRGD2, non-contrast CT data acquisition was performed, followed by a whole-body PET scan from vertex to mid-thighs. Image reconstruction was performed using ordered subsets expectation maximization (OSEM) method.

Image analysis

Two nuclear medicine physicians evaluated all 18F-FPPRGD2 and 18F-FDG PET/CT images by consensus with reference to conventional CT and/or MRI findings. Radiotracer uptakes above the background that did not correspond to physiological uptake was considered significant. Maximum standardized uptake value (SUVmax) and tumor-to-background ratio (T/B) were measured in each lesion. When calculating T/B, background was regarded as mean SUV in the region of interest (ROI) with a diameter of 2 cm in the ascending aorta. For the follow-up 18F-FPPRGD2 PET/CT, ROIs were put in the same location for lesions that were initially 18F-FPPRGD2 positive but showed complete resolution in the course of therapy.

Statistical analysis

We used the EZR software for statistical analyses [6]. Comparison of SUVmax and T/B in detected lesions on 18F-FPPRGD2 and 18F-FDG PET/CT was performed using Mann-Whitney U test and Spearman’s rank correlation coefficient. Evaluation of significance in change of SUVmax and T/B between the initial and follow-up 18F-FPPRGD2 PET/CT was performed using Mann-Whitney U test. P < 0.05 was considered statistically significant.

Results

A total of 60 lesions (3 primary and 57 metastatic) were identified prior to the start of antiangiogenic therapy as shown in Table 1 and Supplemental Table 1. Seven lesions were found to only have uptake on 18F-FPPRGD2 PET/CT and four only on 18F-FDG PET/CT (Fig. 1). In one patient, neither 18F-FPPRGD2 nor 18F-FDG PET/CT showed uptake in the primary tumor due to urinary excretion of radiotracers.

Fig. 1
figure 1

A 73-year-old male patient with mRCC (patient no. 2). This patient had multiple pleural and paraaortic lymph node metastases that were identified on CT. Maximum intensity projection images of 18F-FPPRGD2 (a) and 18F-FDG PET/CT (b) showed significant radiotracer uptake in multiple pleural metastases. 18F-FPPRGD2 PET/CT showed uptake in a paraaortic lymph node metastasis with a short diameter of 12 mm (c, white arrow) that was not seen on 18F-FDG PET/CT (d, white arrow)

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Supplemental Table 1 shows SUVmax and T/B measured on 18F-FPPRGD2 and 18F-FDG PET/CT in each lesion. SUVmax from 18F-FPPRGD2 PET/CT was significantly lower than that from 18F-FDG PET/CT (4.4 ± 2.9 vs 7.8 ± 5.6, P < 0.001). Both SUVmax and T/B showed moderate correlation between 18F-FPPRGD2 and 18F-FDG PET/CT (SUVmax, R = 0.437, P = 0.002; T/B, R = 0.488, P < 0.001) (Fig. 2).

Fig. 2
figure 2

Correlation of uptake between 18F-FPPRGD2 and 18F-FDG PET/CT. Both SUVmax (a) and T/B (b) showed moderate positive correlation between 18F-FPPRGD2 and 18F-FDG PET/CT

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Among five patients who had a follow-up 18F-FPPRGD2 PET/CT, four patients had a total of 40 lesions with significant 18F-FPPRGD2 uptake before systemic therapy. Supplemental Table 2 shows the changes in SUVmax and T/B between the initial and follow-up 18F-FPPRGD2 PET/CT for all detected lesions. Both SUVmax and T/B significantly decreased in these lesions after antiangiogenic therapy (SUVmax, 4.2 ± 3.2 vs 2.6 ± 1.4, P = 0.003; T/B, 3.7 ± 3.2 vs 1.5 ± 0.8, P < 0.001) (Figs. 3 and 4). Average changes in SUVmax and T/B were − 29.3 ± 23.6% and − 48.1 ± 28.3%, respectively. Three of the patients (patients 1, 3, and 7) had decrease of 18F-FPPRGD2 uptake in mRCC lesions on the follow-up PET/CT. Patient 1 had stable disease based on tumor diameter measurements 2 months after initiating pazopanib. Patient 3 showed expansion of necrosis in the tumor on contrast-enhanced CT that correlated with decrease of 18F-FPPRGD2 uptake (Fig. 5). However, this patient had severe bleeding from pazopanib and required a change in therapy after 2 weeks of treatment; therefore, clinical response could not be fully assessed. Patient 7 had long-term tumor control with the combination of lenvatinib and everolimus for more than 2 years, achieving a partial response based on tumor diameter measurements at 8 months after initiating treatment. Patient 5 had bone metastasis with an increase in SUVmax and T/B in the follow-up 18F-FPPRGD2 PET/CT. However, after he received 3 months of bevacizumab, he has had excellent tumor control in the single lesion for more than 2 years without requiring additional treatment. As a limitation of this pilot study, heterogeneity of treatment, RCC subtype and tumor location precluded complete correlation of changes in 18F-FPPRGD2 with clinical response.

Fig. 3
figure 3

Comparison of 18F-FPPRGD2 uptake between the initial and follow-up PET/CT after initiation of antiangiogenic therapy. Both SUVmax (a) and T/B (b) significantly decreased in these lesions after antiangiogenic therapy

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Fig. 4
figure 4

A 48-year-old woman with mRCC (patient no. 7). Two 18F-FPPRGD2 PET/CT studies are shown (a–c, baseline; d–f, after starting antiangiogenic therapy). The largest mass in the left retroperitoneum (b, white arrow) and abdominal wall (c, white arrowhead) showed high 18F-FPPRGD2 uptake before therapy. Both lesions showed decrease in 18F-FPPRGD2 uptake after initiation of antiangiogenic therapy

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Fig. 5
figure 5

A 46-year-old man with newly diagnosed mRCC lesions (patient no. 3). Contrast-enhanced CT (a), 18F-FPPRGD2 PET/CT (b), and 18F-FDG PET/CT (c) before systemic therapy showed the primary tumor with necrosis and elevated radiotracer uptake in the peripheral tumor tissue in the right kidney. After initiation of antiangiogenic drug, expansion of necrosis in the tumor was observed on contrast-enhanced CT (d, white arrows) in concordance with decrease of 18F-FPPRGD2 uptake (e, white arrows)

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Discussion

We evaluated the possible clinical utility of 18F-FPPRGD2 PET/CT in patients with mRCC in terms of lesion detectability and monitoring response to antiangiogenic therapy.

Several studies have shown that SUVmax from 18F-FDG PET/CT was significantly higher than that from 18F-FPPRGD2 PET/CT in various cancers [2, 3, 7,8,9]. One possible reason for this difference is that there is only a small number of endothelial cells expressing integrin αvβ3 in each lesion as opposed to many tumor cells with an increased number of glucose transporters [7, 8]. 18F-FPPRGD2 PET/CT detected more mRCC lesions than 18F-FDG PET/CT, consistent with a previous study in breast cancer patients [4]. In this study, while all lesions had CT or MRI correlates, lesions were not all histopathologically confirmed as mRCC, particularly in pleural or lung nodules. Thus, we could not calculate sensitivity, specificity and accuracy, nor statistically compare their diagnostic ability. However, based on these preliminary results, 18F-FPPRGD2 PET/CT may have comparable detectability for mRCC lesions with 18F-FDG PET/CT.

Significant positive correlation between 18F-FPPRGD2 and 18F-FDG uptake has already been shown in other malignant tumors [7,8,9]. One possible explanation for the correlation between angiogenesis and glycolysis in RCC is a mutation of von Hippel-Lindau (VHL) tumor suppressor gene. Loss of VHL activity leads to activation of the hypoxia-inducible factor pathway, followed by increase of anaerobic glycolysis and enhanced transcription of hypoxia-inducible genes including vascular endothelial growth factor [10].

Our pilot study revealed a decrease of 18F-FPPRGD2 uptake in mRCC lesions after starting antiangiogenic therapy. Taken together with the results of previous studies [2, 3], the early follow-up 18F-FPPRGD2 PET/CT may help evaluate response to antiangiogenic therapy. However, our study is limited by the small patient cohort with heterogeneous treatment and histological subtypes of RCC. As such, we could not evaluate correlation between the change in 18F-FPPRGD2 uptake, clinically best response to treatment, or patient survival. To determine the usefulness of 18F-FPPRGD2 PET/CT for evaluating clinical benefit of antiangiogenic therapy in patients with mRCC, further studies enrolling a larger number of patients with well-defined histology and treatment cohorts are needed.

In conclusion, 18F-FPPRGD2 PET/CT may be an useful tool for monitoring early response to antiangiogenic therapy in patients with mRCC. These preliminary results need to be confirmed in larger cohorts.