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. 2026 Jan 13;16:27. doi: 10.1186/s13550-025-01362-z

Angiogenesis PET/MRI predicts initial growth of sporadic vestibular schwannomas: a prospective study with follow-up in 29 patients using [68Ga]Ga-NODAGA-E[c(RGDyK)]2

Hjalte C R Sass 5,✉, Ramon G Jensen 5,6, Helle H Johannesen 1,3, Johan O Löfgren 1, Annika Loft 1, Thomas L Andersen 1, Adam E Hansen 1,3,4, Per Cayé-Thomasen 5,6, Andreas Kjaer 1,2
PMCID: PMC12886621  PMID: 41530428

Abstract

Background

Vestibular schwannomas (VS) are benign tumors located at the cerebellopontine angle. Although benign, the growth of VS can result in significant morbidity and potential compression of adjacent structures if left untreated. An MRI of the cerebellopontine angle is the standard-of-care examination when diagnosing a VS. 75% of newly diagnosed VS undergo conservative management with follow-up scans every 6-12th months. No robust clinical prognostic marker of initial sVS tumor growth exists. We performed a phase 2 clinical trial evaluating whether our PET tracer [68Ga]Ga-NODAGA-E[c(RGDyK)]2 could be used to predict initial sVS growth rate. The study was a non-randomized prospective clinical phase II study. 43 patients were included, either with a newly MRI-verified sporadic VS (sVS) or in a watchful waiting regime, with only one follow-up MRI scan. All patients were injected intravenously with approximately 200 MBq of the tracer followed by a sequential whole-body dynamic PET/MR scan of 60 min. All volume measurements were performed on T1 w sequences after intravenous gadolinium contrast injection in the Mirada DBx software version 1.2.0. A volume of interest (VOI) was drawn to encompass the lesion on PET images and a maximal standardized uptake value (SUVmax) for the sVS was registered. Growth over time was expressed as initial relative growth rate.

Results

Of the 37 patients initially scanned, results for the first 6 months of follow-up MRI scans are available for 29 of the included patients. The tracer demonstrated stable tumor retention and a high tumor-to-background uptake. SUVmax correlates to the initial growth rate of sVS with a correlation of 0.477 (CI = 0.13–0.72, P = 0.009). A receiver operating characteristic was performed with an area under the curve of 0.7. For the detection of growing tumors (> 20% relative growth annually), a cut-off at 0.555 could be established with a sensitivity of 100% and a specificity of 73% for detecting growing tumors.

Conclusions

This study presents the largest PET-MRI study performed in patients with sporadic vestibular schwannomas. Using the PET tracer [68Ga]Ga-NODAGA-E[c(RGDyK)]2, targeting αvβ3 integrins, we found a significant correlation between uptake of the PET tracer at an initial scan and the initial relative growth rate as measured volumetric on consecutive MRI scans.

Trial registration

NCT, NCT03393689. Registered 02 january 2018, https//clinicaltrials.gov/study/NCT03393689.

Keywords: Vestibular schwannoma, RGD, PET-MRI, αvβ3

Introduction

Vestibular schwannomas (VS) are benign tumors located at the cerebellopontine angle, originating from the Schwann cells, sheathing the 8th cranial nerve [1]. Sporadic VS (sVS) are the most common variant, while approximately 5% of the tumors are associated with Neurofibromatosis type 2 (NF2), giving rise to bilateral VS [2, 3]. Symptoms of a VS include unilateral hearing loss, unilateral tinnitus, dizziness, and less frequent trigeminal affection [4]. Although benign, the growth of VS can result in significant morbidity and potential compression of adjacent structures if left untreated [4]. An MRI of the cerebellopontine angle is the standard-of-care examination when diagnosing a VS. Primary treatment of sVS is debated and differentiated worldwide [5]. In North America and several European countries, tumors with an extrameatal size below 15 mm often enter a watchful waiting regime, and thus conservative management [6]. The most common cause for active treatment when in a watchful waiting regime is tumor growth identified on follow-up MRI scans [7]. Identifying tumor growth is, therefore, one of the most important aspects of sVS treatment. Growth rates of sVS in watchful waiting regimes depend on the location of the tumor, with data from an unselected national cohort showing 21% of intrameatal tumors and 37% of extrameatal tumors showing growth after 5 years increasing to 25% and 42% after 10 years respectively [7]. Previous studies have shown that pro-angiogenetic markers correlate with the growth rate of sVS [8–10]. Integrins are important in angiogenesis and tumor growth. They constitute a large family of noncovalent heterodimeric receptors formed by 18 α- and 8 β-subunits, generating at least 24 different receptor combinations [11]. These membrane-bound receptors mediate interactions between cells and components of the extracellular matrix, with ligand binding activating intracellular signaling pathways that regulate a wide range of cellular processes. Although integrin genes are rarely mutated in cancer, dysregulation of integrin expression or signaling is common, particularly in brain tumors. Of specific relevance to tumor angiogenesis, several integrins bind the tripeptide arginine-glycine-aspartate (RGD), with αvβ3 being one of the best-characterized contributors to angiogenic activity and tumor growth [12, 13].

Our group has evaluated different PET tracers, including tracers specifically targeting the αvβ3 integrin [14, 15]. [68Ga]Ga-NODAGA-E[c(RGDyK)]2 (RGD-tracer) emerged as particularly promising, as it is fast and reliable in radiochemical production, has stable tumor retention and a favourable tumor-to-background ratio. Most importantly, it correlates with integrin gene expression [15–18]. In 2022, we published a first-in-human phase 1 clinical trial, which found that the novel PET-tracer, RGD-tracer, was safe and showed promising tumor uptake [19]. We have also published the results from a prospective phase 2 clinical trial regarding neuroendocrine tumors, where a high uptake of RGD-tracer was associated with a poorer prognosis [20].

A previous study has found a positive correlation between dynamic contrast-enhanced MRI and growth of sVS with a sensitivity of 89% and specificity of 73%, although further studies are required to validate findings [21]. Tumor volume growth rates and Doubling times have also been used to depict growth, although these meassurements require multiple longitudinal scans. As such, no robust clinical prognostic marker of sVS initial tumor growth exists. We performed a phase 2 clinical trial evaluating whether our PET RGD-tracer could be used to predict the sVS initial growth rate.

Materials and methods

Study design

The study was a non-randomized prospective clinical phase II study. 43 patients were included, either with a newly MRI-verified sVS or in a watchful waiting regime, with only a diagnostic MRI scan. They were enrolled between January 2018 and March 2020. All patients fulfilled inclusion criteria and did not meet any exclusion criteria. All patients gave written informed consent prior to inclusion. The study was approved by the Danish Health and Medicine Authority (EudraCT no. 2017–002604-27) and the Regional Scientific Ethical Committee (H-17024682) and registered at ClinicalTrials.gov (NCT03393689). The study was performed in accordance with the Declaration of Helsinki as well as Good Clinical Practice (GCP) and independently monitored by the GCP unit of the Capital Region of Denmark.

All patients were injected intravenously with approximately 200 MBq of RGD-tracer followed by a sequential whole-body dynamic PET/MR scan of 60 min.

Synthesis of [68Ga]Ga-NODAGA-E[c(RGDyK)]2

NODAGA-E[c(RGDyK)]2 acetate was obtained from ABX GmbH. All reagents and cassettes were purchased from Eckert & Ziegler. Gallium-68 (T1/2 = 68 min; Emax, β+ = 1.90 MeV (89%)) labelling of NODAGA-E[c(RGDyK)]2 acetate was performed using a Modular-Lab Pharmtracer module (Eckert & Ziegler) using a 68Ge/68Ga generator (Galliapharm, 50 mCi, Eckert & Ziegler). The generator was eluted with 6 ml 0.1 M HCl. The eluate was concentrated on a Bond Elut SCX cartridge and eluted with 700 µl 5 M NaCl/5.5 M HCl (41:1). NODAGA-E[c(RGDyK)]2 (50 µg, 30 nmol) was labelled in 1,000 µl 1.4 M NaOAc buffer pH 4.5 and 400 µl 50% EtOH at 60 °C for 300 s. The resulting mixture was transferred to a Sep-pak C2 light cartridge and washed with saline. [68Ga]Ga-NODAGA-E[c(RGDyK)]2 was eluted with 1 ml 50% EtOH through a sterile filter and formulated with saline. The synthesis time was 20 min and 533 ± 167 MBq [68Ga]Ga-NODAGA-E[c(RGDyK)]2 was obtained. See Supplemental Data (Sect. 1) for a description of the quality control.

PET/MR acquisition and image analysis

Subjects have no need of fasting before injection of RGD-tracer. One peripheral intravenous catheter was placed for tracer injection. PET/MRI examinations were carried out on a whole-body hybrid PET/MRI system (Biograph mMR, Siemens, Germany). PET data was acquired dynamically for 60 min after injection of 200 MBq tracer as a single bed centered on the head/neck region. Images were reconstructed with 3D-OP-OSEM (4 iterations and 21 subsets, a Gaussian filter with 4 mm FWHM) on a 344 × 344 image matrix with pixel size 0.8 × 0.8 mm2, slice thickness of 2 mm. The data from 50 to 60 min after tracer injection was employed. Images were corrected for attenuation using an MRI ultrashort echo time sequence [22]. Simultaneously with PET, T2 and T1 weighted turbo spin echo were acquired for tumor delineation.

All volume measurements were performed on T1 weighted sequences after intravenous gadolinium contrast injection in the Mirada DBx software version 1.2.0. A manual contouring tool was used guided by the setting of a lover threshold that excluded non-contrast enhancing surroundings of the tumor. The apparent diffusion coefficient (ADC) was also noted, except for patients whose tumors were too small.

Tumor uptake by visual image analysis and activity quantification

Image analysis was performed by two experienced certified specialists in nuclear medicine and radiology, respectively. A volume of interest (VOI) was drawn to encompass the lesion on PET images, with care taken to avoid spill from the sigmoid sinus, and a maximal standardized uptake value (SUVmax) for the sporadic vestibular schwannoma was registered. Tumor size was determined by direct volume measurement on the MRI images. Growth over time was expressed as initial relative growth rate. SUVmax was chosen over SUVmean as a number of our tumors were small, thus significantly reducing the risk of partial-volume effect.

Histology

Histology was confirmed for patients undergoing surgery. No other tissue analysis was performed.

Results

Patients characteristics

A total of 43 patients with a newly diagnosed sporadic vestibular schwannoma were included. No prior treatment except for watchfull waiting was allowed and only patients with a newly diagnosed sporadic vestibular schwannoma was included. For inclusion and exclusion criteria see Table 1. Six were excluded. Three due to claustrophobia and three due to withdrawal of consent. For full summary of the trialprocess see the CONSORT-like flow diagram in Fig. 1 [23].

Table 1.

Inclusion and exclusion criteria

Inclusion criteria Exclusion criteria
Patients > 18 years with an MRI-verified, newly diagnosed sporadic Vestibular Schwannoma Pregnancy or lactation
Patients > 18 years under watchful waiting for a maximum of 12 months, or with only one follow-up MRI Non-MRI-compatible implants
Patients who can understand the study information and provide informed consent Claustrophobia
Current hormone treatment, including birth control pills
Ongoing steroid treatment
Age > 85 years
Obesity with a body weight > 140 kg
Known allergy to the tracer 68Ga-NODAGA-E[c(RGDyK)]₂
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Fig. 1.

Fig. 1

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Flowdiagram summarizing enrollment, exclusions and follow-up completion

Of the included patients, 51.4% were women with a mean age of 63 (range, 30–81) while 48.6% were men with a mean age of 56 (range, 41–78). See Table 2 for patient characteristics. The tumor location was intrameatal in 16 patients and extrameatal in 21 patients. Of the 37 patients initially scanned, results for the first 6 months of follow-up MRI scans are available for 29 of the included patients.

Table 2.

Patient characteristics for the 29 patients receiving a follow-up MR scan approximately 6 months after the PET-RGD MRI scan. L - Left. R - Right

Tumor side and location Patient nr SUVmax SUVmean Initial volume in ccm FollowUp volume in ccm Growth rate in ccm/year Initial relative growth rate in %
L/Extrameatal 1 4.2 2.3 3.0 2.6 −0.80 −26.6
R/Extrameatal 3 3.2 1.8 2.5 3.3 1.35 54.0
L/Intrameatal 5 1.5 0.9 0.4 0.5 0.17 43.5
L/Extrameatal 8 3.1 1.7 2.0 1.9 −0.20 −10.1
R/Extrameatal 9 4.3 2.3 3.1 4.5 4.30 138.5
L/Extrameatal 10 3.4 1.6 1.3 1.2 −0.20 −15.3
R/Extrameatal 11 0.8 0.4 0.5 0.5 0 0
R/Intrameatal 12 1.5 0.8 0.3 0.4 0.21 69.9
L/Extrameatal 13 2.5 1.3 0.9 0.7 −0.40 −43.8
L/Intrameatal 14 0.3 0.2 0.4 0.4 0 0
L/Extrameatal 16 1.7 0.9 0.2 0.2 0 0
L/Extrameatal 17 3.4 1.7 1.3 1 −0.54 −41.3
L/Extrameatal 19 3.6 1.9 1.6 1.5 −0.20 −12.3
L/Intrameatal 21 0.5 0.4 0.1 0 −0.19 −192.1
R/Extrameatal 23 4.1 1.7 3.1 2.5 −1.20 −38.8
R/Intrameatal 26 0.4 0.3 0.1 0 −0.19 −185.3
L/Extrameatal 27 1.4 0.6 0.4 0.3 −0.20 −48.8
L/Intrameatal 29 0.6 0.4 0.2 0.1 −0.19 −95.6
R/Extrameatal 30 3.2 1.6 3.7 3.1 −1.09 −29.5
R/Intrameatal 31 0.2 0.2 0.3 0.1 −0.53 −175.1
R/Extrameatal 33 8.3 4.6 2.3 2.6 0.71 30.9
R/Intrameatal 34 0 0 0.1 0 −0.20 −201.7
R/Extrameatal 35 2.4 1.2 7.4 7.5 0.52 7.0
L/Extrameatal 36 4 2.5 2.9 2.3 −1.40 −48.4
R/Extrameatal 37 2.4 1.1 2.0 2.6 1.29 64.4
L/Extrameatal 39 3.1 1.8 1.6 1.6 0 0
R/Extrameatal 40 1.7 1.2 0.9 0.6 −0.43 −47.9
R/Extrameatal 41 2.2 1.3 1.0 1.1 0.21 21.0
L/Intrameatal 43 0.3 0.2 0.1 0.1 0 0
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Patient safety and dosimetry

The mean and standard deviation of the administered activity was 194 ± 33 MBq (range: 124–233 MBq). There were no adverse or clinically detectable pharmacologic effects in any of the 28 patients, where the administered dose was available. One patient, patient 10, did not have a registered dose, and we were not able to identify the exact number. However, also this patient did not experience any side effects.

Tumor uptake of [68Ga]Ga-NODAGA-E[c(RGDyK)]2

The tracer demonstrated stable tumor retention and a high tumor-to-background uptake. See Fig. 2.

Fig. 2.

Fig. 2

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Primary PET-MRI scan and follow-up scan for patient 1, 3 and 9 respectively. Frem left to right; Primary MRI, Primary PET-MRI, Folllow-up MRI. From top to bottom; patient 1, patient 3 and patient 9. Tumor size, SUVmax and initial relative growth rate are shown in Table 1

We also found that the SUVmax correlates to the initial relative growth rate of sVS with a correlation of 0.477 (CI [0.13–0.72], P = 0.009) as seen in Fig. 3. The mean follow-up was 182 ± 36 days (range, 70–258 days).

Fig. 3.

Fig. 3

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RGD/PET-MRI SUVmax correlated to the initial relative growth rate of sVS with 95% confidence bands. The correlation coefficient is 0.477 with confidence interval of [0.13–0.72] and a p-value of 0.009

A post-hoc power analysis was performed to contextualise the statistical power of the correlation with an observed power of 0.78. See Fig. 4.

Fig. 4.

Fig. 4

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Post-hoc power curve analysis showing the statistical power of the correlation and the relationship with rising N

A receiver operating characteristic (ROC) curve analysis was performed to evaluate and visualize the trade-off between sensitivity (true positive rate) and specificity (false positive rate) at various threshold settings. See Fig. 5. The area under the curve was 0.7. For the detection of growing tumors (> 20% relative growth annually), a cut-off at 0.555 could be established with a sensitivity of 100% and a specificity of 73% for detecting growing tumors. Our cut-off value is based, not on patients terminating or dropping out of follow-up regimes, but rather on patients increasing the interval between follow-up scans. With such a cut-off, 6 of 29 (21%) patients could safely be identified as non-growing without overlooking any growing tumors.

Fig. 5.

Fig. 5

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A ROC curve demonstrating the sensitivity and specificity at various SUVmax values, and the corresponding coordinates of the ROC curve

Discussion

Here we present the results of our phase II study, evaluating RGD-tracer PET imaging as a predictor of initial relative tumor growth. The major finding was a significant correlation between the PET tracer uptake at an initial scan and the initial relative growth rate as measured volumetric on consecutive MRI scans in newly diagnosed sVS. This is the largest PET-MRI study in patients with sVS, and the second study to demonstrate a significant positive correlation between PET-tracer uptake and growth rate [24]. Our study demonstrates that tumor uptake of RGD-tracer was consistent and specific for sVS, and patients reported no changes in well-being and no adverse reactions or events. Secondly, we demonstrated a significant positive correlation between maximum tracer uptake and initial relative growth rate. Our study with n = 29 had good power to detect an effect of the observed magnitude (r = 0.477) at α = 0.05, which supports the reliability of the significant p = 0.009 result. However, the confidence interval reported ([0.13, 0.72]) shows the plausible range of the true effect, which means that while our power is good, the estimate still has some uncertainty.

Over the past two decades, the molecular biology of sVS has been studied extensively, especially as treatment has shifted towards conservative, watchful waiting regimes [25, 26]. As tumor growth is the most common cause of active treatment for patients in watchful waiting regimes [27], understanding the underlying causes is therefore of great interest. Several studies have found that both angiogenesis as well as inflammation take part in driving the sVS growth rate [8–10, 24, 28–38].

Our group has previously found pro-angiogenetic factors such as vascular endothelial growth factor (VEGF), vascular endothelial growth factor receptor 1 (VEGF-R1), Matrix metalloproteinase 9 (MMP-9) and Platelet-derived growth factor C (PDGF-C) correlate positively with the growth rate of sVS [8–10, 29, 30]. Angiogenesis is required for the growth of solid tumors, as growth above 2–3 mm3 requires new vessels to support nutrient and oxygen requirements [39]. During angiogenesis, migration, growth, and differentiation of endothelial cells take place. Endothelial cells must adhere to one another to form new microvessels. Recent research has illuminated the role of the subfamily of Arginine-Glycine-Aspartate (RGD)-recognizing integrins, due to the involvement of their targets in several hallmarks of cancer development [13]. Especially the αvβ3 integrin, a heterodimeric cell surface receptor, which is involved in cell adhesion and signal transduction, influencing various cellular behaviours essential for tumor progression [40]. αvβ3 integrin is highly expressed in activated endothelial cells and has been identified as a critical modulator of angiogenesis [41–43]. It has been found upregulated in different central nervous tumors including VS but has not previously been correlated with tumor growth rate [12]. αvβ3 integrin is a receptor for fibronectin and vitronectin, ECM components critical in angiogenesis. The binding of αvβ3 integrin to these ligands initiates intracellular signalling cascades that promote key steps in new blood vessel formation. Specifically, αvβ3 integrin modulates the activity of focal adhesion kinase (FAK) and Src family kinases, leading to the activation of the PI3K/Akt and MAPK/ERK pathways, which are essential for angiogenic processes, and upregulated in fast-growing sVS [8].

In our study, we did find a significant correlation between sVS initial relative tumor growth and SUVmax. We could establish a cut-off where sensitivity and specificity for the detection of growing tumors were 100% and 73%, respectively. However, it may be discussed whether this diagnostic performance is sufficient to warrant use in a clinical setting. Perhaps a prolonged interval between follow-up MRI scans could be justified. Angiogenesis is correlated to sVS tumor growth, but most likely not as a sole driving mechanism. In recent years, the tumor microenvironment has been gaining attention, with a special focus on tumor-associated macrophages (TAMs), driving inflammatory processes and through this, tumor growth [33, 36, 37, 44–47]. In the first prospective, non-randomized PET/MRI study looking at the tracer maximum binding potential (BPmax) correlated to tumor growth rates [24], the PET-tracer, 11 C®PK11195, was targeting the 18 kDa translocator protein (TSPO), which is expressed by inflammatory cells and can thus be viewed as a marker of inflammation. The PET-tracer demonstrated a significantly higher BPmax in growing versus static and shrinking sVS. They performed tissue analysis and found that macrophage count predominated over tumor cells in growing sVS, underlining the importance of inflammation as well as the tumor microenvironment in sVS tumor growth.

Limitations

Several limitations of this study should be acknowledged. To ensure broad applicability to all patients with vestibular schwannoma, all newly diagnosed cases were included, regardless of tumor size. This approach may lead to an overestimation of changes in tumor size, as the risk of measurement error increases with smaller lesions. Initial tumor growth generally guides subsequent treatment decisions, and reducing the number of follow-up scans offers both socioeconomic and patient centered advantages. Although a follow-up period of about six months may be considered short, we believe it is adequate to assess early tumor growth. Selection bias may be also introduced as 8 of the patients did not receive the initial follow-up scan.

Conclusion

This study presents the largest PET-MRI study performed in patients with sporadic vestibular schwannomas. Using the PET tracer RGD-tracer, targeting αvβ3 integrins, we found a significant correlation between uptake of the PET tracer at an initial scan and the initial relative growth rate as measured volumetric on consecutive MRI scans in newly diagnosed sVS. The tracer was safe and we found no adverse events. The significant although, moderate correlation underlines the partial role of angiogenesis in the growth of sporadic vestibular schwannomas. Non-invasive prognostic markers are pivotal in the future management of sVS. Recent research has focused on the inflammatory processes most likely also driving tumor growth of sVS. Longer follow-up and expanded cohorts may clarify the robustness and durability of this study. Future work could also focus on strategies to strengthen predictive accuracy—such as combining angiogenesis-related tracers with emerging inflammation-targeted PET agents, integrating radiomic features from PET/MRI, or applying multiparametric models that incorporate clinical and molecular markers. Such approaches may ultimately enhance the non-invasive risk-stratification of sVS and meaningfully influence future management paradigms.

Acknowledgements

We would like to acknowledge all funding parties, including all collaborating parties, who contributed to handling the samples.

Author contributions

All authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by HCRS, RGJ, PCT obtained the material for analysis. Radiological data was analyzed and obtained by HCRS, HHJ, JOL, AL while nuclear medicine data was obtained and analyzed by JOL, TLA, AEH and AK. The first draft of the manuscript was written by Hjalte CR Sass and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

Funding

This work has been performed with the help of Copenhagen university hospital, RIgshospitalets internal funding, Aase og Ejner Danielsens Fond and Fabrikant Einar Willumsens Mindelegat.

Data availability

The datasets generated and/or analysed during the current study are not publicly available as data are still undergoing analysis. The data are available from the corresponding author on reasonable request.

Declarations

Ethics approval and consent to participate

The study was approved by the Danish Health and Medicine Authority (EudraCT no. 2017-002604-27) and the Regional Scientific Ethical Committee (H-17024682) and registered at ClinicalTrials.gov (NCT03393689). The study was performed in accordance with the Declaration of Helsinki and Good Clinical Practice (GCP) and independently monitored by the GCP unit of the Capital Region of Denmark. All participants signed informed consent before participation.

Consent for publication

Consent to participate and publication of results were obtained from all individuals included in the study.

Competing interests

Andreas Kjær MD, PhD, DMSc, holds a patent for the PET-MRI tracer [68Ga]Ga-NODAGA-E[c(RGDyK)]2 with publication number 20200282084. No other potential conflicts of interest relevant to this article exist.

Footnotes

Hjalte C. R. Sass is the first author.

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Data Availability Statement

The datasets generated and/or analysed during the current study are not publicly available as data are still undergoing analysis. The data are available from the corresponding author on reasonable request.

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