[18F]SiTATE PET for PRRT selection and monitoring metastatic tumors of the adrenal medulla and extra-adrenal paraganglia

Rare neuroendocrine neoplasms include tumors of the adrenal medulla (e.g. pheochromocytoma (PCC)) or tumors of the extra-adrenal paraganglia (e.g. paraganglioma (PGL)) [1, 2]. Both tumor subtypes, hereinafter PPGL to include both entities, can develop into malignant tumors in < 1 to 79% of cases, as the progression is very heterogeneous and depends on tumor size and genotype, among other factors [3, 4]. Tumor cells express Chromogranin A (CgA) [2], which is furthermore co-stored and secreted with catecholamines [5]. [¹⁸F]SiTATE is a novel radiotracer beyond established ⁶⁸Ga-labeled SSTR-directed tracers, that can be not only used in the imaging of somatostatin receptors (SSTR) expressing tumor entities, but also in a theranostic setting to evaluate PRRT eligibility, as reported for other SSTR-expressing tumor entities [6‐9]. Due to the widespread SSTR expression, PPGLs are suitable candidates for targeted radionuclide therapy when other therapeutic options are either not feasible or ineffective [10‐14].

This study evaluated the use of SSTR-targeted imaging with the novel tracer [¹⁸F]SiTATE in PPGL patients, focusing on eligibility for PRRT and therapy monitoring through changes in tumor volume, RECIST 1.1 criteria and hormone levels.

In this retrospective analysis, we evaluated the use of the novel tracer [¹⁸F]SiTATE in PPGL patients, for selection of PRRT eligibility and therapy monitoring.

To date, [¹⁸F]SiTATE has shown excellent image quality and high lesion detectability in patients with neuroendocrine tumors, but its use for selecting candidates for PRRT in metastatic PPGL, has not been systematically studied [24, 25]. To the best of our knowledge, this is the first study evaluating [¹⁸F]SiTATE PET/CT for patient selection for PRRT in metastatic PPGL.

Our results indicate that [¹⁸F]SiTATE is effective in determining SSTR expression as shown by high image contrast in PPGL patients. A key advantage of [¹⁸F]SiTATE over other ⁶⁸Ga-labelled SSTR directed tracers is its higher spatial resolution due to fluorine radiochemistry [7, 16], indicative for improved read-out capabilities of [¹⁸F]SiTATE. Single-lesion analysis revealed high SUV_max values in metastases, especially in osseous lesions.

The cohort predominantly presented with lymph node and bone metastases, while visceral metastases were only rarely observed. This distribution aligns with existing literature on metastatic patterns in PPGL [26, 27]. However, due to the low number of visceral metastases in our cohort, conclusions regarding the detection performance of [¹⁸F]SiTATE for visceral lesions remain limited. The high standard deviation of SUV_max values observed in osseous metastases likely reflects the inherent biological heterogeneity of metastatic bone involvement in PPGL, encompassing underlying genetic mutations variations and thus SSTR expression [28]. Nevertheless, the high SUV_max values across all detected lesions suggest [¹⁸F]SiTATE to be a good tracer for metastasis detection.

Interestingly, in our cohort, three patients presented with heterogenous response when comparing PET-based and CT-based assessments. Specifically, PET imaging revealed an increase of TTV, while CT-based evaluation according to RECIST 1.1 criteria indicated SD. The prognostic value of whole-body SUV_max in this context remains uncertain, as also reported for gastroenteropancreatic NETs [29]. The underlying reasons for this discrepancy between metabolic (PET) and morphologic (CT) response assessment remain unclear and warrant further investigation in future studies.

Hormonal biomarkers such as CgA, which is co-stored and co-secreted with catecholamines, showed inconsistent correlations with imaging-based tumor response in previous studies [5]. It has been reported, that both imaging and biochemical responses are often only seen in a Subset of patients. In contrast, our results showed a relatively high concordance between CgA levels and disease control as defined by RECIST 1.1, underscoring the potential prognostic relevance of CgA in this setting and the need for further studies to clarify its role [30, 31]. Nevertheless, CgA remains a non-specific biomarker whose levels can be influenced by various factors unrelated to tumor progression or treatment response, such as inflammation or chronic kidney disease [32‐34]. Furthermore, although some studies recommend fasting measurements of CgA to reduce variability, this was not standardized in our cohort [35]. Consequently, the interpretation of CgA levels should be made cautiously and in conjunction with imaging and clinical assessment.

The potential of SSTR-positive TTV as an imaging biomarker for predicting PRRT response and its impact on progression-free survival (PFS) warrants further investigation in long-term studies. While previous research on PRRT in PPGL has yielded encouraging PFS outcomes, larger, prospective studies are essential to confirm these results and establish the prognostic significance of TTV in this specific patient population [14, 36‐38]. Due to the small cohort size, PFS was not a focus of the current study but should be addressed in future research.

The small cohort is furthermore the major limitation of this study, beyond its retrospective design and heterogeneity (e.g. pretreatments and number of PRRT cycles). Subgroup analysis in regard of genetic mutations was not performed due to the limited sample size, although existing literature suggests that mutations might influence PRRT response [39]. However, the small number of patients must be viewed in the context of the rare prevalence of PPGL, even at a high-volume theranostic center, which inherently limits the availability of larger cohorts for Such studies. Although we evaluated 52 lesions in total, allowing for lesion-based observations, the limited cohort size does not permit definitive conclusions regarding diagnostic accuracy, treatment response, or prognostic value. In addition, no intra-individual comparative imaging was available using established reference tracers such as [⁶⁸Ga]Ga-DOTATOC. As such, we cannot comment on the relative diagnostic performance of [¹⁸F]SiTATE compared to these modalities. The findings presented here should therefore be interpreted as preliminary and hypothesis-generating. Nonetheless, we believe this initial clinical experience provides valuable insight into the potential role of [¹⁸F]SiTATE PET/CT for patient selection and follow-up in the setting of PRRT for metastatic PPGL and may serve as a basis for future prospective and comparative studies. The Krenning score remains useful for assessing SSTR expression; however, its validity in SSTR PET has been questioned, since it was first established for In-111-pentetreotide SPECT in NET patients [40]. For quantitative assessment of tumor burden, we applied a fixed threshold approach for TTV segmentation to ensure consistency and reproducibility across patients and lesions. While lesion-specific or adaptive thresholds may offer more individualized volumetric measurements, they also introduce variability and reduce comparability, particularly in small exploratory cohorts [41]. The fixed threshold method has been used in a previous study on [¹⁸F]SiTATE PET/CT imaging and provides a practical, standardized framework for feasibility assessments [8]. Future studies with larger patient populations may benefit from more advanced segmentation strategies, including adaptive or AI-based methods. Long-term follow-up data are needed to more comprehensively evaluate the sustained efficacy and durability of PRRT beyond the short-term results presented in this study.

Despite these limitations, our findings support the use of [¹⁸F]SiTATE PET for patient stratification and therapy monitoring during PRRT. Nevertheless, individualized decision-making regarding continuation of therapy remains essential, particularly in light of heterogenous imaging and biochemical responses as observed in this cohort.

In summary, SSTR PET using the novel tracer [¹⁸F]SiTATE appears to be a feasible tool for visualizing tumor burden and supporting patient selection and treatment monitoring in metastatic PPGL undergoing PRRT. While this tracer offers several practical advantages over conventional ⁶⁸Ga-labeled SSTR ligands, our findings are based on a small, retrospective cohort and should be interpreted accordingly. Notably, we observed discrepancies between PET-based, CT-based, and biochemical (hormonal) response assessments, the mechanisms of which remain unclear and warrant further investigation. Larger prospective studies are needed to explore the role of SSTR-positive tumor burden as a potential predictive biomarker and help elucidate the relationship between imaging and biochemical response patterns.