The Role of [68Ga]Ga-DOTA-SSTR PET Radiotracers in Brain Tumors: A Systematic Review of the Literature and Ongoing Clinical Trials

Simple Summary [68Ga]Ga-DOTA-SSTR PET imaging has recently been introduced in the management of patients with brain tumors, mostly meningiomas and pituitary adenomas or carcinomas. The current literature demonstrated the superior diagnostic accuracy of this imaging modality, especially for lesions difficult to be detected or characterized on conventional imaging protocols, such as skull base or transosseous meningiomas. [68Ga]Ga-DOTA-SSTR PET tracers also seem to provide superior volume contouring for radiotherapy planning and may also be used to evaluate the tumor’s overexpression of somatostatin receptors for devising patient-tailored peptide receptor radionuclide therapy. In this review, we comprehensively analyzed the current literature discussing the implementation of [68Ga]Ga-DOTA-SSTR PET imaging in brain tumors, further presenting ongoing clinical trials and suggesting potential future applications. Abstract Background: The development of [68Ga]Ga-DOTA-SSTR PET tracers has garnered interest in neuro-oncology, to increase accuracy in diagnostic, radiation planning, and neurotheranostics protocols. We systematically reviewed the literature on the current uses of [68Ga]Ga-DOTA-SSTR PET in brain tumors. Methods: PubMed, Scopus, Web of Science, and Cochrane were searched in accordance with the PRISMA guidelines to include published studies and ongoing trials utilizing [68Ga]Ga-DOTA-SSTR PET in patients with brain tumors. Results: We included 63 published studies comprising 1030 patients with 1277 lesions, and 4 ongoing trials. [68Ga]Ga-DOTA-SSTR PET was mostly used for diagnostic purposes (62.5%), followed by treatment planning (32.7%), and neurotheranostics (4.8%). Most lesions were meningiomas (93.6%), followed by pituitary adenomas (2.8%), and the DOTATOC tracer (53.2%) was used more frequently than DOTATATE (39.1%) and DOTANOC (5.7%), except for diagnostic purposes (DOTATATE 51.1%). [68Ga]Ga-DOTA-SSTR PET studies were mostly required to confirm the diagnosis of meningiomas (owing to their high SSTR2 expression and tracer uptake) or evaluate their extent of bone invasion, and improve volume contouring for better radiotherapy planning. Some studies reported the uncommon occurrence of SSTR2-positive brain pathology challenging the diagnostic accuracy of [68Ga]Ga-DOTA-SSTR PET for meningiomas. Pre-treatment assessment of tracer uptake rates has been used to confirm patient eligibility (high somatostatin receptor-2 expression) for peptide receptor radionuclide therapy (PRRT) (i.e., neurotheranostics) for recurrent meningiomas and pituitary carcinomas. Conclusion: [68Ga]Ga-DOTA-SSTR PET studies may revolutionize the routine neuro-oncology practice, especially in meningiomas, by improving diagnostic accuracy, delineation of radiotherapy targets, and patient eligibility for radionuclide therapies.


Introduction
Current imaging modalities for brain tumor diagnoses mainly comprise CT and/or MRI scans, which confer favorable sensitivity and specificity for outlining initial suspects of lesions [1,2]. However, CT and MRI scans may be insufficient to provide a detailed characterization of intracranial masses, in some cases requiring advanced imaging techniques for enhancing the differential diagnosis and supporting the pre-treatment planning of optimal therapeutic options. The increased advances and availability of positron emission tomography/computed tomography (PET/CT) imaging in oncology and neuro-oncology practices have encouraged the research and development of multiple PET radiopharmaceuticals for diagnostic and treatment purposes [1,2]. The use of radiolabeled amino acid PET tracers, which bind to specific tumor-expressed receptors, offers improved accuracy in defining the tumor-to-background contrast and in tailoring treatments [3]. More recently,  Ga) has attracted a lot of interest as an alternative positron emitter to the most common 18 F-2-fluoro-2-deoxy-D-glucose ( 18 F-FDG) [4]. 68 Ga proved to be a versatile tool in several oncology and non-oncology applications, providing a short imaging time and cost-effective cyclotron-free production [5]. In particular, 68 Ga-labeling of DOTA chelatorconjugated somatostatin analogs allows to detect and bind with high-affinity tumors expressing selected somatostatin receptors [6]. Among the different [ 68 [7,8].
In this systematic review, we comprehensively summarized the various applications of [ 68 Ga]Ga-DOTA-SSTR PET tracers in neuro-oncology practice, primarily focusing on their implementation in diagnostics, treatment planning, and neurotheranostics settings.

Literature Search
A systematic review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines [22] and registered to PROSPERO (CRD42022325392). PubMed, Scopus, Web of Science, and Cochrane were searched from database inception to 7 April 2022, using the exact search query: [(Gallium-68 DOTATOC PET OR 68 GA-DOTATOC OR Gallium-68 DOTATATE OR 68GA-DOTATATE OR Gallium-68 DOTANOC OR 68GA-DOTANOC) AND (tumor OR oncology OR neoplasm)]. Articles were uploaded to Mendeley, and duplicates were deleted. Clinical-Trial.gov was then searched in the same fashion to identify ongoing clinical trials evaluating the use of [ 68 Ga]Ga-DOTA-SSTR PET studies in patients with brain tumors.

Study Selection
A priori inclusion and exclusion criteria were defined. Articles written in English were included if they described the use of [ 68 Ga]Ga-DOTA-SSTR PET imaging in patients with brain tumors for: (1) diagnostics purposes, (2) treatment planning, (3) eligibility for therapy with DOTA-tracers β-emitting radionuclides (i.e., neurotheranostics). Articles were excluded if they: (1) were literature reviews, cadaver studies, animal studies, or study protocols, (2) described different uses of [ 68 Ga]Ga-DOTA-SSTR PET imaging not for brain tumors, (3) reported the use of different molecular nuclear medicine imaging techniques.
Two independent authors (G.W. and C.O.) screened titles and abstracts of all collected articles, and then assessed full texts of studies that met inclusion criteria. Disagreements were settled by a third author (P.P.). Eligible articles were included upon the pre-specified criteria and references were searched to retrieve additional articles.

Data Extraction
Two independent reviewers (G.W. and C.O.) extracted data, which were then confirmed by an additional reviewer (P.P.). Missing data were not reported by the authors. Extracted data included: authors, year, the reason for the use of [ 68 Ga]Ga-DOTA-SSTR PET studies, sample size, number of lesions, pathology and location, tracer and administered dose, SUV max, clinico-radiological findings.

Discussion
A growing body of literature is currently focusing on analyzing the role of [ 68 Ga]Ga-DOTA-SSTR PET studies in neuro-oncology, which have proved to be effective and safe for diagnostic and treatment planning purposes. However, the high variability in applications, SSTR2-positive diseases, and findings may pose some challenges in defining the pros and cons of their implementation in routine practice. In this review, we aimed to provide a comprehensive summary of the current literature reporting the use of [ 68 Ga]Ga-DOTA-SSTR PET for brain tumors, hoping to assist all physicians involved in the multidisciplinary management of neuro-oncology patients.

PET Imaging in Neuro-Oncology: [ 68 Ga]Ga-DOTA-SSTR Radiotracers
Although multiparametric MRI represents the current imaging gold standard in primary and metastatic brain neoplasms, PET studies have the unique and complementary ability to evaluate and characterize the metabolic patterns within the tumor and non-tumor tissues through the use of selected radiolabeled tracers [84][85][86]. The roles of different PET tracers in tumor diagnosis and post-treatment response assessment have been largely discussed and validated by international consensuses and recommendations [87][88][89][90]. [ 18 F]F-FDG and amino acid tracers (i.e., [ 11 C]C-MET, [ 18 F]F-FET, and [ 18 F]F-FDOPA) are mostly used in patients with gliomas, brain metastases, and primary central nervous system lym-phomas (PCNSL). They show variable sensitivity and specificity in differentiating tumor tissue from the normal brain tissue, distinguishing post-treatment changes from tumor recurrences, and, more recently, predicting molecular patterns and patient prognosis when implemented for radiomics analyses [91,92]. In view of meningiomas' overexpression of SSTR, especially SSTR2, [ 68 Ga]Ga-labeled DOTA (i.e., somatostatin analogue) tracers targeting SSTR, primarily developed for neuroendocrine tumors, have been largely used to allow highly selected meningioma uptake, low healthy brain tissue uptake, and, thus, higher specificity in the tumor-to-background contrast with excellent tumor visualization [59,79]. To date, three radiotracers have been implemented in neuro-oncology: (1) DOTATATE, targeting SSTR2; (2) DOTATOC, targeting SSTR2 and SSTR5; and (3) DOTANOC targeting SSTR2, SSTR3, and SSTR5. Their main drawback pertains to 68 Ga's short half-life (68 min), which makes necessary the availability of highly expensive 68 Ge/ 68 Ga generators in-house or within easy reach. Yet, the lack of patient preparation, the easy tracer synthesis, and the superior diagnostic accuracy compared to other radiotracers, make [ 68 Ga]Ga-DOTA-SSTR PET the preferred modality in SSTR-positive tumors, including meningiomas and pituitary neoplasms ( Figure 2). In addition, newer hybrid PET/MRI systems have further improved the diagnostic performances of PET studies for brain tumors, combining PET high accuracy with MRI high morphological tumor visualization [13].

Diagnostic [ 68 Ga]Ga-DOTA-SSTR PET Studies
Since the study by Henze et al. [11] in 2001, [ 68 Ga]Ga-DOTA-SSTR PET studies have expanded beyond neuroendocrine neoplasms in neuro-oncology, primarily for meningiomas, with the goal to improve tumor detection, differentiation, and extent-ofinfiltration. While most meningiomas are easily identifiable at standard MRIs by showing typical pathognomonic features, lesions with intraosseous extensions, invading the skull base, or adjacent to the falx cerebri, may pose some diagnostic challenges [63,[93][94][95]. By selectively binding to SSTR, [ 68 Ga]Ga-DOTA-SSTR radiotracers allow for targeted uptake by SSTR-positive neoplasms and high tumor-to-background contrast, offering higher accuracy in evaluating the infracranial/transosseous extent of meningiomas infiltration and detection of synchronous lesions undetected by MRI studies [31,34]. This also provides improved accuracy in preoperatively differentiating suspected meningiomas from different lesions. As confirmed by Purandare et al. [54] and Unterrainer et al. [55], [ 68 Ga]Ga-DOTA-SSTR PET can be effectively used to differentiate meningiomas against dural-based brain metastases, also when synchronous in the same patient, despite their largely similar imaging patterns at standard MRI studies. Similarly, Klingenstein et al.

Diagnostic [ 68 Ga]Ga-DOTA-SSTR PET Studies
Since the study by Henze et al. [11] in 2001, [ 68 Ga]Ga-DOTA-SSTR PET studies have expanded beyond neuroendocrine neoplasms in neuro-oncology, primarily for meningiomas, with the goal to improve tumor detection, differentiation, and extent-of-infiltration. While most meningiomas are easily identifiable at standard MRIs by showing typical pathognomonic features, lesions with intraosseous extensions, invading the skull base, or adjacent to the falx cerebri, may pose some diagnostic challenges [63,[93][94][95]. By selectively binding to SSTR, [ 68 Ga]Ga-DOTA-SSTR radiotracers allow for targeted uptake by SSTRpositive neoplasms and high tumor-to-background contrast, offering higher accuracy in evaluating the infracranial/transosseous extent of meningiomas infiltration and detection of synchronous lesions undetected by MRI studies [31,34]. This also provides improved accuracy in preoperatively differentiating suspected meningiomas from different lesions.
As confirmed by Purandare et al. [54] and Unterrainer et al. [55], [ 68 Ga]Ga-DOTA-SSTR PET can be effectively used to differentiate meningiomas against dural-based brain metastases, also when synchronous in the same patient, despite their largely similar imaging patterns at standard MRI studies. Similarly, Klingenstein et al. [40], Vay et al. [71], and Yarmohammadi et al. [72] proved that [ 68 Ga]Ga-DOTA-SSTR PET may distinguish optic nerve sheath meningiomas from other non-tumor optic pathway lesions with higher accuracy than other imaging studies, allowing for prompt surgical/radiation planning on a case-by-case basis. However, in some cases, tumors may mimic meningiomas by presenting unexpected high tracer uptake, including PCNSLs [58] or brain metastases [64] (Figure 3). Hence, despite the promising results, [ 68 Ga]Ga-DOTA-SSTR PET should still be considered only as a valuable diagnostic adjunct complementary to preoperative MRI, suitable to aid the multidisciplinary management of neuro-oncological patients but required to be confirmed by histopathology reports.  Rachinger et al. [14] defined a diagnostic threshold of 2.3 for SUVmax to discriminate meningiomas from tumor-free tissue in both pre-treatment and post-treatment settings. Although their limited cohort (n = 21) appears insufficient to universally prove their findings, which would require further external validation with larger studies, their threshold has largely been used in the literature to differentiate residual or recurrent meningiomas from post-treatment changes, such as radiation necrosis, scarring, and pseudoprogression [38,53]. Similarly, post-operative [ 68 Ga]Ga-DOTA-SSTR PET has also been studied to quantify the extent of meningioma resection in comparison to postoperative MRI and intraoperative Simpson grading, showing lower rates of falsenegative and superior detection of tumor remnants [65]. From these findings, a newer "Copenhagen grading" system, including postoperative [ 68 Ga]Ga-DOTATOC PET and biopsy confirmation of peri-cavitary "areas of doubt", has been preliminarily proposed to evaluate the completeness of meningioma resection.
The diagnostic role of [ 68 Ga]Ga-DOTA-SSTR PET studies has also been investigated in pituitary adenomas and carcinomas, in view of their SSTR overexpression. As the normal pituitary gland is characterized by physiological tracer uptake, Zhao et al. [16] showed that combined 18   Rachinger et al. [14] defined a diagnostic threshold of 2.3 for SUVmax to discriminate meningiomas from tumor-free tissue in both pre-treatment and post-treatment settings. Although their limited cohort (n = 21) appears insufficient to universally prove their findings, which would require further external validation with larger studies, their threshold has largely been used in the literature to differentiate residual or recurrent meningiomas from post-treatment changes, such as radiation necrosis, scarring, and pseudoprogression [38,53]. Similarly, post-operative [ 68 Ga]Ga-DOTA-SSTR PET has also been studied to quantify the extent of meningioma resection in comparison to postoperative MRI and intraoperative Simpson grading, showing lower rates of false-negative and superior detection of tumor remnants [65]. From these findings, a newer "Copenhagen grading" system, including postoperative [ 68 Ga]Ga-DOTATOC PET and biopsy confirmation of pericavitary "areas of doubt", has been preliminarily proposed to evaluate the completeness of meningioma resection.
The diagnostic role of [ 68 Ga]Ga-DOTA-SSTR PET studies has also been investigated in pituitary adenomas and carcinomas, in view of their SSTR overexpression. As the normal pituitary gland is characterized by physiological tracer uptake, Zhao et al. [16] showed that combined 18

[ 68 Ga]Ga-DOTA-SSTR PET for Planning Radiotherapy Protocols and/or Surgical Resection
Accurate tumor volume contouring and target definition are of vital importance for optimizing the planning of surgical resection and radiotherapy protocols. This is especially true in recurrent tumors, such as malignant meningiomas or pituitary carcinomas, characterized by aggressive invasive growth patterns, which often require high doses of radiation, and by post-treatment changes, which may pose some challenges in the delineation of target volumes using morphological imaging studies [96][97][98][99]. In addition, skull base meningiomas are frequently difficult to contour at contrast-MRI and/or CT, as the degree of bone/dura infiltration may be underestimated. As discussed above, PET elicits high tumor-to-background ratios by allowing the detection of receptor overexpression beyond the morphological extent of conventional imaging studies, offering a superior tumor visualization and target definition [100]. The use of [ 68 Ga]Ga-DOTA-SSTR PET for treatment planning has been first described by Milker-Zabel et al. [26], who imported and fused CT, MRI, and PET studies in their planning software for fractionated stereotactic radiotherapy (FSRT). The authors compared planning target volumes (PTVs) on fused PET to those on CT/MRI only, reporting improved PTV delineation in 73% of patients after PET-fused planning, which better identified the transosseous extent of meningiomas. Comparable results were also obtained in other studies, which further reported [ 68 Ga]Ga-DOTA-SSTR PET detection of additional information on meningiomas not detected at MRI [28,69] and superior target delineation of post-surgery/radiation meningioma recurrence from post-treatment tissue scarring or edema/pseudoprogression [27,29]. The role of [ 68 Ga]Ga-DOTA-SSTR PET for tumor volume contouring has been validated for FSRT [20,66], radiosurgery [17,18], and proton/carbon therapy [32,69] planning, optimizing PTV delineation, improving target dose escalation, and minimizing radiation to organs at risk, especially for the highly challenging optic nerve sheath meningiomas [18]. Likewise, d'Amico et al. [36] confirmed the potential benefits of using [ 68 Ga]Ga-DOTA-SSTR PET for radiosurgery planning in pituitary carcinomas infiltrating the cavernous sinus, as it allows precise tumor contouring of residual post-surgery volumes.
In contrast to the well-described PET-guided glioma surgery [101], the use of intraoperative [ 68 Ga]Ga-DOTA-SSTR PET for navigation-guided meningioma resection has been less investigated. To date, only Guinto-Nishimura et al. [19] reported their experience with [ 68 Ga]Ga-DOTATOC PET-guided resection of one primary intraosseous meningioma. In this technical note, the authors noted their ability to achieve gross total tumor removal by including in the resection peripheral bone areas showing high tracer uptake, which appeared macroscopically intact and extended beyond the tumor margins identified on the MRI. The postoperative pathology report confirmed the presence of tumor cells in the PETpositive peripheral bone and their absence in the specimen's surgically resected margins. In addition, the fusion of PET/CT with MRI images, coupled with their integration with the navigation system, allowed for high accuracy for intraoperatively visualizing radiological anatomical structures and tumor margins, without altering the surgeon's performance, compared to routine navigation-guided surgical protocols. Hence, [ 68 Ga]Ga-DOTA-SSTR PET-guided meningioma resection may be feasible and effective in challenging cases with great intraosseous and/or skull base extension, but further surgical studies should be conducted to analyze the surgical performances from multiple centers and operators.

[ 68 Ga]Ga-DOTA-SSTR PET for Planning Neurotheranostics Therapy
Precision medicine approaches are constantly expanding in neuro-oncology to devise patient-tailored treatments directed against individual molecular and genetic profiles, responsible for the high intra-tumor and between-tumor heterogeneity, so as to selectively target cancer cells while minimizing damage to the healthy brain tissue [102]. The development of neurotheranostics in nuclear oncology follows the same path, identifying "theranostic pairs" composed of one diagnostic and one therapeutic nucleotide with identical target molecules [103]. At first, the diagnostic radiotracer selectively binds to specific target receptors to identify the tumor's expression and molecular pathology. Secondarily, the therapeutic radionuclide is paired with the same tumor-specific biomarker and administered to deliver a dose-effective and selective radioablative dose only to the tumor tissue. Among the literature on [ 68 Ga]Ga-DOTA-based theranostic agents in neuro-oncology, the only validated theranostic pair is composed of [ 68 Ga]Ga-DOTATATE (diagnostic) and [ 177 Lu]Lu-DOTATATE (therapeutic), clinically used for meningiomas [21] or pituitary carcinomas [41,68]. Recent studies confirmed that higher SSTR2 expression by targeted tumors (evidence with higher uptake of [ 68 Ga]Ga-DOTATATE) predicts longer and more favorable treatment responses [21,41,68]. Verburg et al. [57] also demonstrated that selective transfemoral intraarterial injection of DOTATATE significantly increased tracer uptake from meningiomas, which showed insufficient tracer uptake after standard venous infusion. This technique, which proved to be well tolerated and without any risk of complications, may be further implemented in selected patients with inoperable meningiomas to provide additional treatment options. Finally, although Collamati et al. [39] devised a pilot study to analyze the safety and effectiveness of the [ 68 Ga]Ga-DOTATOC and [ 90 Y]Y-DOTATOC theranostic pair for radioguided high-grade glioma and meningioma resection, their findings still need to be externally validated before being implemented in clinical practice.

Ongoing Clinical Trials and Future Perspectives
Four ongoing clinical trials are currently evaluating [ 68 Ga]Ga-DOTATOC and [ 68 Ga]Ga-DOTATATE in patients with meningiomas [82,83], pituitary adenomas [80], and other SSTR2-positive brain tumors [81]. Three trials are focused on analyzing [ 68 Ga]Ga-DOTA-SSTR diagnostic accuracy: (1) compared to MRI for meningiomas [81]; (2) for distinguishing normal pituitary tissue versus pituitary tumors [80]; (3) for measuring post-radiation tumor response [82]; and/or (4) for correlating tracer uptake to SSTR2 expression and other tumor molecular patterns [80][81][82]. Separately, the trial led by Merrell aims to evaluate the safety and effectiveness of neurotheranostics ([ 68 Ga]Ga-DOTATATE and [ 177 Lu]Lu-DOTATATE) for meningiomas in terms of progression-free survival, overall survival, and adverse events. While the trial conducted by Filipsson Nyström [80] is set to include patients with primary untreated pituitary adenomas, the three other trials [81][82][83] are devised to involve patients with recurrent meningiomas, planning to receive radiation, and with radiologically measurable volumes. The findings achieved with these trials are expected to provide a more comprehensive and heterogeneous understanding of the benefits of [ 68 Ga]Ga-DOTA-SSTR PET studies for different populations. Future studies should also evaluate the role of intraoperative [ 68 Ga]Ga-DOTA-SSTR PET-guided resection of skull base and transosseous meningiomas in terms of surgical feasibility, additional operating time, the extent of tumor resection, and its impact on postoperative patient performance status.

Limitations
Our review has some limitations. All included studies were retrospective case reports and case series likely exposed to selection bias. Owing to the recent introduction of [ 68 Ga]Ga-DOTA-SSTR in clinical settings and the reduced availability of studies currently published, we have also included many case reports. These case reports may limit any statistical evaluation of the accuracy, sensitivity, and specificity of this technique as of the current day, but offer valuable information on the several potential uses of [ 68 Ga]Ga-DOTA-SSTR in neuro-oncology. The high costs and recent development of [ 68 Ga]Ga-DOTA-SSTR tracers may have prevented the implementation of such a technique worldwide, limiting published studies and our findings only to experiences from a few selected institutions. Due to a lack of granular data, we could neither comprehensively assess differences in SUVmax rates among different tumors nor the impact of [ 68 Ga]Ga-DOTA-SSTR PET studies on posttreatment patient outcomes. Future studies should better analyze the diagnostic accuracy of [ 68 Ga]Ga-DOTA-SSTR PET imaging compared to other imaging modalities for each type of brain tumor and how these studies impact the management of affected patients.

Conclusions
The recent development of [ 68 Ga]Ga-DOTA-SSTR PET tracers in brain tumors has provided a valuable diagnostic adjunct primarily in the management of patients with meningiomas and pituitary adenomas/carcinomas. In particular, current routine applications of [ 68 Ga]Ga-DOTA-SSTR PET imaging are shown to correlate with improved diagnostic accuracy, delineation of radiotherapy targets, and patient eligibility for radionuclide therapies. Ongoing trials are set to better define the diagnostic performance of these approaches, and future studies should evaluate the impact of [ 68 Ga]Ga-DOTA-SSTR PET studies for imaging-guided surgical tumor resections.