*3.1. Pretreatment PET Imaging vs. Routine SSTR Expression Assessment*

Before PRRT can be considered for meningioma treatment, PET imaging is used to provide important information about the expected treatment efficacy. PET imaging with 68Ga-labeled somatostatin analogs is used to estimate the potential for radionuclide uptake in meningioma tissue during PRRT. Similarly, this method was demonstrated in an imaging study of 11 meningioma patients who underwent several whole-body and single-photon emission computed tomographies (SPECT/CT) during PRRT to assess the radionuclide kinetics [39]. Furthermore, a correlation between the DOTATATE/-TOC PET imaging signal and the response to PRRT was demonstrated in a retrospective analysis of 20 patients suffering from recurrent or high-grade meningioma. The authors also performed immunohistochemical staining of SSTR2A and observed that a high expression signal was associated with improved 6-month progression-free survival [50].

Only a few studies have investigated the expression of the different somatostatin receptors in meningioma tissue, and different methods were applied in these studies. Our recent retrospective analysis described the distribution of the immunohistochemical expression of all five somatostatin receptors in 726 meningiomas, which is the largest analysis of this kind so far [24]. Whether a certain level of SSTR expression is associated with PRRT efficacy is unclear. Currently, SSTR expression as assessed by PET imaging is used to predict treatment efficacy. However, additional immunohistochemical studies on the distribution of SSTRs, and especially their correlation to DOTATATE/DOMITATE PET data, are still warranted. This would allow the definition of an immunohistochemical scoring cutoff that may have predictive value regarding PRRT. Because immunohistochemical staining is easy to perform and analyze, it could be integrated in the routine meningioma workup and possibly replace the more expensive PET imaging for the pre-PRRT assessment. However, the expression of SSTRs may not be homogeneous throughout the entire tumor tissue. Consequently, the immunohistochemical detection of SSTRs and the calculation of total SSTR expression from intraoperative tumor samples may not be representative of the whole tumor. Moreover, SSTR expression may change over time, and the immunohistochemical results from tumor tissue that was resected several years ago may not be representative of the tissue in a recurring tumor later in the disease course. Therefore, a noninvasive assessment of whole-tumor SSTR expression through PET imaging will probably remain a practical, useful, and reliable alternative, despite its costs. Additionally, more experience with grading SSTR expression must be gained, and a standardized scoring system needs to be established.

#### *3.2. Development of New Substances and the Potential of Tailored PRRT*

Peptide receptor radionuclide therapy to treat meningiomas is based on its interaction with the somatostatin receptor 2A expressed in meningioma cells. The somatostatin analog applied in PRRT is octreotide, which has a high affinity to SSTR2A [51–53]. Patients who suffer from a meningioma that does not show sufficient SSTR expression through PET imaging should theoretically not be considered for PRRT. Our recent retrospective analysis has demonstrated that SSTR1 and SSTR5 are also highly expressed in many meningiomas. SSTR3 and SSTR4, by contrast, show low immunohistochemical expression [24]. However, there is currently very little knowledge about the link between immunohistochemical somatostatin receptor expression and treatment efficacy. A strong immunohistochemical signal does not necessarily mean that the PRRT will be effective. In our opinion, if the indication of this treatment approach is to be widened, it is crucial to explore the targetability of somatostatin receptors other than SSTR2A. An important factor that supports this idea is the variability of the distribution of SSTR expression among clinical subgroups. For example, SSTR2A expression is significantly lower in neurofibromatosis type 2 meningiomas [24]. Therefore, alternative substances to octeotride should be considered as a vehicle for PRRT. For example, pasireotide has a high affinity to somatostatin receptors 1, 2, 3, and 5 [54], making it a potential candidate for a more efficacious PRRT. In addition, it has not yet been shown whether PRRT would be more efficacious if it were directed towards multiple SSTRs. Extending this idea leads to the prospect of applying a patient-tailored mixture of PRRT vehicles designed after a thorough tissue or imaging analysis of the somatostatin receptor profile of an individual meningioma. Routine immunohistochemistry seems to be an ideal tool for this because it is inexpensive and easy to implement. However, standardized scoring is necessary to ensure comparable results. We utilized the scoring system described by Barresi et al., 2008, which incorporates the staining intensity and area of immunopositivity into a product called the intensity distribution score [25]. Computational quantification can potentially eliminate interobserver variance, which is the main limitation of this score.

Another point which could ensure a better efficacy of PRRT is, as already mentioned in the previous chapter, the intra-arterial application of PRRT. Vonken et al. were able to demonstrate a higher tracer accumulation in the tumor tissue [42]. Apart from another case report and a small study [41,43], which also showed a better uptake in meningioma, further studies are missing. It would therefore be desirable to conduct future studies on the effect of intra-arterial application on the difference in efficacy, overall survival and progression-free survival.

#### *3.3. Refining PRRT through Preclinical Models*

Preclinical research in animal models may also help to develop novel personalized therapies by refining the in vivo evaluation of receptor expression in multiple tumor entities. For example, high SSTR2A affinity to radiolabeled octreotide has been previously characterized in rats [53]. Moreover, Soto-Montenegro et al. successfully demonstrated the feasibility of imaging somatostatin analogs using PET/CT in a mouse meningioma xenograft model [55]. Our literature review found that although several meningioma animal models have been established [56,57], preclinical PRRT evaluations are still extremely limited. Specifically, the preclinical evaluation of receptor subtypes focusing on affinity and distribution in multiple tumor grades is lacking. We believe that this information would be highly relevant to validate novel radiopeptide candidates.

Preclinical research has focused on improving the current SSTR2A analogs. For example, the theranostic treatment efficacy of 67Cu-CuSarTATE was shown to be similar to that of 177Lu-DOTATATE in a mouse pancreas tumor model, identifying a novel agent for dosimetry calculation in humans [58]. SSTR2 expression has also been demonstrated in tumor models of pheochromocytoma, small cell lung cancer and thyroid cancer in mice [59–61]. Recent work has also focused on the evaluation of SSTR2 using 177Lu-DOTATATE in combination with small-molecule poly (ADP-ribose) polymerase-1 (PARP) inhibitors, which showed an increased antitumor efficacy in mice [62].

In our opinion, more knowledge is needed about the distribution of SSTRs other than SSTR2A, in order to expand the armamentarium of PRRT. At the same time, more data is required regarding the dynamics of receptor expression in the tumor over time and the influence of adjuvant treatments, such as radiotherapy on SSTR expression. This could be easily accomplished preclinically, where noninvasive in vivo PET imaging can be performed longitudinally and be directly corroborated by immunohistochemistry. This could also provide preliminary evidence on treatment efficacy and the receptor expression profile of specific tumor types. At the same time, these experiments would increase the characterization and evaluation of novel theranostic radiotracers poised for clinical application.
