**1. Introduction**

With an incidence of 8.81/100,000, meningiomas are the most common primary intracranial tumor [1]. These slow-growing tumors develop along the meningeal coverings of the cerebral convexities, skull base, and spine, and in rare cases even within the ventricles. Depending on the size and location, a variety of different symptoms and syndromes can emerge [2]. Treatment is advisable for lesions that show concerning growth, cause symptoms, or have a significant size in a critical location. Most meningiomas can be effectively treated by surgical resection. Radiation therapy can be applied in selected cases but is particularly important in recurrent cases or for meningiomas that are histopathologically graded as more aggressive [3]. Other than surgery and radiation, there are no established treatment modalities outside of previous clinical trials [4]. The management of meningiomas that recur after resection and radiation treatment remains especially challenging, and alternative treatment options are urgently needed. Targeted therapies based on molecular aberrations [5] are currently under investigation in several clinical trials, with a focus on high-grade and recurrent meningiomas (e.g., NCT02648997, NCT03279692, and

**Citation:** Fodi, C.-K.; Schittenhelm, J.; Honegger, J.; Castaneda-Vega, S.G.; Behling, F. The Current Role of Peptide Receptor Radionuclide Therapy in Meningiomas. *J. Clin. Med.* **2022**, *11*, 2364. https://doi.org/ 10.3390/jcm11092364

Academic Editors: Arnoldo Piccardo and Francesco Fiz

Received: 24 March 2022 Accepted: 20 April 2022 Published: 23 April 2022

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NCT03631953). However, an innovative treatment option for recurrent meningiomas has been applied in difficult cases. Peptide receptor radionuclide therapy (PRRT) utilizes the expression of somatostatin receptors (SSTRs) in meningioma tissue. Somatostatin analogs coupled to a radionuclide apply radiation directly to tissue that expresses somatostatin receptor 2A, such as meningioma cells [6,7]. In recent years, this targeted treatment approach has been investigated for use against meningiomas. This review focuses on the current use of PRRT to treat meningiomas and provides an outlook regarding its potential future therapeutic role.

#### **2. Peptide Receptor Radionuclide Therapy**

#### *2.1. Somatostatin Receptors*

Somatostatin receptors, through which somatostatin exerts its effects, were first described in 1978 by Schonbrunn and Tashjian [8]. Five different subtypes have been discovered in humans and other mammals. The SSTR2 subtype has one intron, which can result in two different receptors, SSTR2A and the SSTR2B, by alternative splicing. The remaining subtypes do not possess introns [9]. However, SSTR2B has only been detected in mouse tissue, and it is unclear whether this subtype is also expressed in humans [10]. These G protein-coupled receptors are composed of glycoproteins [11] and are membranebound with seven alpha-helical transmembrane domains [10]. They have an extracellular N-terminal end, which is responsible for binding the specific ligand somatostatin. The Cterminal end is intracellular and transmits signal transduction [10] through a heterotrimeric G protein that consists of an α-, β-, and γ-subunit and triggers different intracellular pathways with the help of GTP. Upon binding of a ligand to the SSTR, the cascade further triggers activation or inhibition of cytoplasmic targets via membrane-bound proteins [12]. Examples of commonly triggered pathways include the adenylate cyclase and the phospholipase C system, which act as signal amplifiers. However, the direct stimulation of potassium or calcium channels can also be triggered to achieve the desired effects [13,14]. Somatostatin is involved in numerous physiological regulatory mechanisms in several different organ systems, including the inhibition of endocrine and exocrine secretions, gastrointestinal motility and nutrient absorption, and neurotransmitter regulation [15].

A central task of SSTR is the inhibition of cell proliferation. The antiproliferative effects of somatostatin and its receptors are mediated through several mechanisms. SSTR2 and SSTR3 can induce apoptosis of single cells via p53 or independently of p53. SSTR1, SSTR4, and SSTR5 can induce cell arrest in the G1 phase of the cell cycle via the modulation of mitogen-activated protein (MAP) kinase [16]. There are numerous other modes of action of SSTRs that are reserved for their respective tissues. SSTRs occur in varying densities and in different expression patterns. They are found in the brain, pituitary gland, and peripheral nervous system. In the gastrointestinal tract, they are found in large numbers in the stomach, duodenum, jejunum, and pancreas. They are also present in the kidneys, adrenal glands, thyroid gland, and immune cells [11,17,18].

An important discovery was the expression of SSTRs in a large variety of tumors, including most neuroendocrine tumors, such as gastroenteropancreatic neuroendocrine tumors (GEP-NETs) and carcinoids. SSTRs also occur in renal cell carcinoma, breast cancer, and lymphoma. Furthermore, SSTRs are expressed in brain tumors, such as glial tumors, pituitary adenomas, and meningiomas [18,19]. Studies conducted on meningiomas have shown the presence of all five different SSTR subtypes in varying degrees of expression. SSTRs could be detected by immunohistochemistry and by mRNA identification with RT-PCR [20–24]. In these studies, SSTR2A showed the strongest expression [20–23,25]. We performed a large retrospective analysis of immunohistochemical expression of all five SSTRs in 726 meningiomas. This large cohort also showed strong expression of SSTR1 and SSTR5 and different expression patterns within various clinical subgroups, such as neurofibromatosis type 2 and WHO grades II and III meningiomas [24].

Whether somatostatin expression is linked to tumor proliferation or progression remains unclear, especially because its main function is essentially antiproliferative.

#### *2.2. History and Development*

In 1987, Krenning et al. examined 1000 patients with various tumors by octreotide receptor scintigraphy (Octreoscan) to visualize SSTR expression. It was hypothesized that tumors showing high uptake may respond well to therapy with somatostatin analogs [26] because somatostatin exerts an antiproliferative effect. Furthermore, the idea of combining somatostatin with radiation was developed so that the radiation dose could be directly delivered to the tumor tissue. These so-called "theranostic substances", with diagnostic (peptide receptor scintigraphy) and therapeutic (peptide receptor radionuclide therapy) features, were first used in neuroendocrine tumors [27]. The first instance of PRRT was in the early 1990s for a patient with metastatic glucagonoma, which resulted in tumor growth impairment as well as decreasing levels of circulating glucagon [28].

Initially, 111In-DTPA octreotide, which emits Auger and conversion electrons, was applied for PRRT, with SSTR as the target. However, this compound exhibited affinity exclusively for SSTR2 and was additionally not suitable for commercially available ßemitters such as 90Y and 77Lu. Therefore, other somatostatin analogs such as DOTATOC and DOTATATE were coupled with the corresponding ß-emitters to form 177Lu-DOTATATE and 90Y-DOTATOC [29] and used in subsequent studies. PRRT was increasingly used in the treatment of neuroendocrine tumors. It is often applied for metastasized tumors for which the usual treatment methods, such as surgery or localized radiation therapy, are no longer suitable options. Often, standard chemotherapy is no longer sufficient or does not achieve adequate symptom control. In these cases, treatment can be carried out with PRRT [29–31]. The phase III NETTER-1 trial demonstrated that PRRT significantly improved the quality of life and progression-free survival of patients with midgut neuroendocrine tumors who received 177Lu-DOTATATE and high-dose octreotide [32]. With the knowledge that several tumor types highly express SSTRs [33], PRRT has also been used therapeutically for other tumor types as an individual curative attempt after the exhaustion of current treatment methods [34–36].

In many cases, meningiomas can be cured by surgical excision or stabilized radiation therapy [3]. However, sometimes these treatments are not sufficient, and it becomes difficult to treat recurrences or multifocal occurrences of meningiomas; for example, a meningiomatosis cerebri. This often affects patients suffering from neurofibromatosis type 2 (NF2) or tumors corresponding to WHO grades II or III. Through various studies, we know that virtually all meningiomas express SSTRs, although to a varying extent [20,22,24,25,37]. This has been recognized as an opportunity to apply PRRT in individual cases of advanced meningioma [29,38].

#### *2.3. Clinical Application and Experience in Meningioma*

Certain conditions must be met to perform PRRT. To assess whether there is sufficient receptor expression, the standard procedure prior to therapy is to detect it via peptide receptor positron emission tomography (PET), e.g., with 68Ga. This also includes imaging the kinetics of the therapeutic substance [39]. Once sufficient receptor expression has been determined through PET imaging, the patient becomes a candidate for therapy. Somatostatin analogs, such as DOTATOC or DOTATATE, which bind to SSTRs (particularly SSTR2A), are administered intravenously. The administered peptides are coupled to a ßemitter, usually 90Yttrium (Y). This coupling allows the systemic delivery of a cytotoxic level of radiation to individual target cells expressing SSTRs [40]. In addition, adjacent tumor cells that do not necessarily express SSTRs are also irradiated. Alternatively, small studies and case reports have shown that intra-arterial administration of the radiopharmaceutical increases the uptake in meningiomas [41–43].

However, there are no specific guidelines regarding this treatment for meningiomas, but general standards for PRRT in NETS are applied. A glomerular filtration rate of at least 40 mL/min or a creatinine value <2.0 mg/dL must be present in order to assure sufficient clearance and to maintain functional organ reserve because the treatment is nephrotoxic. Likewise, there is a risk of hematotoxicity and pretherapeutic cutoffs for

platelet and leukocyte count and hemoglobin need to be considered. Therefore, regular monitoring is necessary, which may lead to a pause in treatment [44]. There could also be a risk of acute bone marrow toxicity, particularly in patients who received extended external beam radiation or myelotoxic chemotherapy before PRRT. The number of cycles for non-compromised patients varies from two to five for 90Y-DOTATATE/-DOTATOC and 177Lu-DOTATATE/-DOTATOC. The time interval between cycles ranges between 6 and 12 weeks. The approved activity levels range from 2.78–4.44 GBq for 90Y-DOTATATE/- DOTATOC and from 5.55–7.4 GBq for 177Lu-DOTATATE/-DOTATOC. Therapy needs to be adjusted for patients with restricted renal function or borderline bone marrow capacity [45].

Currently, there are only a few studies on PRRT for meningiomas with small patient cohorts. However, some have shown stabilization of the disease. In one study, 5–15 GBq of 90Y-DOTATOC was administered to a group of 29 patients with recurrent meningiomas, and disease stabilization was observed in 66% of the patients [6]. Another study demonstrated that a combination of external beam radiation therapy (EBRT) and PRRT was well-tolerated in patients with unresectable primary or recurrent meningioma and resulted in disease stabilization in 7 of the 10 patients [46]. These results confirmed the findings of a previous analysis of the outcome of patients treated with EBRT and PRRT in combination. In that study, ten patients with unresectable WHO grades I or II meningiomas experienced disease stabilization [47]. PRRT was also investigated in patients suffering from NF2. They received four cycles of 177Lu-DOTATOC with a median activity of 7.4 GBq. Tumor stabilization occurred in six of eleven patients [48]. A meta-analysis regarding PRRT in meningiomas was performed by Miriam et al. They included 111 patients with treatmentrefractory meningiomas, and 63% achieved disease control. The 6-month progressionfree survival rates and the 1-year overall survival decreased with higher WHO grades. Explicit guidelines for the treatment of meningioma using SSTR-targeted PRRT have still yet to be internationally established. However, the mentioned comprehensive metaanalysis recently evaluated SSTR-targeted PRRT using 90Y-DOTATOC, 177Lu-DOTATOC, 177Lu-DOTATATE, or combinations in histologically validated meningioma [49]. The evaluated studies in the meta-analysis applied SSTR-targeted PRRT on treatment-refractory meningioma patients with exhausted conventional treatment modalities such as: surgery, fractioned or stereotactic radiotherapy, or chemotherapy prior to SSTR-targeted therapy. Before the start of therapy, intense SSRT-expression was confirmed in the meningiomas using PET/CT. Independent of the tumor grade for up to six cycles of therapy, a median of 12,590 Mbq (range: 1688–29,772) was applied for treatment. Manageable mild transient hematotoxicity (anemia, leukopenia, lymphocytopenia, and thrombocytopenia) was the major side effect co-occurring under PRRT and as such, constant evaluation of hemoglobin, granulocytes, leukocytes, and thrombocytes is warranted before and between PRRT cycles. Overall, PRRT showed a positive treatment effect with manageable side effects. Treatment response was evaluated using different radiological assessment protocols finding favorable overall survival in the combined outcome of all studies [49].

The meta-analysis underlines the small number of cases that have been published so far. At present, no larger controlled trials have been conducted. One randomized trial is currently recruiting patients with recurrent or progressive meningiomas for treatment with the radiolabeled somatostatin antagonist 177Lu-satoreotide (PROMENADE study, NCT04997317). An overview of the studies already conducted can be seen in Table 1.


**Table 1.** Studies that have investigated the effect of PRRT on meningiomas.

PFS: progression-free survival. OS: overall survival. PFS and OS are given as mean values.
