A literature search up to 30 April 2025 was conducted using the PubMed, Scopus, and Web of Science databases. Four authors (M. S., I. G., S. N., and e I. M.) suggested the terms for the research. The following terms were used: meningioma peptide receptor radionuclide therapy/PRRT, meningioma radioligand therapy/meningioma RLT, meningioma 90Y/90Y DOTA, meningioma 177Lu/177Lu DOTA, glioma peptide receptor radionuclide therapy, glioma 90Y/90Y DOTA, and glioma 177Lu/177Lu DOTA. Furthermore, a chronological filter—from 2006 to the present day—was applied to make the research more consistent and aligned with advances in imaging. The search was carried out with the addition of filters, such as English language only and humans subjects only, when possible, that is to say for Pubmed and Scopus. Additionally, filters regarding the type of articles were considered and they were: “Article” for Scopus, while for Pubmed selecting “article” was not possible, so this filter was not applied and the articles were selected later. One reviewer (I. G.) conducted the literature search. Critical appraisal was performed by two reviewers (I. G. and M. S.). and discrepancies, if any, were solved by discussion with the other authors.

Considering the heterogeneity of the studies, a meta-analysis was not performed.

A search was conducted on clinical trials.gov until May 2025. The terms for the research were suggested by four authors (M. S., I. G., S. N., and e I. M.) and included: peptide receptor radionuclide therapy/PRRT, radioligand therapy/RLT, 90Y/90Y DOTA, 177Lu/177Lu DOTA, and meningioma and glioma regarding “Condition/disease.” No additional filters were used. One author (I. G.) conducted the research.

The inclusion criteria were established by three authors (I. G., M. S., and I. M.) and included original articles and clinical studies, and the studies primarily focussed on therapeutic interventions.

Exclusion criteria were reported in Figure 1.

One reviewer (I. G.) screened each record and each report retrieved, without the use of automation tools in the process.

Two authors (I. G. and M. S.) carried out the selection process. Trials addressing neoplasms other than meningiomas and gliomas, evaluating agents other than radiopharmaceuticals, or investigating radiopharmaceuticals intended solely for diagnostic purposes were excluded as not relevant to the scope of this review.

One reviewer (I. G.) handled the extraction of the data. For any article, the following parameters were taken into account: editorial information (first author, journal, and year of publication), material and methods (study design, radiopharmaceutical used, and treatment schedules), main topics, main findings (efficacy and its endpoints, toxicity and its endpoints, the availability of a post-therapy whole-body scintigraphy WBS, single or serial studies), the number of patients, the WHO tumor grade, the presence or absence of demographic data and the follow-up times.

The studies were analyzed according to the Critical Appraisal Skills Programme (CASP) (https://casp-uk.net/casp-tools-checklists) for qualitative studies, based on ten items and questions. Two reviewers (I. G. and F. M.) filled out the form separately and, in case of discrepancy, a discussion among the authorial group was done.

One reviewer (M. S.) handled the extraction of the data. For any trial, the following parameters were taken into consideration: title, study site(s), year of first submission, investigating radiopharmaceutical, type of study, main endpoints, and current status.

A formal quality assessment was not performed, as results are not yet available.

The results of PRISMA search strategy is reported in Figure 2. From the systematic literature search, 30 papers were finally selected, including 22 papers dealing with meningiomas and eight with gliomas, for the sum of 290 patients with meningioma and of 259 patients with glioma.

Tables 1, 2 summarize the main findings of the selected studies regarding meningiomas and Tables 3, 4 summarize all the studies regarding gliomas. In Table 5, a comparison is provided between meningioma studies and glioma studies in terms of study design, radiopharmaceuticals, and main findings.

13 Studies were retrospective (59.1%), six were prospective (27.3%), two (9.1%) were pilot trials, in one case (4.5%) the study could not be classified in this sense.

In 15 studies (68.3%), patients were treated with LuPRRT; in three studies (13.6%), with YPRRT; in another three studies (13.6%), with a combination of Lu- and Y-based PRRT; and in one study (4.5%), with [¹¹¹ In]In-Pentetreotide, administered in two patients together with a beta-emitting radiolabelled peptide (13). In the case of LuPRRT, total cumulative activity (TCA) amounted between 7.4 (14) and 39.5 GBq (15). With the exception of two studies, where intra-arterial usage was required, the administration method was intravenous. In the case of intra-arterial administration, [¹⁷⁷Lu]Lu- high-affinity (HA)-DOTATATE was used: It exhibits some structural and functional differences when compared to the DOTATATE compound currently employed (16, 17). In the phase-0 PROMENADE study, the use of LuDOTA was combined with the use of [¹⁷⁷Lu]Lu-DOTA-JR11 (18). This latter agent is a radiolabelled SSRs antagonist designed for PRRT. Unlike somatostatin receptor agonists, which internalize upon binding to the receptor, JR11 binds to a broader range of SSR subtype 2 sites. This includes both internalizing and non-internalizing sites, leading to higher tumor uptake and prolonged tumor retention.

In the case of YPRRT, the TCA ranged between 7.4 GBq (19) and 15 GBq (20). In one prospective phase 2 study, which combined the use of LuPRRT and YPRRT, the cycles were repeated until progression or until toxicity manifests (21).

Safety was the main topic in 17 studies (77.3%) and the registration of the adverse events (AEs) was its endpoint (20, 22).

Efficacy was evaluated in 16 studies (72.7%), with the endpoints of progression-free survival (PFS) (2, 15, 17, 19, 23, 24), disease control rate (DCR) (2, 13, 20, 25), OS (15, 23), and time to progression (TPP) (20, 25). Response criteria were variable: In eight studies, they were based on Response Assessment in Neuro-Oncology Working Group (RANO) criteria (26); in three on Southwest Oncology Group standard response criteria (SWOG) criteria (27); and in two on Response Evaluation Criteria in Solid Tumors (RECIST) criteria (28).

WBS was performed in 16 studies (72.7%), mostly using LuPRRT. In four cases, OLINDA/EXM software was used. Dosimetry was the main topic in two studies (18, 25, 29, 30). Only two of these studies reported the use of YPRRT. In particular, one study aimed exclusively to optimize the peptide amount and activity for YPRRT, while in the other, a sub-cohort of 14 patients received co-infusion of [¹¹¹In]In DOTA⁻TOC to assess YPRRT biodistribution (20).

With regard to safety, the authors primarily focused on major toxicities, of hematological or renal nature, as shown in the synoptic table. In a study by Severi, patients were treated with YPRRT (five) or LuPRRT (37) and with different TCA, based on the presence of risk factors for toxicity. According to this study, the treatment was well tolerated, and only one patient had G3 toxicity on platelets. No deterioration of clinical conditions occurred in any case. Some authors reported no major (G3 or G4) toxicities with YPRRT (20), LuPRRT (23) or with [¹¹¹In]In Pentetreotide (13).

In other studies, toxicities were more significant. Amerein reported retrospective data on patients treated with intra-arterial HA-LuPRRT. Three patients experienced G3 thrombocytopenia, five had G3 lymphocytopenia, and one developed G4 lymphocytopenia. In addition, one patient showed transient G3/G4 renal toxicity, probably unrelated to PRRT, and another developed local necrosis likely associated with angiography. Kertels also reported higher toxicity rates in patients with meningioma and neurofibromatosis treated with LuPRRT, describing severe anemia in five cases, severe thrombocytopenia in seven and severe leukopenia in nine.

Eigler and the PROMENADE group conducted a phase-0 study on patients treated with one cycle of LuPRRT followed by two or three cycles of [177Lu]Lu-DOTA-JR11 PRRT. They reported G3 lymphopenia in two patients, and combined G3 lymphopenia and neutropenia in one patient.

Finally, in a study by Dubois, short-term toxicity prediction was retrospectively investigated in patients with SSRs tumors treated with LuPRRT. Only five of them were affected by meningioma. The authors reported considerations about the increased risk of toxicity generally, without separating between the different primary tumours, and found that risk factors were gastrointestinal primary tumor diagnosis, bone metastases, peritoneal metastases, pancreatic metastases or pulmonary metastases, and high tumor grade (31).

With regard to efficacy, DCR was investigated by Severi and it was reported of 57%. Other studies on LuPRRT reported stable disease (SD), respectively, in 8/10 patients (14, 17), in 4/5 patients (22), and in 5/6 patients (32). In patients treated with [¹¹¹In]In Pentetreotide SD was found in 5/8 patients[13]. When associated with antagonist, according to the study on [¹⁷⁷Lu]Lu-DOTA-JR11 PRRT reported above, the DCR could reach 83% (18). Together with DCR, also PFS and OS were considered. In the study by Hartrampf, patients were treated with the combination of LuPRRT and EBRT with a long-term follow-up (median of 105 months). Median PFS (mPFS) was reported ranging from 13.8 to 107.7 months, median OS (mOS) from 38.2 to 111.4 months.

To provide an alternative definition of treatment response, some researchers looked for a volumetric parameter. A study by Graillon evaluated the impact of PRRT with Lutathera in nonanaplastic meningiomas, according to the three-dimensional volume growth rate (3DVGR) measured with MRI (33). 3DVGR significantly decreased at 3, 6, and 12 months after treatment initiation, analysing each lesion separately. In particular, at 3, 6, and 12 months after treatment initiation, 4/8, 6/7, and 5/6 patients were class 2 (stabilization or severe 3DVGR slowdown), respectively. Moreover, its antitumor activity persisted for 12–18 months following treatment initiation (34).

Other studies focused on dosimetry. Hänscheid retrospectively assessed activity kinetics from planar images in patients with various tumors, including meningioma, treated with LuPRRT. Mono- or biexponential functions were applied to data from the kidneys, liver, spleen, and neuroendocrine tumor (NET) lesions. Tissue-specific deviations of the approximation from the time integral were calculated at 24, 48, 72, 96, 120, and 144 h. The authors concluded that a single quantitative measurement of abdominal activity concentration by SPECT/CT, performed four days after PRRT, could provide a three-dimensional dose map and estimate the actual absorbed doses.

In a study by Kletting, a whole-body physiologically based pharmacokinetic (PBPK) model was developed to determine in YPRRT biologically effective doses (BEDs) to the tumor, to the liver, to the spleen, and to the red marrow for a maximal kidney BED (20 Gy _2.5) for different peptide amounts and activities. The authors found that these two parameters depended on tumor perfusion and receptor density. For meningioma and for YPRRT, the optimal amount and pertaining activity was found to be 76 ± 46 nmol (118 ± 71 μg) and 4.2 ± 1.8 GBq.

Finally, to assess the short-term response to radiation therapies such as PRRT and EBRT, Reuvers et al. developed a 3D spheroidal culture model for meningiomas. The authors noticed that in general meningioma spheroids retained characteristics of the parental tumor during the initial days of culturing, but a subset of tumors veered toward a more aggressive phenotype. PRRT induced DNA damage which was detectable for an extended timeframe as compared to EBRT. Furthermore, levels of DNA damage in spheroids after PRRT correlated with SSR2-expression levels of parental tumors (35).

Follow-up times were extremely variable, ranging from 3 months (36, 37) to a median of 105.0 months (23).

Three of the included studies were prospective (39, 41, 42); one was a retrospective cohort study (40); one was a pilot trial (43); and for the other three studies, a similar classification was not possible (38, 44, 45).

YPRRT was proposed in the study by Heute on three patients. A TCA of 1.7–2.2 GBq was delivered in three or four cycles and locally injected into a previously implanted catheter system every 3 months (38).

LuPRRT was proposed in a study by Nemati, who treated 16 patients for 1–4 cycles every 1–2 months and with a TCA of 3.7–26.9 GBq.

Other radiopharmaceutical used were:

LuPSMA was considered in one study (40). Several previous studies had shown that PSMA is overexpressed in the tumor-associated neovasculature of high-grade gliomas (46–48), so building on this premise, 20 patients were firstly evaluated with [⁶⁸Ga]Ga-PSMA PET/MRI (PSMA PET). Three of them likely to benefit from LuPSMA according to the maximum tumor-to-background ratio (TBRmax) of tumor and liver, which had been chosen by the authors as a criterion for recommending LuPSMA, with a predefined cut-off set at 1. In 11 samples, immunohistochemical PSMA expression was determined using the H-score (49) and correlated with uptake on PSMA PET. The H-score in the three patients eligible for LuPSMA was higher than the H-score in patients who were not (respectively 65 versus 30, p = 0.08). While this review primarily focuses on primary brain tumors, it is essential to recognize that LuPSMA may play a role also in brain metastases, according to recent evidence from the literature (50).

In seven studies, safety was the main topic and the registration of the adverse events (AEs) its endpoint (38, 41–43, 45). Four studies regarded efficacy, in terms of recurrence-free survival and DCR (38, 39, 45).

One study regarded dosimetry (44). It was conducted through injections of [¹¹¹ In] In-substance P and [⁹⁰ Y] Y-substance P in 12 patients with malignant gliomas. Over a period of 24 h, serial SPECT scans were performed on a dual-head SPECT camera. Quantitative voxelwise dose distribution maps (in Gy/ GBq) were computed from these data and pre- and post-therapeutic values were compared.

WBS was performed in all studies, except for two (41, 45).

With regard to toxicity, in the case of radioimmunotherapy (RIT), the combination with temozolomide (TMZ) was not associated with an increase in toxicity. Adverse events occurred in seven patients (3.6%), and were generally mild, including flushing, nausea, hypotension, and local skin irritation at the injection site. Only four patients developed human anti-mouse antibodies (HAMA). Regarding the studies on TAT, neurotoxicity appeared to be minimal. In the case of [¹¹¹ In]In/[⁹⁰Y]Y –DOTAGA substance P, no short-term side effects were observed, too; moreover, intraoperative bleeding appeared to be reduced. For YPRRT, side effects were mild and an overall improvement in quality of life was reported (38, 41, 42).

In terms of efficacy, the combination of TAT and substance P provided a recurrence-free survival time ranging from 2 to 16 years. This was observed in eight patients with astrocytoma, who were treated with TAT following a biopsy or tumor debulking. Regarding oligodendrogliomas, the recurrence-free survival time was 24 years in the first case treated and 4 and 5 years in the two second-line cases, with low toxicities (45). Furthermore, the use of YPRRT in three patients showed the following results: One patient had a complete response (CR) and two patients a partial response (PR) at follow-up imaging with ceMRI, DOTA PET, [18F]F FDG PET, and [18F]F Fuoroethyltyrosine PET. Clinical improvements and a global improvement in quality of life (qol) was noticed, too (38). Finally, in the study by Nemati on LuPSMA, the radiological response according to RANO criteria was considered: Two patients showed a CR, five patients a PR, three patients a SD, and six patients a progression disease (PD). No significant improvement of qol was noticed.

With regard to the dosimetric study, it was found a very good agreement between pre- and post-therapeutic dosimetry and a good correspondence between the pretherapeutic test injection and the dose deposition (44).

In most cases, the follow-up period was not clearly defined. In one study, it ranged from 1 to 24 years (median 10 years) (45); in another, patients were monitored for up to 15 weeks (40); and in a third study, the follow-up period ranged from 1 to 26 months (39).

The results of CASP analysis is reported in detail in Table 6 and Figure 3 for meningiomas and in Table 7 and Figure 4 for gliomas. Below, the most noteworthy data are summarized.

Regarding meningiomas, with the exception of one paper, all of the works had clear aims. The statement of findings was evidently reported in 20/22 (91%) of the papers, too. The general quality of the researches and the quality of the methodology, of the study design, of the recruiting strategy, and of the data analysis were variable. In more detail, the quality of the methodology was considered appropriate in 16/22 (72.7%) of the studies, and the study design was considered adequate in 17/22 (77.3%), as was the recruiting strategy. The overall value of the research was found high in 5/22 (22.7%) of the papers, moderate in 11/22 (50%) of them, and low in 6/22 (27.3%).

Regarding gliomas, all of the works had clear aims but one, as well as regards the clear statements of findings.

The following parameters, however, showed variability: The ethical issues, which have been taken into consideration in five out of eight studies, the quality of the methodology, which was considered as appropriate in six, the quality of the research design, considered as appropriate in six, the quality of the recruiting strategy, considered as adequate in four.

The general quality of the research resulted high in four studies, moderate in two, and low in two.

The results of the search strategy is reported in Figure 5.

Fourteen studies on meningiomas and eight on gliomas were included in the final analysis. The characteristics of the trials on meningiomas and gliomas are presented in detail in Tables 8, 9, respectively, so what follows is strictly an overview of the trials.