Peptide Receptor Radionuclide Therapy in Advanced Refractory Meningiomas: Efficacy and Toxicity in a Long Follow-up

Visual Abstract

Meni ngiomas arise from the arachnoid granulation cells in the meninges, which enclose the brain and spinal cord.They are the most common type of all nervous system tumors, accounting for over 30% of all cases, with an incidence of 7.8 cases out of 100,000 (1,2).
Benign meningiomas make up about 80% of all cases and are classified as typical (World Health Organization grade I).The remaining 20% are either atypical (grade II) or anaplastic (grade III) and are characterized by a more aggressive phenotype and a shorter survival time compared with typical phenotypes.Meningiomas can be intra-or extraaxial neoplasms and are usually asymptomatic.Symptoms, such as seizures, headaches, vision loss, and other neurologic deficits, are related to the size and position of the tumor.Certain familial syndromes and exposure to ionizing radiation can increase the risk of developing meningiomas by 6-10 times (2,3).
The leading strategies in the management of meningiomas are based on tumor size, position, and grade, with treatment being particularly challenging for skull base tumors because of the presence of vital structures.
Frequently diagnosed as incidental findings in asymptomatic patients, less than 50% of the newly diagnosed meningiomas have surgical indications and may be fully resectable (4).
Nevertheless, surgical resection is the most important treatment for symptomatic meningioma patients to obtain R0 or debulking to decompress the affected areas and reduce symptoms.
Typical meningiomas are observed clinically and radiographically after the initial resection.Radiation therapy is decided on the basis of the meningiomas' grade and recurrence risk when the tumor could be surgically approached.For surgically untreatable meningiomas, radiotherapy represents a valid alternative to control local growth, but it is not as effective as surgery for symptom relief (5).
Radiotherapy is generally used after surgery for anaplastic meningiomas; however, in cases with atypical tumors, radiotherapy is not always mandatory, and the decision should be considered within a multidisciplinary board (6).
Despite some positive experiences, however, the use of radiotherapy remains the subject of controversial discussions.
At the present time, medical treatments for meningiomas remain largely experimental because of the limited results obtained.Generally, medical treatments are used in cases of recurrent or progressive disease not suitable for surgery or radiotherapy.Although drugs such as bevacizumab, sunitinib, everolimus, and different chemotherapy approaches with temozolomide, irinotecan, imatinib, and others have been tried, there is no clear evidence on the standard of care, and enrollment in clinical trials is recommended in cases of disease progression (7,8).
There is evidence that a significant percentage of meningioma cells (80%) express somatostatin receptors (SSTRs), making it possible to apply a nuclear medicine theranostic approach with 68 Ga-DOTA peptide for diagnosis and electrons for therapy with b-emitters such as 177 Lu or 90 Y (9)(10)(11).
In analogy with experiences in gastroenteropancreatic neuroendocrine tumors, for which a specific radiopharmaceutical with 177 Lu-DOTATATE is registered (12), peptide receptor radionuclide therapy (PRRT) can also be applied in other neuroendocrine or SSTR2-positive tumors.Furthermore, some published studies have shown a certain effectiveness of PRRT retreatment in neuroendocrine tumors when the positivity of the 68 Ga-DOTA peptide PET/CT persists at all disease sites (13)(14)(15).
Over time an extensive experience has been gained by applying 90 Y-DOTATOC and 177 Lu-DOTATATE PRRT to many different histotypes.Despite its proven potential, this option has been scarcely practiced in patients with symptomatic or progressive meningioma lesions (16)(17)(18)(19)(20)(21).In the present work, we report the  overall outcome for meningioma patients treated with PRRT in our institute.

MATERIALS AND METHODS
From October 2009 to October 2021, 42 patients with progressive meningiomas were enrolled in various phase II protocols (see additional information below).Initially, we used 90 Y-DOTATOC on the basis of availability, and later, when 177 Lu-DOTATATE became available, it was used exclusively.
Disease progression was assessed by MRI.The possible inclusion in a clinical trial was decided after a multidisciplinary discussion and approval (Fig. 1).The IRCCS, IRST review board, and AVR Ethical Committee approved all phase II protocols, and all enrolled subjects provided written informed consent.Patients were treated with 90 Y-DOTATOC at a dosage of 1.1 or 5.5 GBq or with 177 Lu-DOTATATE at a dosage of 3.7 or 5.5 GBq.In both cases, lower dosages of 1.1 and 3.7 GBq were reserved for patients with bone marrow or kidney toxicity risk factors.Protocols provided 4 to 5 cycles of therapy performed 5-8 wk apart.Six patients had indication for PRRT retreatment performed with 177 Lu-DOTATATE at a dosage of 3.7 GBq per 4 or 5 cycles repeated 5-8 wk apart.Favorable conditions for this indication were the absence of alternative therapies, an occurrence of symptoms or a fast-progressing disease, a pronounced benefit from prior PRRT, and the lack of G4 or protracted toxicity after the latter.
Patients were pre-and posttreated with standard PRRT amino acid infusions (22).Patients were administered 4 mg of dexamethasone intravenously once a day and 500 mL of 10% mannitol twice a day, the same day and the day after the treatment to lessen the potential of posttherapy edema in the brain lesion.Dexamethasone was also continued with a decreasing dosage for at least 10 d after therapy.
All treated patients had 111 In-octreoscan and 68 Ga-DOTATOC PET/CT (SSTR2 scintigraphy) images that were positive with high tracer concentration, with a grade of at least G3 or G4 on the Krenning scale ( 23) in all lesions, and were classified for grading according to the World Health Organization as detailed.
The tumor burden was classified into 2 different grades: 1-3 lesions were classified as moderate; more than 3 and huge lesions were classified as extended.The masked qualitative evaluation was performed by 2 highly qualified nuclear medicine doctors.In cases of disagreement, the involvement of a third expert aided in achieving a consensus.
Performance status (PS) was defined according to the Eastern Cooperative Group criteria, and patients were excluded if PS was greater than 2. Significant clinical neurologic details, including the existence of neurologic symptoms ranging from mild headaches to neurologic impairments, and the requirement for anticonvulsant or antiedema medication therapy were recorded.
Due to previous experiences with successful PRRT tolerance, the use of modest dosages and in consideration of the patient's age and general well-being, transient G1 or G2 medullary and kidney toxicities have not been reported in the present article.We decided to point out only the sustained G3 and G4 toxicity (Common Terminology Criteria for Adverse Events versions 4.0 and 5) and the side effects conditioning a subsequent cycle delay.
The response assessment was defined with morphologic diagnostic testing (MRI or CT) every 3 mo for the first 2 y then every 6 mo until progression.Response Assessment in Neuro-Oncology criteria were used to assess the radiologic response (24).Functional 111 In-octreoscan or 68 Ga-DOTA-peptide PET/CT imaging was performed 6 mo after PRRT and then was performed once a year.

Statistical Analysis
Overall data were summarized by median and range for continuous variables and by frequencies and percentage for categoric variables.
Disease control rate (DCR) was defined as the percentage of patients who achieved complete response, partial response, or stable disease at the end of PRRT.A Fisher exact test was used to evaluate the association between DCR and patients' clinical features.DCRs were reported along with 95% CIs.
Progression-free survival (PFS) was defined as the time from the start of PRRT to the date of progression or death or last tumor evaluation, whereas overall survival (OS) was considered the time from the start of PRRT to the time of death or last follow-up.The Kaplan-Meier method and log-rank test were used to compare PFS and OS among groups of patients.
According to the SSTR2 PET images, 7 patients (17%) had a lesion activity higher than that in the liver and were classified as G3 according to the Krenning scale, whereas the other 35 (83%) patients had an activity higher than that in the spleen and were classified as G4.The tumor burden was considered moderate in 16 patients (38%) and extended in the remaining 26 patients (62%).Table 1 reports the distribution of patient characteristics.

Toxicity
In our series, the treatments were well tolerated by the patients, and there were no cases of symptomatic worsening of patient conditions due to early or late toxicity.Only 1 patient had grade 3 platelet toxicity, which persisted at the time of subsequent treatment, causing therapy delay first and subsequent therapy cessation.Of the 6 retreated patients, 4 had persistent G1 anemia as side effect, whereas 1 had transient G2 toxicity for neutrophils.

DISCUSSION
Meningiomas, commonly detected in clinical practice, present a significant clinical management problem because of the high number of symptomatic patients and frequent recurrence of the tumor despite surgical treatments and primary or second-line radiotherapy (1,2).There are still certain unanswered questions about the management of meningiomas, which highlights the need for fresh therapeutic opportunities.One such opportunity is represented by the predominant SSTR2 expression, which can be used by labeling somatostatin analogs with 68 Ga for PET/CT diagnosis and b-emitting radiopharmaceuticals for therapy.
Of 42 patients enrolled, 5 were treated with 90 Y-DOTATOC and 37 with 177 Lu-DOTATATE.All patients were in a progressive status and had a positive SSTR2 scintigraphy obtained with 111 In-octreoscan in some of the first enrolled patients and with 68 Ga-DOTATOC PET/CT for the large majority.The uptake intensity was evaluated semiquantitatively in a double-masked procedure by 2 nuclear medicine expert according to the Krenning score which could be used for 68 Ga-PET/CT images.To guarantee the proper tumor irradiation, only patients with grades 3 and 4 tumors have been designated for therapy.The significant proportion of patients (83%) who had 4 uptake included in the present study could  condition the efficacy of the treatment and could be considered as a limitation.
There are currently few studies reported treating recurrent meningiomas; these studies have small cohorts and do not always indicate the number of cycles, doses, or the standard radiopharmaceutical used.In a previously published study comprising 29 patients who received 5-15 GBq of 90 Y-DOTATOC, a disease stabilization was observed in 66% of the patients and the mOS was 40 mo (16).A metaanalysis regarding 111 patients with treatmentrefractory meningiomas considered performing PRRT with a radiopharmaceutical based on either 90 Y or 177 Lu, with different DOTA-peptide and cumulative dosages (21).This study documented a 63% DCR, a 6-mo PFS, and a 12-mo OS.Both PFS and OS were correlated with tumor grade: 94% and 88% for G1, 48% and 71% for G2, and 0% and 52% for G3, respectively.
The patients involved in the present study exhibit a significant frequency of certain features linked to a poor prognosis when compared with the population of previous studies that have already been published.These findings merit additional discussion.We had a high proportion of G2 and G3 patients (72%), a high disease burden in 62% of cases, specific symptoms in 81% of patients, and a high rate of previous cytotoxic therapy (76% of cases), beginning with high levels of radiation and surgery as pretreatments (Table 1).These data indicate that all patients are in an advanced stage of disease and that their overall clinical state is progressing.
Despite the high frequency of negative prognostic characteristics in the patients, the overall results obtained for DCR, mPFS, and mOS are representative of a good treatment activity that offers in an orphan pathology a well-tolerated and effective tool (Tables 2 and 3).
Unfortunately, because of the study design, we did not have a control group.With well-known adverse effects typical of antiangiogenic medications, the mOS for mixed grades II/III meningioma in a recently published trial using bevacizumab was 24 mo.If we look to our data, GII/III meningioma patients obtained a mOS of 32.9 mo (range, 18.3-44 mo) with a good toxicity profile (26).
Data are confirmed from the active and effective results obtained in the specific 177 Lu-DOTATATE group of 37 patients with advanced disease despite only 62% of them completing at least 4 cycles.This group first confirmed the treatment homogeneity that the patient had with the different protocols with a mean injected activity of 22 GBq in 4 cycles and then showed activity and efficacy results similar to the best data already reported with 90 Y-DOTATOC (16,17).A significantly better result was obtained in patients with a lower tumor grade and only 2 previous surgeries, but in general, the higher efficacy seen in younger people, G1, less extensive tumors, better well performing and asymptomatic patients, albeit not statistically significant, suggests a reasonably better response in earlier stages of the disease.
Retreatment PRRT in relapsed patients is an interesting option also in very advanced situations when blood tests are permissive and there is a persistent positivity on 68 Ga-DOTA-peptide PET/CT lesions.This retreatment PRRT is well tolerated by patients and offers the opportunity to obtain lesion stabilization, although in a less effective way.
It is also intriguing to investigate the extremely low reported toxicity.We can first explain it by the minimal dosages used and the absence of visceral disease.Our research confirms the commonly acknowledged acceptable tolerability up to dosages of 29.6 GBq, the cumulative activity provided with the registered Lutathera (Novartis).In this work, we additionally highlight the well-tolerated PRRT retreatment to more than 37 GBq of 177 Lu-DOTATATE, as evidenced by the lack of renal and bone marrow toxicity as well as the absence of neurologic impairment.Actually, despite advancements in technology, the main limit to additional radiotherapy courses remains the risk of brain toxicity.
To the best of our knowledge, this is the largest prospective study on PRRT in patients with meningiomas with pending results of some prospective trials testing the use of 177 Lu-and 90 Y-PRRT (NCT03971461, NCT04082520, NCT03273712).
The development of dedicated clinical trials should be encouraged (27).

CONCLUSION
Our data from patients with advanced refractory meningiomas, collected in a consecutive way for more than 10 y, confirmed PRRT tolerability, highlighted a good effectiveness, and suggested its potential improvement if applied in an earlier stage.Further studies are encouraged to confirm the efficacy of salvage PRRT in meningiomas, a well-tolerated therapy that may extend disease control.Because of the preliminary data reported here, in patients with persistent 68 Ga-PET/CT positivity, retreatment with PRRT should be investigated in a larger study.The hypothetical incremental efficacy of the association of radiotherapy and PRRT have promising results and deserves further studies.

FIGURE 1 .
FIGURE 1. Flow diagram of patients selection and treatment.R/R 5 recurrent or refractory.

FIGURE 2 .
FIGURE 2. (A) 68 Ga-DOTATOC PET/CT-positive image of symptomatic patient who underwent 2 resections in 1990 and in 1992.(B) MRI from 2018 of same patient with recurrent and progressive meningioma, who also received radiotherapy (50 Gy/25 fractions) with neither disease nor symptom improvement.After multidisciplinary discussion, decision was made to include patient in our 177 Lu protocol, and after 5 cycles of 177 Lu-DOTATATE PRRT, patient obtained partial response with clinical improvement. 68Ga-DOTATOC PET/CT performed in 2022 (C) showed persistent positivity and partial response that was confirmed at last MRI on June 3, 2023 (D).

DISCLOSURE
This work was partly supported by contributions from Ricerca Corrente by the Italian Ministry of Health, innovative therapies, phase I-III clinical trials, and therapeutic strategy trials based on preclinical models, oncoimmunologic mechanisms and nanovectors, and AIRC.No other potential conflict of interest relevant to this article was reported.

TABLE 1
The median PFS and OS values and the corresponding 95% CIs were reported.All P values were 2-sided, and P values of less than 0.05 were considered statistically significant.Analyses were performed with STATA 15.1 statistical software (StataCorp).Full details can be found in the trial protocols on ClinicalTrials.gov(protocol number: IRST 100 01;