Radiosurgery for Intracranial Meningiomas

Abstract

The classical definition of stereotactic radiosurgery (SRS) involves administering a high dose of radiation within a limited treatment area. More recently, it has also encompassed the concept of hypofractionated radiosurgery, which involves delivering radiation over up to five treatment sessions. Intracranial meningiomas (IM) are commonly encountered primary brain tumors. Currently, there has been a rise in the number of asymptomatic individuals with IM, who subsequently require treatment due to the development and onset of symptoms. Small and medium-sized IM treatment standard options encompass radical surgery; however, this may not always be feasible due to surgical risks and patient preferences. In contrast, SRS stands out as an effective tool for managing tumor growth and alleviating symptoms. It is an outpatient procedure that eliminates the need for general anesthesia and extensive postoperative care. This holds particular significance in countries with long surgical waitlists, providing a cost-effective and low complication alternative. Furthermore, SRS plays a crucial role not only in grade I IM but also in addressing some cases of recurrent and residual grade II and even grade III IM. It also has a place in the management of radiation-induced meningioma.

1. Introduction

Intracranial meningiomas (IM) represent the most prevalent primary central nervous system (CNS) tumors in adults, with an incidence rate ranging from 8.58 to 9.15 cases per 100,000 individuals. They account for 55% of nonmalignant brain tumors within the general population of the United States [1, 2]. While most meningiomas are typically benign, their presence within the CNS can lead to significant morbidity or even mortality, thereby profoundly impacting both patient survival and quality of life. Meningiomas can originate from various locations within the dura mater, most frequently occurring within the skull and sites of dural reflection (falx cerebri, tentorium cerebelli, venous sinuses) [3].

Recognized risk factors for this condition include age > 65 years, female (double age-adjusted) [2], African-American race, exposure to ionizing radiation, and genetic factors as neurofibromatosis type II (NFII) [1]. According to studies, males are more likely to be higher grade II and III [4, 5, 6].

It is believed that these tumors originate from meningoendothelial cells within the arachnoid cap. In a prospective magnetic resonance imaging (MRI) study involving 5800 participants, incidental IM was estimated to occur in approximately 2.5% of cases [7]. These tumors exhibit a mean annual growth rate of 1 cm³, and about 11% of incidentally asymptomatic meningiomas will demonstrate growth, potentially causing symptoms if the growth rate exceeds 2.1 cm³ per year and the tumor size surpasses 4 cm in diameter [8, 9].

Meningiomas are predominantly benign (WHO grade I), accounting for 80–85% of cases, while a smaller but growing proportion in recent years is classified as atypical (WHO grade II), ranging from 15–18%. A minority of cases are categorized as anaplastic (WHO grade III), constituting 1-3% of cases [10].

The most common locations for IM are supratentorial, occurring in 40–60% of cases [11]. They can be further classified into skull base and non-skull base tumors, with subclassification based on the location of dural attachment [4]. In individuals with neurofibromatosis type II (NFII), it is possible to develop multiple meningiomas [12].

Radiosurgery, as originally described by Leksell (and later developing Gamma Knife (GK)), involves the precise delivery of a single high dose of radiation to a small and well-defined target volume [13]. This precision is achieved through the utilization of multiple radiation beams that converge on the target with the full therapeutic dose confined to the area where all these beams overlap. In contrast, nontarget areas receive substantially smaller doses from just one or a limited number of the radiation beams, with a rapid reduction in dose beyond the target to spare the surrounding healthy tissue. To enhance the accuracy of radiation targeting and delivery, an external localization system is employed [13].

One crucial requirement for successful stereotactic radiosurgery (SRS) is that the radiation target must be adequately separated from normal tissues that could be harmed by the high dose administered in a single treatment session. This technique has emerged as an effective alternative for managing selected small and medium IM [1].

In cases involving larger tumors, an alternative approach is hypofractionated radiosurgery (HSRS), which will be reviewed later.

The suggested mechanisms for restraining tumor growth involve a combination of impairment of the tumor cells’ ability to replicate and the induction of vascular hyalinization, leading to fibrosis and necrosis. Biopsies from patients with WHO grade I IM who underwent SRS treatment revealed distinct findings in enhanced and non-enhanced regions. In enhanced areas, there was evidence of inflammation, demyelination, and the development of cystic changes. Meanwhile, in non-enhanced areas, coagulative necrosis, edema, vasculopathy, and reactive astrocytosis were observed (Figure 1) [14].

Figure 1.

Radiosurgery mechanism of action. Figure created with Biorender.com.

The therapeutic approach relies on a combination of factors, including the presence of symptoms, the size of the tumor, and its location. When dealing with a symptomatic tumor that is actively growing and causing mass effect, especially if it is in an accessible location, surgical resection becomes the recommended course of action. However, if complete and safe tumor removal is not achievable, as is often the case with tumors located at the skull base, then alternative treatments may be considered. For small remaining growing tumors, radiosurgery can be employed, while fractionated radiotherapy is a viable option for larger ones [1].

According to EANO guidelines, in the case of incidental asymptomatic suspected intracranial meningiomas, it is advisable to conduct annual MRI scans over a 5-year period. This monitoring is crucial for observing any growth in the tumor or the development of symptoms that may warrant treatment. It is also essential to remain vigilant for potential cognitive deficits that could be easily overlooked during this surveillance process [15].

The primary reasons to consider SRS for IM include cases where the tumor is either asymptomatic or causing minimal symptoms, particularly when there is documented tumor growth or the potential for symptom development [12]. Additionally, SRS is a viable option in situations where the surgical risks are prohibitively high or when it aligns with the patient’s preferences. Furthermore, SRS can be considered for cases of recurrence of small to moderate size following a gross total resection (GTR) [1, 12]. An article from a Swedish group showed that in patients with deliberated non-radical IM surgery (Simpson grade IV) associated with a combined adjuvant-GK radiosurgery treatment allowed return to a low recurrence rate of 10% (similar to Simpson grade I) in tumors with a low proliferative index (direct GK SRS after tailored microsurgical resection Simpson IV gamma) [16]. An alternative approach known as staged SRS has been documented for larger tumors, typically ranging from 20 to 30 cm³ in size. These sizable tumors are divided into several manageable portions, each of which can be treated at intervals spanning months [17].

2. SRS technique

Stereotactic radiosurgery can be conducted in two primary ways. The classic approach involves a single session, during which a frame is securely fixed in place under local anesthesia, ensuring submillimeter precision. Alternatively, there is hypofractionated radiosurgery (HSRS) (i.e., Cyberknife and GK Icon), which divides the treatment into two to five fractions and a dose per fraction ≥5 Gy. In HSRS, the most frequently used dose regimen is 25 Gy delivered over five fractions [18]. This irradiation technique can be used in larger tumors or those near organs at risk (OAR). It is important to note that in such cases, specific dose constraints are adhered to the maximum allowable dose for the optic nerve is <8 Gy, for the brainstem it is <12 Gy, and for the cochlea it is <4 Gy [12].

In SRS, the most favorable outcomes are typically observed in tumors with a diameter of less than 3 cm and a volume smaller than 10 cm³ [1]. For HSRS, which is a frameless technique utilizing a thermoplastic mask, precision is paramount. Various systems, such as online navigation, as exemplified by the GK Icon, are employed to ensure the accuracy of the procedure [1, 12].

Single-session SRS and HSRS use thin slide pre/post-contrast MRI fused with a CT scan obtained with a stereotactic frame for treatment planning [1]. The treatment volume should include the entire tumor and nodular thickened dura [1]. The usual prescription dose for IM is 12–16 Gy to the tumor margin at the 50% isodose [12]. Single-session SRS with prescription dose of at least 14 Gy is associated with a 5-year control rate of ≥90% for benign meningiomas [18, 19]. Dose greater than 16 Gy is associated with a higher rate of SRS-induced edema [20].

3. General clinical outcomes with SRS

In 2008, the Pittsburg experience reported 1045 IM with a tumor control rate of 97% and 95% at 5 and 10 years in patients who underwent primary SRS. A total of 49% of these patients underwent a prior resection with a mean treated volume of 7.4 cm³, and the control rate was 93% at 5 years and 91% at 10 years. The symptom control was 93% in primary and 91% in adjuvant patients. The overall morbidity was 7.7% and symptomatic but transient imaging changes were present in 4% of patients [21]. The tumor control rate was poorer for WHO grade II (50%) and grade III (17%) [22].

The European multicenter study of Santacroce et al. involved the examination of 4566 patients with IM of an average volume of 4.8 cm³ and an average treatment margin dose (MD) of 14 Gy. Their results revealed a progression-free survival (PFS) rate of 95.2% at the 5-year and 88.6% at the 10-year. Notably, the study demonstrated a reduction in tumor volume by 58%, stability in 34.5%, and an increase in 7.5% of cases. The study documented enduring morbidity at a rate of 6.6%, with a concomitant disability incidence of 1.2% [23].

The International SRS Society published a meta-analysis with 3750 non-cavernous sinus IM from 27 studies (1964–2018) with an average volume of 5.6 cm³ for single-dose treatment with an average MD of 14 Gy and 6.4 cm³ for HSRS treated with 25 Gy in five fractions. They reported post-SRS that neurologic deterioration was from 0% to 13.3%, with a median of 7.4% according to eight studies. The meta-analysis of 6 of these studies, suggests an overall symptom control rate of 95.1% (95% CI: 92.1–97.5%). The radiation toxicity ranged from 2.5% to 34.6% (median 8.0%) in 13 papers. The meta-analysis of 11 of the studies, showed an overall post-SRS toxicity of 11% (95% CI: 6.4–16.5%) but with a high heterogeneity among the original studies [18].

4. IM locations specific outcomes

4.1 Non-skull base IM

4.1.1 Convexity meningioma

Convexity meningiomas are the most common location (30%); the preferred first option treatment is GTR (Simpson grade I or II) [12]. But in some patients, this is not possible, and SRS is an option for small to medium tumors. More detail is presented in Table 1.

IM location	Dose	Results	Comments	Reference
Convexity	14.2 Gy	Control rate at: 3 years: 95% 5 years: 86%	Morbidity rate: 10% Symptomatic tumoral edema: 5%.	Kondziolka et al. [24]
Parasagittal and Parafalcine	15 Gy	Control rate* at: 3 years: 85% 5 years: 70%	Symptomatic tumoral edema: 8.2% Permanent clinical sequelae: 2%	Ding et al. [25]
	10–20 Gy	PFS: 2 years: 98% 5 years: 90%	New peritumoral edema that progress: 14%	Sheehan et al. [26]
	12.7 Gy	Control rate at: 5 years: 91% 10 years: 89%	Symptomatic tumoral edema: 3% Symptomatic improvement: 41% Volume reduction: 61%	Martínez-Pérez et al. [27]

Table 1.

Non-skull base IM — Summary of findings from different studies.

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The study of Ding et al. achieved a low level of tumor control because treatment planning did not always cover the long dural tail.

4.1.2 Parasagittal and parafalcine

This is the second most common location and surgical resection may be limited by the anatomical involvement of the nearby venous sinuses, so there is a place for SRS as primary or adjuvant therapy [12]. Sheehan in 2015 from the same group reported about the factors that are associated with new or progressive edema: tumor volume greater than 10 cm³, a higher margin dose, and absence of prior resection [26].

4.2 Skull base

Skull base meningiomas locations include clivus, petroclival, parasellar, and cerebellopontine angle (Figure 2).

Figure 2.

Main tumor locations of IM — Skull base meningioma and non-skull base meningioma. PFS, progression-free survival; SRS, stereotactic radiosurgery. Figure created by authors using Biorrender.com.

The retrospective Austrian study from Kreil and Cols. analyzed long-term data from 200 patients with benign skull base meningioma. The median tumor volume was 6.5 cm³ treated with median MD of 12 Gy with GK. They reported a 5- and 10-year PFS of 98.5 and 97.2%, respectively. Neurological status improved in 41.5% of cases, remained unaltered in 54%, and deteriorated in 4.5%. Of the deteriorated subgroup, the majority was transient (7 of 9 patients). Treatment failure that required reoperation was reported in 2.5% of cases [28]. The retrospective American study from Starke et al. documented 225 patients with skull base meningiomas (average pre-GK volume of 5.0 cm³). In this cohort, with a median follow-up duration of 6.5 years, only 14% of cases exhibited an increase in tumor volume and 86% exhibited a decrease or stable tumor volume. PFS rates reported at 3-, 5- and 10-years were 99, 96, and 79% respectively. Neurological status deteriorated in only 10 and 90% remained unaltered or improved (Table 2) [36].

IM location	Median dose	Results	Comments	Reference
Petroclival	13 Gy	PFS rates at: 5 years: 91% 10 years: 86%	Volume reduction: 46% Symptom control: 85%	Flannery et al. [29]
	13.5 Gy	PFS rates at: 5 years: 91–100% 10 years: 69.6–89.9%	Tumor control: 94.3%; Less complications with primary SRS versus adjuvant therapy: 3.7% Improve or remain unchanged of functional status	Bin Alamer et al. [30]
Cavernous sinus	14 Gy	PFS rates at: 5 years: 86–99% 10 years: 69–97%	Neurological preservation rate post SRS: 80–100%	Lee et al. [31]
	13.5 Gy	PFS rates at: 5 years: 93.4% 10 years: 84.9% 15 years: 81.3%	Cranial nerve deficit improvement: 36.4%, primary SRS > adjuvant Widening of cranial nerve deficit: 11.5% Imaging regression: 57.8% Tumor progression: 8.5%	Martínez-Pérez et al. [32]
Parasellar	14 Gy	Tumor control rate: 6 Years: 91.5%	Tumor progression: 8,5% Direct complications related to SRS: 2.64%	Cohen-Inbar et al. [33]
Orbital	10–15 Gy	Tumor control rate: 5 years: ≈ 90%*	Volume reduction: 53.5% Remain stable: 41.6% Tumor progression: 4.7%	Xu et al. [34]
Intraventricular	14 Gy	Tumor control rate; 4 years: 100%	Volume reduction: 55% Transient perifocal edema: 37%	Umekawa et al. [35]

Table 2.

Skull base IM — Summary of findings from different studies.

^*

This study included a variety of orbital tumors. The most prominent were meningiomas.

SRS for skull base IM produces excellent tumor control with low morbidity rates compared with surgery alone for asymptomatic small skull base IM, patients with high surgical risk, and as an adjuvant therapy for recurrent or residual lesions [37].

4.2.1 Petroclival meningiomas (PCIM)

Petroclival meningiomas arise from the upper two-thirds of the clivus with dural attachment centered on the petroclival junction and medial to the V nerve [3]. If it is possible, skull base microsurgery is the first-line choice of treatment considering that GTR is the only curative option, offering immediate relief from mass effect and decompression. However, it is often impossible to achieve a complete resection due to invasion to neurovascular structures, and it is associated with high morbidity rates from 28 to 76% and mortality from 3.7 to 17% [30]. Indeed, considering the high rates of surgical complications, SRS is a low-rate complication procedure that offers high levels of tumor control and is a valid option as an adjuvant in residual or recurrent PCIM [12].

The retrospective American study of Flannery et al. reported 168 patients with PCIM (average pre-GK volume of 6.1 cm³) who underwent GK SRS (median marginal dose was 13 Gy). In this report, with a median follow-up of 72 months, only 10% of cases exhibited an increase in tumor volume and 90% exhibited a decrease or stable tumor volume. Symptoms and neurological status were controlled in 85% of cases. PFS rates reported at 5- and 10-years were 91 and 86%, respectively. Also, initial or further surgical resection were obviated in 98% of patients with a low risk of adverse radiation effects [29].

Bin Alamer et al. conducted a systematic review and meta-analysis, encompassing seven articles that involved 722 patients with PCIM. Neurovascular invasion to cavernous sinus, brainstem, and Meckel’s cave occurred in 37, 23.9, and 21.7%, respectively. Additionally, most cases were classified as WHO grade I, constituting 97.3% of the total cases [37].

The mean tumor volume was 8.1 cm³, and these patients received a marginal dose of 13.5 Gy. Primary SRS was administered to 61.9% of patients, achieving a tumor control rate of 94.3% with SRS complications at 3.7%. Additionally, 38.1% underwent adjuvant SRS, resulting in lower tumor control (88.2%) and higher rate of complications (10.3%).

Post SRS, symptoms improved in 28.7%, remained unchanged in 61.3%, and worsened in only 10%, while the functional status of primary SRS remained stable or improved. Tumor PFS ranged from 91 to 100% over 5 years and 69.6–89.9% over 10 years. The most common post-SRS complications included V deficit (15.1%), followed by hydrocephalus (9.3%), ataxia (8.1%), and dizziness (8.1%) [30].

In a clinical setting, a total safe resection is ideal, including debulking and decompression of the brainstem and cranial nerves, (especially in the case of large symptomatic tumors exceeding 10 cm³). Subsequently, adjuvant SRS is recommended for any remaining post-resection PCIM to attain effective tumor control with minimal complications [38, 39, 40].

4.2.2 Cavernous sinus meningiomas (CSIM)

Cavernous sinus meningiomas represent 10% of skull base meningiomas and are the most common primary cavernous sinus tumors [41]. In general, CSIM are benign skull base tumors with low volumetric tumoral growth [11]. According to Klinger and Cols, 34–77% of patients with CSIM showed tumoral growth within 4 years [42].

Surgery for CSIM is linked with high rates of morbidity and mortality [42, 43]. Therefore, SRS is a valid option for CSIM control either as primary or as adjuvant therapy [32].

The study of Lee et al. reported 159 patients treated with GK SRS for CSIM. A total of 52% of the patients were treated as primary radiosurgery, and 98% were benign WHO grade I. After treatment, the neurological status improved in 29%, remained stable in 62%, and worsened in 6% of patients. The results reveal that 60% of patients sustained a stable tumor volume, with an increase observed in only 6% of cases. Moreover, the 5-year tumor control rate stood notably high at 96.9% among individuals who exclusively underwent SRS as their therapeutic intervention [44].

The International Stereotactic Radiosurgery Society conducted a systematic review and guideline about the treatment with SRS for benign CSIM. They analyzed 49 retrospective studies, most of them with favorable outcomes with 5- and 10-year PFS rates ranging from 86–99% and 69–97%, respectively. The post-SRS neurological preservation rate ranged from 80–100%. Based on the observed results, SRS offers a favorable benefit-risk profile. Using single-session with a marginal dose of 11-16 Gy offers a local tumor control rate of ≥ 90% at 5 years with low risk of complication. The authors recommend the use of SRS as a primary treatment option for an asymptomatic or mildly symptomatic CSIM. The study recommended to consider SRS for tumor recurrence or progression for residual tumor [31].

In a more recent systematic review and meta-analysis of Martinez-Perez et al. analyzed seven studies, comprising 645 CSIM patients with documented long-term follow-up (more than 60 months). The calculated PFS at 5, 10, and 15 years were 93.4, 84.9, and 81.3%, respectively. Most patients had no changes in cranial nerve function; the improvement of cranial nerve deficits was found in 36.4% and worsening or new onset of cranial nerve deficits was observed in only 11.5%. The imaging regression was found in 57.8%, and tumor progression was seen in 8.5% [32].

In conclusion, these studies have shown that SRS can achieve long-term tumor control in CSIM as primary and adjuvant therapy with a low rate of complications [32].

4.2.3 Parasellar meningiomas (PSIM)

Parasellar meningiomas often extend into the suprasellar, cavernous sinus, and petroclival regions, potentially involving critical neurovascular structures. In such complex scenarios, achieving total resection can be challenging and may carry significant morbidity. In such cases, SRS presents itself as a viable alternative for both primary and adjuvant therapy [12]. In a 2018, study involving 189 patients diagnosed with PSIM and a median tumor volume of 5.6 cm³, approximately 44% of the cases underwent primary GK SRS. The findings showed a favorable tumor control rate of 91.5%, with in-field recurrences occurring at a rate of 4.2%, and out-field recurrences also at 4.2% [33]. New or worsening neurological deficits were observed in 28.5% due to tumor progression in 90.7% of patients and 9.3% due to SRS. A total of 10% involved trigeminal nerve and 9.5% optic nerve dysfunction. The early follow-up (3 years) measurements predicted long-term volume changes and tumor volume control at 10 years [33].

4.2.4 Orbital (OIM): orbital wall meningiomas and optic sheath meningiomas

Orbital IM can be divided into two groups. One group, which is implanted in orbital walls and compresses the optic nerve, which can be resected. On the other hand, the second group called optic sheath meningiomas (OSM) cannot be excised. In a series of 19 OIM implanted in orbital walls, 54% had been operated before with a mean volume of 6 cm³ and received a median dose of 12.8 Gy. A total of 5% showed better vision, 75% were unchanged, and 20% were blind in that eye [45]. A total of 20% suffered transient neuropathic orbital pain. OSM represents 2% of the orbital tumors [46, 47], and untreated, compression of the optic nerve leads to amaurosis in the affected eye. They may be primary or secondary from the extraorbital meninges and if visual impairment occurs then active therapy is indicated also because of the risk of contralateral involvement, especially in secondary origin. Surgery is only indicated in poor visual function, proptosis, intracranial extension, or contralateral growth [47, 48]. Then as Turbin et al. [49] concluded that radiation therapy was the better therapy, and more recently hypofractionated GK SRS has been reported as the therapy of choice [50, 51].

4.2.5 Intraventricular meningiomas (IVM)

Meningiomas located within the ventricles are infrequent, accounting for approximately 0.3–5% of all IM [52].

Despite recent advancements in surgical techniques, such as neuroendoscopy, the management of intraventricular meningiomas (IVM) remains challenging due to their deep-seated location and proximity to critical neural tracts. This challenging surgical scenario is associated with a notably high complication rate of approximately 33% and a mortality rate of about 1.6% [52, 53, 54]. There are few studies about SRS in IVM, in which Umekawa reported 12 patients treated with SRS GK with 14 Gy as an MD [35]. The tumor volume decreased in 58% of cases, and an additional 48% remained stable. Consequently, effective tumor control was achieved in 100% of the tumors. As adverse radiation effects (ARE) transient perifocal edema was reported in 33% of cases. Other studies report that salvage SRS for progressive recurrent tumors failed in 67% [55, 56] but better results were obtained with upfront SRS [19]. Also, ARE was reported in 28–50% of cases and being symptomatic between 5-43% [57]. The risk of symptomatic signal MRI change was older age, larger tumor volume, higher dose, presence of pre-SRS edema, and primary SRS [57, 58]. Hence, SRS emerges as a valuable approach for achieving tumor control in IVM while preserving functional anatomy, particularly in cases where there is no significant symptomatic risk, and it is associated with minimal adverse effects.

5. SRS for IM WHO grade II and III

Biopsies from WHO grade II IM show focal necrosis with 4–10 mitosis/10 HPS and brain invasion. WHO grade III or anaplastic meningioma biopsies show marked elevation of mitotic activity, harbor a TERT promoter mutation, and homozygous detection of CDKN2A/CDKN2B [59]. The management for both grades II and III includes maximal safe resection and commonly external beam radiation therapy (EBRT) after subtotal resection (STR) to reduce the incidence of tumor recurrence [60, 61, 62, 63].

The role of radiosurgery for WHO grade II and III and recurrent tumors is more controversial due to the suboptimal tumor control rates in some series and the need to treat the entire surgical bed in addition to gross disease, which is not often feasible with SRS [64]. However, several retrospective studies have reported acceptable local control with margin doses of 12–20 Gy [65, 66, 67].

More recently SRS has been performed as an alternative for EBRT as adjuvant treatment or for recurrence in patients that have already been irradiated [68]. Pollock reported 54 patients in Mayo Clinic with WHO grade II and III meningioma, which included four with radiation-induced meningioma [68]. The median volume was 14.6 cm³, and the median tumor margin dose was 15 Gy. Post SRS showed tumor progression in 30% of patients, nine patients needed repeated SRS, six required tumor resection, and three repeated EBRT. The PFS at 1 year was 76% and 5 years was 40%. Multivariate analysis showed that failure of previous EBRT was a negative predictor of PFS. The incidence of radiation-induced complications (RIC) was 21% at 1 year and 23% at 5 years. A total of 18 patients had major complications. These results may be discussed that the medium margin dose that may be needed to control grade II and grade III tumors but is not always possible because they are large tumors (median 14.6 cm³), and the fact that patients have undergone previous EBRT. Also, the fact that most of the tumor series were supratentorial with a superior rate of this complication. Another issue is to recommend SRS to those patients that have a nodular recurrence away from critical structures (ARO) after GTR in grade II tumors. But if the recurrence is diffuse in contact with optic pathways, then EBRT must be recommended. Other institutions as the University of Virginia have similar results, and they recommend adjuvant therapy depending on the residual tumor if it is medium or small SRS and EBRT for large residual volume or close to OAR. For large recurrences, they prefer repeated surgical resections, but if it is not possible, they recommend salvage SRS for focal tumors or fractionated radiation therapy for larger recurrences or widespread disease. Also, systemic therapy as bevacizumab may be considered [69].

Based on previous evidence suggests that radiation-induced immunogenic cell death increases antigen presentation and activation of immune cells, and in combination with immune checkpoint inhibitors, subverts the immunosuppressive tumor microenvironment (abscopal effect). There is great interest in combined treatments of immune checkpoint inhibitors plus radiosurgery for recurrent or grade II/III meningioma; two ongoing clinical trials are testing SRS plus Pembrolizumab (NCT04659811) or with Nivolumab Plus or Minus Ipilimumab (NCT03604978) [70, 71].

6. SRS for treatment of radiation-induced meningioma

Radiation-induced meningioma (RIM) is a late adverse effect of cranial irradiation from pediatric malignancies [72], and they must satisfy the Cahan criteria [73]. RIMs are distinguished by specific criteria: (a) the lesion must manifest within the previously irradiated field, (b) it should emerge after a reasonable time interval following the initial therapy, (c) it must exhibit radiological and/or histological differences from the preceding neoplasm, and (d) the patient must not possess a genetic predisposition to tumor development. Notably, RIMs differ from sporadic meningioma, as they often feature histological atypia, can appear at multiple locations, posing challenges for resection and local control, and generally carry a less favorable prognosis [74]. A recent multi-institutional study from 12 institutions participating in the International Radiosurgery Research Foundation reported 52 patients treated with 60 GK SRS for histological or radiological suspected WHO grade I RIMS. The initial age at cranial irradiation was 5.5 years, and the age at SRS for RIMs was 39 years. The most common reasons for RIM were leukemia (21%) and medulloblastoma (17%). There were 39 multiple RIMs, and the mean target volume was 8.61 ± 7.5 cm³, and volume of >5 cm³ predicted progression. The medium prescription dose was 14 Gy. RIM progressed in 17% of patients at a median duration of 30 months after SRS. PFS at 5 years was 83%. A total of 14% of patients developed new neurological symptoms or experienced complications post SRS from 1 to 72 months after SRS. Increased risk of progression was age, volume > 5 cm³, and multiple lesions [74].

Another study from Australia and Canada [75] reported 37 patients with 72 lesions, 62 were WHO grade I or radiologically diagnosed, six were grade II, and 4 grade III. Median volume was 2.13 cm³ a median margin dose was 13 Gy with SRS GK single-fraction treatment. Local control at 88.6% at 5 years and for grade II and III was 40% at 5 years. Post-SRS edema was developed in 23.6% of lesions and was symptomatic in 16.7%. As a general conclusion SRS is an effective option for certain patients such as poor surgical candidates or difficult surgical access with WHO grade I RIMs to achieve local control with acceptable safety profile and to those who progress after surgery as salvage therapy.

7. Hypofractionated radiosurgery (hypo SRS)

Hypofractionated radiosurgery represents a synergistic amalgamation of the favorable attributes inherent in SRS and the fractional administration of radiotherapy, thereby affording an expanded therapeutic domain while preserving the inherent attributes of precise targeting and conformal dosage dispersion. Additionally, a strategically planned application of this modality is discerned in cases following optic nerve decompression with residual tumor, thereby underscoring its nuanced clinical utility in select indications. Recently a prospective phase two trial was reported with 178 patients with large or critically located radiological (51%) or histological WHO grade I IM [76]. All patients were aged > 18, and Karnofsky performance status was > 70. Critical structures were optic nerve, chiasm, cavernous sinus, and brain stem. Local control was defined as complete response disappearance, partial as reduction of >20%, stable no change, or reduction <20% of tumor volume. The SRS mean dose was 25 Gy in five fractions with CyberKnife. The locations were skull base (87%), falcotentorial (14.8%), and supratentorial (6.4%), and mean tumor volume was 14 cm³. A total of 30% were asymptomatic and 70% presented one or more nerve dysfunction. Toxicity was 12.7% and the main events were V numbness and visual impairment. Radiation-induced optic neuropathy was observed in 5%, especially in patients with severe visual impairment before Hypo SRS. Local control was 97% at 5 years and 95% at 10 years, and partial response was achieved at 5% and stable at 45%. Only seven patients (5%) showed progression, three required surgery, and one biopsy showed an atypical meningioma grade II. In these patients, three died of progression and one of meningiomatosis progression. In 6% of asymptomatic patients, a pseudoprogression disease was observed with transient increase in tumor volume in the first 2 years after irradiation but with later tumor reduction. In conclusion, Hypo SRS is a good therapy for large IM and or for those located near OAR with good local control and low morbidity for WHO grade I IM.

8. Local experience with meningioma GK SRS treatment

Here, we present a retrospective small case series of patients with suspected IM treated with GK SRS at a Chilean radiosurgery center.

8.1 Materials and methods

8.1.1 Patient population

This is a retrospective, single-center study involving consecutive patients managed with GKRS for IM from 2011 to 2023. All data were collected in a prospective registry from the clinical patients records and then analyzed retrospectively.

201 patients who received SRS for meningioma at Centro Gamma Knife Chile during 2011-2023 were retrospectively identified. From this consecutive cohort, only 43 patients were selected for further analyses that had macroscopic tumors on baseline MRI, and additional post-SRS follow-up MRI with volumetric calculation. Irradiation treatment scheme had been recommended by experts in neurosurgery.

Data collected included patient demographics, tumor location, radiological features prior to GKRS, and at the last follow-up procedural details (e.g., radiation doses).

8.2 Radiation therapy: radiosurgical technique and gamma knife parameters

In the procedure room and under local anesthesia, patients underwent placement of a Leksell stereotactic frame. Stereotactic brain CT scanning was then obtained and fused with the preoperative, thin slice (1 mm) axial, and coronal pre- and post-contrast administration brain MRI for treatment planning. The co-registered CT and MRI images were fused in the Leksell Gamma Plan. The radiosurgical plan was formulated by the treating neurosurgeon in conjunction with a medical physicist. All patients were treated in an ambulatory setting with single-session SRS using the Leksell Gamma Knife 4C (Elekta Instruments AB). A medial marginal dose of 12.8 Gy (range from 12 to 15 Gy) was delivered in a single session with a median prescription isodose line of 48.3% (range from 35 to 60%).

8.3 Clinical and radiological follow-up

Routine clinical and radiologic follow-up was obtained at approximately 6-month intervals following GKRS. At follow-up evaluations, patients underwent a clinical examination, and new neurologic deficits were recorded. Brain MRI studies were reviewed and tumor response to GKRS was evaluated by the treating neurosurgeon (Figures 3 and 4).

Figure 3.

A 45-year-old female with a pontocerebellar angle meningioma. She was treated in may 2012 with GK SRS 13 Gy, 55% isodose. At 3 years follow-up, there was a significant tumor volume reduction (41% tumor reduction – Minor response according to RANO) [77].

Figure 4.

A 45-year-old female with a clivus meningioma. She was treated in December 2012 with GK SRS 13.5 Gy, 50% isodose. At 3 years follow-up, there was a significant tumoral volume reduction (53.5% tumor reduction — Minor response according to response assessment in neuro-oncology [RANO] criteria) [77].

8.4 Study endpoints

Tumor volumes were calculated on T1 post-contrast MRI sequences using. Tumor stability (i.e., tumor control) was defined according to the RANO criteria [77].

8.5 Statistical analysis

Statistical analyses were performed with GraphPad Prism 9 and IBM SPSS statistics.

For all statistical tests, a p-value of <0.05 was considered as statistically significant. Change in meningioma volume at last brain MRI was compared to the pre-GKRS MRI before SRS.

9. Results

In our study, we collected 43 cases of IM treated with single-dose GK SRS. All the patients were hospitalized for 1 day for stereotactic neuroimage acquisition and then treated in an ambulatory setting. A total of 70% were skull base meningioma, and 30% were non-skull base meningioma. The prescription dose ranges between 12 and 15 Gy at an isodose of 35–60%, mean dose of 12.8 Gy, and a mean isodose of 48.3% (Table 3). Only one patient from the non-skull base IM presented transient edema as a complication of SRS (2.3%). Our results showed that there is a statistically significant tumor volume reduction in the skull base IM group (mean initial volume: 5.32 cm³/last follow-up volume: 4.34 cm³) as shown in Figure 5A. This tendency was not evident in the non-skull base group (mean initial volume: 5.78 cm³/last follow-up volume: 5.36 cm³). Also, at the volumetric follow-up, all the patients at least achieved a stable disease according to RANO, as shown in Figure 5B. The mean tumor volume change at 24 months post SRS was −10,6 and −23,9% for non-SB and SB meningiomas, respectively.

Factor		Total: 43
Sex (n, %)	Male	6 (14%)
	Female	37 (86%)
Age in years (mean ± SD, range)		54.7 ± 14.2 (30–85)
Initial tumor volume (n, %)	< 5 cm^3	25 (58%)
	5–10 cm^3	12 (28%)
	> 10 cm^3	6 (14%)
	Tumor volume in cm^3 (mean ± SD, range)	5.4 ± 4.7 (0.6–25.2)
Tumor localization	Skull base (n, %)	30 (70%)
	Tentorium (n)	8
	Cerebellopontine angle (n)	6
	Petroclival (n)	6
	Clivus (n)	3
	Sphenoidal (n)	3
	Cavernous sinus (n)	2
	Other skull base (n)	2
	Non-skull base (n, %)	13 (30%)
	Falx(n)	9
	Convexity (n)	2
	Parasagittal (n)	2
Prescription margin dose (Gy) (Mean ± SD, range)		12.8 ± 0.72 (12–15)
Isodose (%) (Mean ± SD, range)		48.3 ± 4.72 (35–60)

Table 3.

Demographics for the IM patients who underwent GK SRS. SD, standard deviation.

Figure 5.

A: Meningioma tumor volume changes before and after GK SRS (at last follow-up period). Separated by skull base and non-skull base meningiomas. Wilcoxon matched-pair signed rank test showed a statistically significant tumor volume reduction in skull base meningioma group after GK (p-value of p < 0,0001); but this result was not evident in the non-skull base group (p = 0.0764). Column graph with mean and SEM. B: Longitudinal follow-up of meningioma tumor volume subsequent to treatment with GK SRS, spanning a duration exceeding 48 months. Importantly, all participants demonstrated a status of at least stable disease, as determined by the RANO criteria. Grouped graph with box and whiskers type showing minimum and maximum data. IV, initial volume; LFU, last follow-up; SB, skull base.

10. Discussion of our results

Our small series shows similar results to the literature (as shown in this review). To our knowledge, this is the first Chilean report of IM patients’ outcomes with GK SRS. All the patients were managed in an ambulatory setting. In our series, there was a low incidence of SRS-related compilations. The long-term outcomes were satisfactory because all the samples achieved at least a stable disease stage. This means that the radiosurgical procedure could achieve tumor control as shown in Figure 5B.

Interestingly, the skull base group showed a statistically significant tumor volume reduction, as well as other reported series [37].

Of the collected cases, the most common IM treated with GK SRS was skull base IM. Among these, more than 50% were tentorial, cerebellopontine angle, and petroclival meningiomas. The posterior fossa tumors are located in a critical region considering the presence of the brainstem, and in close relation with cranial nerves and vertebrobasilar circulation. Moreover, IM surgery is associated with more complications which may explain why SRS is preferred for skull base compared to non-skull base IM.

From an economic perspective, several reports have revealed that SRS treatment is less expensive than microsurgery [78, 79, 80]. The Dutch study of Tan et al. demonstrated that initial treatment cost is about five times higher for microsurgery ($12,288 euros) compared to SRS ($1547 euros for LINAC radiosurgery and $2412 euros for GK radiosurgery) [79].

For this reason, our attention is directed toward SRS as an economically viable treatment option within the domain of public health and neurosurgery. By prioritizing SRS, we aim to adopt a therapeutic approach that not only proves effective in addressing health issues but also demonstrates cost-effectiveness on a larger scale and well-being of individuals.

There are several limitations of this study, first, it is a retrospective case series of a single-center experience. Also, there is a low consecutive follow-up of patients that diminished our sample size of collected cases.

11. Conclusion

In conclusion, primary SRS emerges as a safe and valuable therapeutic option for addressing small to medium-sized symptomatic intracranial meningiomas. It boasts a high degree of tumor control while maintaining low complication rates and ensuring favorable long-term functional outcomes. It is indicated in tumors classified as WHO grade I IM that cannot be resected without important morbidity and mortality, in patients that are poor surgical candidates or by patient preferences with delayed and low radiotoxicity. Also, SRS can be used as adjuvant therapy in gross total and subtotal resection as well as recurrent small IM. It is also useful but with lower control rates in WHO grade II or III residual operated tumors with more but reasonable morbidity. Permanent morbidity is low from 5.7%. There is an alternative hypofractionated SRS for large WHO grade I tumors or that are near organs at risk with good local control and low morbidity. SRS also has a place in difficult tumors, such as radiation-induced meningiomas, to achieve local control, especially in WHO grade I that progress after surgery or as primary in poor surgical candidates with acceptable toxicity.

Furthermore, as an ambulatory therapy from an epidemiological point of view, this approach can be used to treat selected IM patients, thereby reducing the waiting list. This is especially important in countries with less neurosurgical facilities achieving a safe and low toxicity technique.