Stereotactic radiosurgery for meningioma
Article information
Abstract
Stereotactic radiosurgery (SRS) is a validated treatment option for intracranial meningioma as an upfront, adjuvant, or salvage modality. SRS was initially used as an alternative treatment for patients with unfavorable surgical risks or high-risk tumors. However, evidence from large cohort and long-term follow-up studies has consolidated the efficacy and long-term durability of SRS in the treatment of meningioma. Here, we review the current indications and patient outcomes following SRS.
INTRODUCTION
Meningiomas, originating from the arachnoid cap cells, represent the most prevalent primary intracranial tumors, accounting for 13–26% in adults [1]. The frequency of meningioma occurrence increases with age, in the overall population ranges from 2.3 cases per 100,000 people throughout their lifespan to 5.5 per 100,000 when autopsy data is taken into account [2,3]. Meningiomas are found in various regions, including the convexity (20–37%), parasagittal (13–22%, including falcine meningiomas [5%]), frontobasal (10–20%), sphenoid and middle cranial fossa (9–36%), posterior fossa (6–15%), tentorium cerebelli (2–4%), cerebellar convexity (5%), cerebellopontine angle (2–11%), foramen magnum (3%), and petroclival (<1–9%). They may also occur in intraventricular (1–5%), orbital (<1–2%), and ectopic locations [4]. Multiple meningioma may manifest due to prior radiation exposure or neurofibromatosis type 2.
According to the World Health Organization (WHO) 2021 classification, benign meningioma constitute roughly 90% of cases, with the remainder categorized as atypical (WHO grade 2) or anaplastic (WHO grade 3) [1,5]. While benign meningiomas typically display well-defined borders, they can demonstrate biologically aggressive behavior by infiltrating adjacent dura, brain tissue, and bone, thereby heightening the risk of recurrence. Currently, maximal safe surgical resection remains the preferred treatment for meningiomas, achieving complete resection can be challenging due to large tumor size, deep tumor location, and proximity to critical neural or vascular structures. Postoperative complications, neurological deficits, tumor recurrence, and mortality can be potential outcomes associated with craniotomy [6-12]. Despite subtotal resection being pivotal for alleviating mass effect symptoms, it proves insufficient as a standalone modality, with 5-, 10-, and 15-year progression-free survival (PFS) rates hovering around 50%, 40%, and 30%, respectively [13].
Stereotactic radiosurgery (SRS) including Gamma Knife radiosurgery (GKS), provides a minimal invasion, is a more efficient treatment, and has fewer complications for patients with intracranial meningiomas, and is now attracting increasing attention from neurosurgeons. Hence, alternative approaches such as SRS in single or staged sessions, along with hypo-fractionated stereotactic radiotherapy, have been employed in both primary and adjuvant settings [14-19]. In this study, we reviewed the current indications, radiobiology, and clinical outcomes following GKS for meningioma.
INDICATIONS FOR GAMMA KNIFE IN INTRACRANIAL MENINGIOMA
When considering single-session SRS for intracranial meningiomas, key factors include tumor size, ideally less than 3 cm in diameter or 10 cm3 in volume, presence of surrounding edema, and proximity to vital structures such as the optic apparatus, brainstem, pituitary stalk, and cochlea. While large symptomatic meningiomas typically require surgical removal, management choices for small or incidentally discovered meningiomas encompass watchful waiting, surgery, and SRS [20]. Radiosurgery could be considered as the initial treatment for small to medium-sized tumors showing progression on successive imaging studies. Furthermore, several authors suggested that upfront GKS for asymptomatic meningiomas could be advantageous and involve minimal morbidity, as two-thirds of asymptomatic meningiomas under observation eventually increased in size, with half of them ultimately requiring neurosurgical intervention [21]. Alternatively, it may serve as part of a combined approach alongside planned subtotal resection for tumors situated in critical areas [22]. In fact, a comparative study revealed that patients undergoing a combined approach of planned GKS following a non-radical resection led to a substantially lower recurrence rate of 10% [23]. Furthermore, staged radiosurgery has been documented for larger tumors ranging from 20 to 30 cm3, wherein two or more distinct tumor volumes are treated with an interval of several months [24].
TREATMENT PLANNING AND RADIOBIOLOGY OF GAMMA KNIFE RADIOSURGERY FOR MENINGIOMA
In modern radiosurgical protocols, it's common to prescribe a dose of 12–16 Gy to the tumor margin at the 50% isodose level [17]. Slight modifications to the treatment isodose may be implemented to guarantee optimal coverage of the tumor with the prescribed dose. Nevertheless, tumors located near radiation-sensitive critical structures may receive a lower dose than prescribed to adhere to radiation tolerance limits for these structures. These criteria consist of ensuring a maximum optic nerve dose of less than 8–10 Gy, a mean cochlea dose under 4–6 Gy, and a maximum brainstem dose below 15 Gy (with a goal of restricting the brainstem volume receiving 12 Gy to less than 10 mm3) [25]. The quantity of isocenters needed to achieve precise treatment varies depending on the tumor's shape, which can be irregular, particularly when addressing meningiomas, especially those involving the dural tail. The effectiveness of GKS treatment for meningiomas is believed to result from a dual mechanism: the suppression of tumor cell replication and the induction of vascular changes leading to fibrosis and necrosis. Upon examining the pathological samples from patients with benign meningioma following GKS, biopsies of enhancing regions are associated with inflammation, demyelination and cystic degeneration [26,27]. Biopsies taken from non-enhancing areas revealed coagulative necrosis, edema, vasculopathy, and reactive gliosis [26].
OVERVIEW OF MENINGIOMA OUTCOMES FOLLOWING GAMMA KNIFE
The tumor control rates and its long-term durability of GKS is excellent (Table 1) [17,28-34]. In a recent systematic review and meta-analysis examining radiosurgery outcomes for intracranial meningiomas, it was found that the overall rates of disease control ranged from 87% to 100% at the 5-year and from 67% to 100% at the 10-year [35]. In addition, 5-year PFS rate varied between 78 and 98.9%, while at ten years, it ranged from 53.1% to 97.2%. The comprehensive symptom management rate was 92.3%, with an overall toxicity rate of 8.1%.
Tumor control rates and long-term durability of Gamma Knife radiosurgery
In the case of benign meningiomas, numerous studies indicate that the long-term control rate with GKS surpasses 90%. Kondziolka et al. [36] examined outcomes in 972 patients with a collective total of 1,045 intracranial meningiomas. Approximately half (49%) of these patients had previously undergone surgical resection, with the mean volume of treated tumors measuring 7.4 cm3 [36]. For patients receiving adjuvant GKS treatment following prior resection, the overall control rate was 93%. Among primary GKS patients who had not undergone prior surgery, the tumor control rate reached 97%. However, outcomes were less favorable for adjuvant SRS in WHO grade 2 and 3 tumors, with tumor control rates of 50% and 17%, respectively. After a follow-up of 10 years or longer, adjuvant treatment resulted in the control of grade 1 tumors in 91% of patients (n=53). The overall morbidity rate was 7.7%, with symptomatic imaging changes occurring in 4% of cases at an average of 8 months after GKS, with a higher incidence observed in patients with parasagittal and convexity meningiomas. The authors emphasized minimal risks of radiation-induced optic neuropathy (RION) by limiting the optic apparatus dose to less than 8 Gy.
Convexity meningiomas
Meningiomas predominantly occur in the convexity region, representing about 30% of cases. In a study by Kondziolka et al. [37], 115 patients with benign convexity meningiomas were treated with irradiation, receiving a mean dose of 14.2 Gy. The 3- and 5-year actuarial control rates were reported as 95% and 86%, respectively [37]. The overall morbidity rate was 10%, with 5% of cases experiencing symptomatic peritumoral edema or adverse radiation effects on imaging. Hence, for non-surgical cases involving small to medium-sized tumors, Gamma Knife therapy offers a viable treatment option for achieving long-lasting tumor control with minimal toxicity risks.
Parasagittal/parafalcine meningiomas
Parasagittal and parafalcine meningiomas are the second most frequent sites for intracranial meningiomas. Due to their proximity to critical structures such as the superior sagittal sinus or other venous sinuses, achieving complete surgical removal can be challenging. This scenario often necessitates the use of SRS either as the primary treatment modality or as an adjunctive therapy. A study conducted by the Virginia group investigated 65 patients with parasagittal (59%) and parafalcine (41%) meningiomas. These patients received treatment with a median prescription dose of 15 Gy, resulting in 3- and 5-year tumor control rates of 85% and 70%, respectively [38]. The authors suggested that the relatively lower control rates compared to other locations could be attributed to longer dural tails, potentially leading to higher recurrence rates. Symptomatic peritumoral edema was observed in four patients (8.2%), with three patients (6.1%) experiencing temporary symptoms and one patient (2%) facing permanent clinical consequences. Additionally, two patients (4.1%) succumbed to tumor progression. In a subsequent publication from the same group focusing on cerebral edema following Gamma Knife treatment for parasagittal meningiomas, it was found that new or increased peritumoral edema occurred in 40% of treated cases [39]. The median time to peak edema was 36 months post-GKS. Persistent and progressive edema led to surgical resection in 11 tumors, while 20 patients exhibited initial edema progression followed by regression at a median of 18 months after radiosurgery (range, 6–24 months). Notably, factors such as initial tumor volume exceeding 10 cm3, absence of prior resection, and a higher margin dose were significantly associated with an increased risk of new or progressive edema after GKS.
Skull base meningiomas
An increasing number of long-term studies has provided evidence supporting the enduring efficacy, symptom stability or improvement, and favorable safety profile of GKS for skull base meningiomas. In a study by Kreil et al. [40], which included 200 patients with skull base meningiomas treated with a median marginal dose of 12 Gy and followed for at least 5 years, the actuarial PFS rate was 98.5% at 5 years and 97.2% at 10 years. Only two patients (1%) experienced transient radiation-induced edema. In 83 cases (41.5%), there was an improvement in neurological status, while it remained unchanged in 108 cases (54%) and deteriorated in nine cases (4.5%). Five patients (2.5%) underwent repeat microsurgical resection following GKS. The Virginia group reported similar long-term results for 255 patients of skull base meningiomas located in areas such as the cerebellopontine angle, clivus, petroclival, and parasellar regions [39]. Over a median follow-up period of 6.5 years (range, 2–18 years) and with an average volume of 5.0 cm3, overall tumor control rate was 86% and the actuarial PFS rates at 3, 5, and 10 years were 99%, 96%, and 79%, respectively. Cox multivariate analysis identified risk factors correlated with tumor progression, including age over 65 years (hazard ratio [HR]=3.41; 95% confidence interval [95% CI], 1.63–7.13; p=0.001) and a decreasing dose to tumor margin (HR=0.90; 95% CI, 0.80–1.00; p=0.05).
Parasellar/cavernous sinus/petroclival region meningiomas
Meningiomas situated in the parasellar region often extend into the suprasellar, cavernous sinus, and petroclival regions, posing challenges due to their proximity to adjacent neurovascular structures. Given the risks associated with complete surgical resection, GKS emerges as a viable alternative or adjunctive therapeutic approach. Involving 189 patients diagnosed with parasellar meningiomas, the study revealed a median tumor volume of 5.6 cm3. These patients underwent treatment with GKS, either as the primary approach (44%) or as adjuvant therapy, demonstrating effective control of tumor volume in 91.5% of cases. Notably, tumor progression occurred at similar rates for infield recurrences (4.2%) and out-of-field recurrences (4.2%) [41]. Out of the 54 cases where new or worsening deficits were observed, 19 were associated with trigeminal nerve dysfunction, and 18 were linked to optic nerve dysfunction. Remarkably, 90.7% (n=49) of these deficits were attributed to tumor progression, with only 9.3% (n=5) attributable to GKS (i.e., 2.64%; n=5/189). Patients who received a margin dose exceeding 16 Gy exhibited significantly improved PFS rates for up to 15 years. Early follow-up volumetric measurements conducted at the 3-year mark reliably predicted long-term volume changes and tumor volume control, with a statistical significance at the 10-year follow-up.
In a study conducted at the University of Pittsburgh involving 159 individuals who underwent 164 interventions for cavernous sinus meningiomas, 83 patients (52%) underwent primary radiosurgery [42]. Only two patients (1%) had previously undergone fractionated radiotherapy, while four patients (2%) presented with atypical or malignant meningiomas. The median dose administered to the tumor margin was 13 Gy. Improvements in neurological status were noted in 46 patients (29%), stability was observed in 99 (62%), and deterioration occurred in 14 (9%). Adverse effects from radiation were observed in 11 patients (6.7%). Tumor volumes decreased in 54 patients (34%), remained stable in 96 (60%), and increased in nine (6%). Among the 83 patients treated solely with GKS, the tumor control rate after 5 years was forecasted as 96.9%. In another study series, involving 168 patients with petroclival meningiomas treated with GKS, the overall PFS rates at 5 and 10 years were reported as 91% and 86%, respectively [43]. These patients had a median tumor volume of 6.1 cm3. Notably, tumor volume reduction was observed in nearly half (46%) of the cases, and symptom control was achieved in approximately 85% of the patients. Given the significant surgical risks and the intricate proximity to critical neurovascular structures in the cavernous/petroclival region, Gamma Knife emerges as a safe and effective management strategy for meningiomas, presenting itself as a primary treatment option for tumors of appropriate volume.
Intraventricular meningiomas
Intraventricular meningiomas (IVMs), rare tumors with challenging locations, pose considerable treatment morbidity. Research conducted at the University of Pittsburgh presents a 35-year experience in utilizing GKS for IVMs [44]. Among 19 patients with 20 meningiomas, a median tumor volume was 4.8 mL and a median margin dose was 14 Gy. PFS rates were 95% at 5 years and 85% at 10 years. In a recent systematic review identified 33 patients who received primary SRS between 1999 and 2015 [45]. The mean tumor volume was 8.7 cm3, and the mean radiation dose administered was 14 Gy. The study revealed that 67% exhibited a partial or marginal response, while 33% maintained stable disease. Notably, no disease progression was observed. SRS for IVMs demonstrates excellent treatment efficacy and low toxicity over a long follow-up period. GKS emerges as an effective and safe management option for these tumors.
Atypical and malignant meningiomas
Atypical meningiomas, comprising 5–10% of all meningiomas, pose a higher risk of local recurrence despite thorough surgical removal, prompting consideration of postoperative radiotherapy. In a study involving 18 patients with 58 atypical lesions treated with GKS and followed up for a median of 36 months, noted three cases of local relapse, five cases of marginal relapse, and seven cases of distant relapse [46]. The actuarial rates for local control were 89% at 1 year and 71% at 3 years, for marginal control were 81% at 1 year and 74% at 2 years, and for distant control were 100% at 1 year, 81% at 2 years, and 53% at 3 years, with a median distant control of 38 months. The PFS rates stood at 71% at the end of the first year, 36% by the second year, and dropped to 23% by the third year, with a median PFS duration of 18 months. Lesions receiving ≤12 Gy radiation dose had significantly higher rates of local relapse, and marginal control was notably influenced by tumor growth rate, with slower growth associated with better marginal control. The authors reported few complications with no lasting effects and recommended an expanded target volume encompassing the dural tail to optimize local and marginal control.
Malignant meningiomas have a considerably poorer prognosis due to high rates of both local and distant recurrence. A recent analysis of an extensively managed cohort revealed a median overall survival of 55 months [47]. The authors employed SRS either as an augmentation to fractionated radiotherapy or as a rescue therapy. Present evidence regarding radiosurgery indicates its potential in addressing residual or recurrent malignant meningioma, encompassing distant focal ailments. However, additional investigations are required to completely delineate this function.
The role of fractionated radiosurgery for large meningiomas
With the recent introduction of Gamma Knife ICON (Elekta AB), the possibility of hypofractionation, treating a lesion in 2–5 fractions, has become more viable [48]. This strategy may be contemplated to reduce the potential risk of radiation-induced toxicity of a single-session GKS, especially for large meningiomas located near critical structures. In a retrospective study involving 70 patients treated with GKS for meningiomas larger than 10 cm3 in volume [49], the results of those who underwent single-session treatment were contrasted with those who received fractionated treatment. Among the 42 patients in the single-session GKS cohort, the median tumor volume measured 15.2 cm3, with a median prescribed dose of 12 Gy. In the fractionated GKS cohort consisting of 28 patients, the median tumor volume was 21 cm3. The fractionated GKS group showed a higher trend of 5-year PFS rate (92.9% vs. 88.1%). Moreover, patients in the fractionated GKS group showed a reduced incidence of complications compared to those in the single-session GKS group (p=0.017; HR=5.7:1). Additional long-term studies are necessary to confirm these results.
RADIATION-INDUCED COMPLICATIONS
Radiation-induced optic neuropathy
Radiation damage to the optic apparatus can lead to decreased visual acuity, visual field impairments, or vision loss, typically occurring within 3 years after treatment. In the context of single-fraction SRS or fractionated radiosurgery, RION is relatively rare, with an incidence of approximately 1–2% in studies from the 2000s [50]. In a study by Tishler et al. [51], 62 patients treated with radiosurgery, focusing on cranial nerve tolerance, especially in cases involving meningiomas near the cavernous sinus. Twelve patients experienced new cranial neuropathies between 3 to 41 months after radiosurgery [51]. Among these, four cases resulted in optic system damage. Notably, a higher incidence of complications was observed with increasing dose to the optic apparatus. Specifically, 24% of patients receiving doses exceeding 8 Gy to any part of the optic apparatus developed visual complications, compared to none among those receiving less than 8 Gy. In a study involving 50 patients treated with GKS for benign skull base tumors, a total of 66 visual system sites and 210 cranial nerves in the middle cranial fossa were examined. The mean follow-up period was 40 months and the occurrence of optic neuropathy was dependent on the radiation dose: no cases were observed for doses under 10 Gy, while 26.7% occurred for doses between 10 to less than 15 Gy, and 77.8% for doses of 15 Gy or higher [52]. Prior exposure to radiation exhibited a crude 10-fold increase in RION risk compared to individuals with no previous radiation therapy. Among patients lacking a history of radiation therapy who underwent single-fraction or hypofractionated SRS in 1–5 fractions, maximum doses to the optic apparatus associated with RION risks of less than 1% include 12 Gy in one fraction, 20 Gy in three fractions, and 25 Gy in five fractions.
Peritumoral edema
Peritumoral edema is frequently observed in para-sagittal and parafalcine meningiomas and can be classified as either transient or persistent [39]. Transient edema may persist for several months and may necessitate a corticosteroid regimen to facilitate edema resolution. Managing persistent edema poses greater challenges due to the adverse effects profile associated with prolonged steroid use, potentially leading physicians to consider surgical resection of the implicated tumor. Recently, Kim et al. [53] developed a predictive model for post-GKS peritumoral edema using a deep-learning algorithm. They reported 13.9% of peritumoral edema including five radiation necrosis in 202 patients underwent GKS for meningioma. The deep-learning model showed a favorable predictive power [53].
Vascular complications after radiosurgery for meningiomas
Following radiosurgical treatment of meningiomas, vascular complications are uncommon but can be classified as either hemorrhage or vessel occlusion resulting in ischemia [54]. Vascular occlusion, with an incidence of 1–2%, tends to manifest in a delayed manner, often occurring 14–60 months after GKS. Case reports and experimental studies indicate that occlusion of cerebral arteries following radiosurgery occurs due to luminal narrowing related to endothelial damage—a phenomenon seemingly influenced by radiation dosage. Radiation doses surpassing 25 Gy to arteries have been linked to vascular occlusion. However, the exact mechanisms leading to hemorrhage are less clear, potentially involving vessel thrombosis, edema, and rupture in combination.
CONCLUSIONS
GKS has revolutionized the approach of numerous neurosurgeons and radiation oncologists in treating patients with meningiomas. With outcome studies demonstrating prolonged follow-up, the long-term efficacy of tumor control, symptom management, and minimal toxicity is substantiated. Despite the scarcity of reports on radiation-induced complications, it remains crucial to maintain monitoring patients, even when tumor control is satisfactory.
Notes
CONFLICTS OF INTEREST
No potential conflict of interest relevant to this article was reported.