Introduction

Meningiomas are the most common primary intracranial tumors and account for more than one-third of all brain tumors [1]. Based on local invasiveness and cellular features of atypia, meningiomas are histologically characterized as benign (grade 1), atypical (grade 2), or anaplastic (grade 3) tumors by the latest World Health Organization (WHO) classification scheme [2]; accordingly, the proportion of meningiomas that have been classified as atypical and anaplastic meningiomas is around 20–25% and 1–3%, respectively [3]. For both, surgical resection is the first choice of treatment; however, a significant proportion of tumors display a more aggressive behavior associated with an approximately 6–8-fold increased risk of recurrence and a significantly higher risk of dying of tumor progression compared to benign meningiomas [4, 5].

Beyond surgery, external beam radiation therapy (RT) has been usually recommended to increase local control after resection of grade 2 and 3 tumors [6]. The evidence supporting this treatment recommendation largely comes from systematic reviews including retrospective series [7,8,9] and two recent nonrandomized observational prospective trials conducted by the Radiation Therapy Oncology Group (RTOG 0539) [4, 10] and the European Organisation for Research and Treatment of Cancer (EORTC 22042) [11]; however, several issues remains a matter of debate, including the timing of the treatment (early versus delayed postoperative RT), the optimal radiation technique, and types of radiation dose and fractionation. One of the most controversial topics is the superiority of early adjuvant RT over observation in reducing the risk of tumor recurrence after gross total surgical resection in patients with atypical meningiomas. In addition, there is concern regarding potential risks of RT-related toxicity, which include but are not limited to neurocognitive impairment, hypopituitarism, and the development of a second tumor. Hopefully, these important questions will be answered by two prospective controlled phase III trials where patients were randomized to receive adjuvant RT or observation after surgical resection of an atypical meningioma: the recently closed ROAM/EORTC 1308 trial [12] and the ongoing NRG-BN003 (ClinicalTrials.gov Identifier: NCT03180268) trial.

In this review, we discuss some of the most recent advances in radiation treatment of patients with atypical and anaplastic meningiomas, as well as evidence supporting its use in the context of different clinical situations. The safety and efficacy of different radiation approaches and techniques were also examined.

Histopathologic classification

The systematic adoption of the histopathologic criteria provided by the 2016 update of the WHO classification of brain tumors has markedly increased the relative proportion of atypical and anaplastic meningiomas [13]. Both tumors exhibit a much greater recurrence rate compared to benign meningiomas, which negatively impacts survival. As confirmed by the latest WHO classification, tumors with low mitotic rate (less than 4 per 10 high power fields (HPF) are generally classified as benign, WHO grade 1 tumors. For grade 2 atypical meningiomas, brain invasion or a mitotic count of 4–19 per HPF are a sufficient criterion for the diagnosis [2]. Atypical meningiomas can also be diagnosed in presence of 3 or more of the following properties: sheetlike growth, spontaneous necrosis, high cellularity, prominent nucleoli, and small cells with high nuclear-cytoplasmic ratio. Grade 3 anaplastic meningiomas are characterized by elevated mitotic activity (20 or more per HPF) or frank anaplasia. In addition, specific histologic subtypes such as clear cell or chordoid cell meningiomas are classified as grade 2, and rhabdoid or papillary meningiomas as grade 3 tumors. A new finding of WHO 2021 classification is the inclusion of several molecular biomarkers associated with the classification and grading of meningiomas, e.g., SMARCE1 in clear cell subtype, BAP1 in rhabdoid and papillary subtypes, KLF4/TRAF7 in secretory subtype mutations, and TERT promoter mutation and/or homozygous deletion of CDKN2A/B in anaplastic meningiomas. When these criteria are applied, up to 3 and to 25% of all meningiomas are atypical or anaplastic.

Radiation techniques

Assuming that RT is of value in improving tumor control, new advanced radiation techniques can provide excellent target dose coverage, precise target localization, and accurate dose delivery [14]. For large postoperative resection cavity and/or residual tumors, sophisticated techniques using intensity-modulated radiotherapy (IMRT) or volumetric modulated arc therapy (VMAT) allow highly conformal dose distribution and should be preferred over three-dimensional (3D) conformal RT. Stereotactic radiation techniques, given as either radiosurgery (SRS) or hypofractionated radiotherapy (SRT), have been employed in patients with residual or recurrent atypical and anaplastic meningiomas [15,16,17,18,19,20,21,22,23,24,25,26,27,28]. The main advantage of stereotactic techniques is their ability to achieve a steep dose fall-off at the edge of the target volume lowering the radiation dose to surrounding brain structures, then limiting the potential toxicity of treatments. Current stereotactic techniques include Gamma Knife (Elekta Instruments AB, Stockholm, Sweden) and linear accelerator (LINAC)-based SRS systems, such as CyberKnife (Accuray, Sunnyvale, CA, USA) or Novalis (NTx) (BrainLAB AG, Feldkirchen, Germany). Patients receiving Gamma Knife SRS are traditionally placed in a rigid stereotactic frame with a submillimetric target accuracy while those treated with LINAC-based SRS systems are usually immobilized in a high precision frameless stereotactic mask fixation system. A submillimeter accuracy of patient positioning in the treatment room is achieved using modern image-guided radiation therapy (IGRT) technologies, such as orthogonal x-rays (ExacTrac®Xray 6D system) or cone-beam CT (CBCT) [29]. Although dosimetric characteristics of these SRS systems can be different, no comparative studies have demonstrated the clinical superiority of one technique over another in patients with brain tumors in terms of local control and treatment-related toxicity.

Protons have been employed for skull base tumors either as fractionated RT or as SRS [14]. A radiobiological advantage of protons over photons is that they deposit most of their energy at the end of their range, with very little exit dose beyond the target volume. This narrow region of energy deposition is known as the Bragg peak and it may allow for a lower integral dose delivered to the surrounding normal tissues with protons as compared with photons. Because of the limited number of published series and their retrospective nature (see chapter below), current clinical data do not allow any definitive conclusion about the superiority of proton-based over photon-based techniques in terms of effectiveness and long-term toxicity.

Imaging and tumor delineation

For resected tumors, the treatment planning is based on postoperative MRI, although preoperative MRI may provide useful information on the initial extent of disease and persistent postoperative brain infiltration. The gross tumor volume (GTV) delineation is based on the resection cavity plus any residual tumor using pre- and post-contrast T1-weighted postoperative magnetic resonance imaging (MRI) sequences, without the inclusion of the perilesional edema [30]. Additional images that can help to improve target delineation include T2-weighted high-resolution gradient and fast spin-echo sequences with and without fat suppression, and fluid-attenuated inversion recovery (FLAIR) sequences which can help to assess the extent of peritumoral edema and dural tail abnormalities [11, 31]. In selected cases, PET imaging mainly with DOTATOC-tracers or DOTANOC-tracers has shown to improve target volume definition, e.g. patients with large tumors infiltrating the parapharyngeal soft tissues or for those located in the bony structures which are difficult to be distinguished on MRI and CT [32, 33]. The clinical target volume (CTV), defined as the volume of tissue that contains any microscopic disease and potential paths of microscopic spread, comprises the preoperative tumor bed and a geometrical expansion of 10 mm around the GTV, which may be reduced to 5 mm around anatomic barriers, such as non-infiltrated bone or non-infiltrated brain. The CTV can be extended along the dura up to 20 mm to encompass thickened dural tail or clearly involved hyperostotic bone, especially in the area of adjacent reactive dura. Depending upon the localization method and reproducibility, an institution-specific margin of 0.3–0.5 cm is usually added to the CTV to generate the planning target volume (PTV). For planning purposes, MRI scans are subsequently fused with thin-slice non-contrast-enhanced CT scans. Of note, CT scans may have a complementary role in the imaging of skull base, specifically showing the pattern of bone involvement, e.g. hyperostosis and osteolysis, as well identifying intratumoral calcification better than MRI [34].

Radiation therapy outcome

Fractionated RT following resection of atypical meningiomas

Fractionated RT remains an important component of the therapeutic armamentarium for the treatment of patients with atypical meningiomas [4, 5, 10, 35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,57,58,59,60,61]. Selected studies reporting clinical outcomes of patients with atypical meningioma following surgery with or without adjuvant RT are summarized in Table 1 [4, 5, 10, 35, 36, 38,39,40,41, 43,44,45,46, 48,49,50,51,52,53, 56, 57, 59, 61].

Table 1 Summary of main published studies on radiotherapy for atypical (grade 2) meningiomas
Full size table

Results of two prospective phase II trials have been recently published by the RTOG and the EORTC [4, 11, 53]. The first report of The NRG Oncology/RTOG 0539 trial reported the initial outcome for 48 patients with intermediate-risk meningiomas, i.e., recurrent WHO grade 1 or newly diagnosed WHO grade 2 tumors after gross total resection, who were treated with IMRT or 3D conformal RT using doses of 54 Gy given in 30 fractions [4]. The estimated 3-year progression-free survival, overall survival, and local failure rates were 93.8%, 96%, and 4.1%, respectively. Clinical outcomes were similar between patients with recurrent benign meningiomas and atypical meningiomas receiving gross total resection. Adverse events were limited to grade 1 and grade 2 only. In a second report from the same trial, Rogers et al. [10] reported the clinical outcome for 53 patients with a high-risk meningioma, defined by new or recurrent anaplastic or recurrent atypical meningioma of any resection extent, or new atypical tumor after subtotal resection; treatment consisted of IMRT using simultaneous integrated boost, with the higher-dose volume receiving 60 Gy and lower-dose volume receiving 54 Gy in the same 30 fractions.

At a median follow-up of four years, 3-year progression-free survival was 58.8%, local control 68.9%, and overall survival 78.6%. Combined acute and late adverse events occurred in about 40% of patients and were limited to grades 1 to 3, except for a single necrosis-related grade 5 event. In the EORTC 22042-26042 phase II study, fifty-six patients with newly diagnosed WHO grade 2 meningioma who underwent gross total resection received adjuvant fractionated RT with a dose of 60 Gy delivered in 2 Gy per fraction [57]. Five patients did not receive the planned radiation dose: three patients prematurely stopped RT due to grade 3 cerebrospinal fluid leakage (unrelated to RT), vomiting, and epidermitis on scar, and two patients received 70 Gy instead of the planned 60 Gy. The estimated 3-year progression-free survival, overall survival, and local failure were 88.7%, 98.2%, and 14.3%, respectively, with a late toxicity of grade 3 or more observed in about 14% of patients.

The effectiveness of postoperative adjuvant RT in patients with atypical meningiomas has been evaluated in several retrospective series [5, 35, 36, 38,39,40,41, 43,44,45,46, 48,49,50,51,52,53, 56, 59, 61] (Table 1). A recent meta-analysis of 17 studies published between January 200 and January 2019 and including 2008 patients who have undergone gross total resection of atypical meningiomas showed a significant improvement in 5-year local control and progression-free survival rates for those receiving adjuvant RT [9]. Local control, progression-free survival, and overall survival rates were 82.2%, 84.1%, and 79%, respectively, for patients treated with adjuvant RT, and 71%, 71.9%, and 81.5%, respectively, for those not receiving the treatment. Lee et al. [22] reported the outcome of 179 patients who underwent surveillance versus 51 patients who received postoperative adjuvant RT with photons (39%) or protons (57%) after resection of an atypical meningioma. Compared with patients who underwent surveillance, patients who received adjuvant RT showed better progression-free survival; 5-year and 10-year rates were 79% and 64%, respectively, in the adjuvant RT group, versus 62% and 54%, respectively, in the surveillance group (log-rank p=0.03). Rates were significantly better in the adjuvant RT group after either gross total resection or subtotal resection; however, analysis of overall survival showed no difference between groups. Five-year and 10-year overall survival rates were 91% and 85%, respectively, in the adjuvant RT group, and 94% and 88%, respectively, in the surveillance group. In another series of 91 patients with atypical meningioma who received or who did not receive adjuvant RT at Dana-Farber/Brigham and Women’s Cancer Center between 1997 and 2011, Aizer et al. [36] observed 5-year local control rates of 82.6% and 67.8% in patients who did and did not receive RT, respectively (p=0.04). In multivariate analysis, the association between RT and local recurrence was significant (HR, 0.24; 95% CI, 0.06–0.91; p=0.04); however, no differences in overall survival were seen between groups. In another series of 108 patients with an atypical meningioma who underwent gross total resection at the University of California from 1993 to 2004, Aghi et al. [35] observed actuarial tumor recurrence rates of 41% at 5 years and 48% at 10 years. Adjuvant RT was associated with a trend toward decreased local recurrence (p=0.1) in eight patients who underwent gross total resection. Better progression-free survival rates in patients receiving postoperative RT compared with those who did not have been observed in few other retrospective studies [35, 36, 41, 50, 52, 55].

In contrast, some other studies showed no significant advantages in terms of either overall survival or progression-free survival for patients undergoing adjuvant RT [45, 59, 62, 70]. In a series of 158 patients with atypical meningiomas treated at the University of Wisconsin between 2000 and 2010, Yoon et al. [59] did not observe any beneficial impact of adjuvant RT on disease-free survival, irrespective of the extent of resection; survival rates were 89% for patients receiving gross total resection and 83% for those having subtotal resection. In another retrospective series of 133 patients treated between 2001 and 2010 in 3 different UK centres, Jenkinson et al. [45] reported similar outcomes for patients who received surgery with or without postoperative RT. Following gross total resection, 5-year overall survival and progression-free survival rates were 77.0% and 82%, respectively, in patients who received early adjuvant RT, and 75.7% and 79.3%, respectively, in patients who did not receive adjuvant treatment. Stessin et al. [70] published a Surveillance, Epidemiology, and End-Results (SEER)-based analysis of 657 patients who were diagnosed with atypical and anaplastic meningiomas in the period 1988–2007. Amongst a total of 244 who received adjuvant RT, the treatment was not associated with survival benefit even after stratification by grade, the extent of resection, size and anatomical location of the tumor, year of diagnosis, race, age, and sex. In addition, analysis of cases diagnosed after the WHO 2000 reclassification of meningiomas showed that RT led to inferior overall survival. Using the National Cancer Database, Wang et al. [62] have recently compared the survival outcome in 2515 patients with atypical meningioma diagnosed according to the 2007 WHO classification, treated with or without early postoperative RT after surgical resection. Gross total resection was associated with improved overall survival compared to subtotal resection; however, the favorable impact of adjuvant RT on survival was only seen in patients who underwent subtotal resection.

Overall, most studies indicate that adjuvant RT improves progression-free survival in patients with atypical meningiomas. The rate of tumor progression following subtotal resection is higher than that seen following gross total resection; however, the superiority of adjuvant RT over observation for totally excised atypical meningiomas in terms of overall survival remains a controversial issue. Although several studies showed a trend toward clinical benefit with adjuvant RT after gross total resection, the small number of patients evaluated, different WHO criteria for defining atypical meningiomas over the last decades, and the retrospective nature of published studies preclude any meaningful conclusion on whether adjuvant RT improves outcomes over nonirradiated patients. In this regard, the ongoing phase III randomized NRG-BN-003 trial and the recently closed ROAM/EORTC 1308 trial comparing surgery plus adjuvant RT with surgery alone in grade 2 meningioma following gross total resection will help answer the important clinical question on the efficacy of early postoperative RT. The primary outcome measure is progression-free survival (i.e., time to MRI evidence of tumor recurrence) and secondary outcome measures include radiation treatment-related toxicity, the quality of life, neurocognitive function, time to second-line treatment, and overall survival. Importantly, secondary analysis of trials will help to identify molecular features that will predict most benefit for patients receiving adjuvant RT. The results of this potentially practice-changing trial will be available in 2025.

Fractionated RT following resection of anaplastic meningiomas

Few retrospective studies have evaluated the efficacy of RT in patients with anaplastic meningiomas [65, 69, 71,72,73,74,75,76,77,78,https://www.impact-meningioma.com).

After gross total resection, the 5-year and 10-year progression-free survival rates were 94% for both in the adjuvant RT group versus 42% and 36%, respectively, in the salvage RT group. Results of ROAM/EORTC 1308 trial which are expected in 2025 will help to better define the postoperative management of these patients.

Reirradiation

Thanks to the continuous improvement in radiation science and technology, reirradiation has emerged as a feasible approach for patients with different brain tumors [55]. Few retrospective studies have reported the feasibility of reirradiation for patients with recurrent meningiomas [66, 68, 88]. In a series of 43 patients receiving a second course of RT, Lin et al. [74] showed local control, progression-free survival, and overall survival rates of 77%, 60%, and 87% at 1 year, and 70%, 43%, and 68% at 2 years, respectively, for grade 2 and grade 3 meningiomas, with no significant differences between fractionated RT and SRS. The treatment was associated with an acceptable toxicity profile, with 15% of patients who developed grades 2 to 4 radionecrosis. This is consistent with previous studies on reirradiation of brain gliomas suggesting that the risk of symptomatic brain necrosis is low if the cumulative equivalent dose of 2 Gy per fraction (EQD2) is less than 100 Gy [88].

Overall, a few studies support the role of reirradiation as a feasible treatment option for selected patients with recurrent atypical and anaplastic meningiomas that recurred after previous standard treatment. Prospective studies with appropriate follow-up are needed to validate the favorable impact of reirradiation, delivered either as fractionated SRT or as SRS, for recurrent meningiomas.

Toxicity

The reported toxicity after postoperative RT for atypical and anaplastic meningiomas is modest; using typical doses of 54–60 Gy, toxicity ranges from 0 to 17% and includes radiation-induced brain necrosis (0–15%), visual disturbances (2–5%), hypopituitarism (5–30%), and cognitive disturbance (2–17%) (Tables 1, 2, 3, and 4). In the EORTC 22042–26042 observation study, the rate of the late adverse effect of the Common Terminology Criteria for Adverse Events grade 3 or more associated with adjuvant RT following gross total resection for atypical meningioma was 14.3% with no toxic death using a radiation dose of 60 Gy is given in 2 Gy per fraction [57]. In the NRG Oncology/RTOG0539 trial reporting the clinical outcome for 53 patients who received IMRT with a dose of 60 Gy given in 30 fractions for a high-risk meningioma, Rogers et al. [10] reported combined acute and late adverse events in about 40% of patients, although they were limited to grades 1 to 3, except for a single necrosis-related grade 5 event at a median follow-up of 4 years. Of note, only grade 1 and 2 adverse events occurred in patients with intermediate-risk meningiomas who were treated with IMRT or 3D conformal RT using doses of 54 Gy given in 30 fractions in the same trial [4]. A similar acceptable incidence of radiation-related toxicity has been reported in the majority of published studies of conventionally fractionated RT including either atypical or anaplastic meningiomas (Tables 1 and 2). For patients receiving SRS, neurological toxicity rates up to 26% have been reported in few studies [22, 24, 27, 82], although it remains below 10% when limited volumes are treated [15, 17, 21]. Potential neurocognitive toxicity of adjuvant RT is a major cause that makes physicians hesitate to apply it to patients with an atypical meningioma after gross total resection. The incidence of neurotoxicity ranges from 3.4 to 16.7% according to the location of the lesion, radiation dose, and radiation modality, although no published studies have evaluated neurocognitive changes after RT using formal neuropsychological testing.

In general, studies support the safety of radiation treatment given adjuvantly or at recurrence. The impact of advanced techniques for RT such as IMRT and VMAT can lead to improvement in safety profile. Conventionally fractionated RT is usually employed as adjuvant treatment for patients with large resection cavity or large recurrent tumors, while SRS or hypofractionated schedules may represent a feasible treatment option for small-to-moderate tumors, usually less than 3 cm or not in close proximity to sensitive brain structures, such as brainstem or optic apparatus.

Conclusions

At present, surgery retains a central role in the management of atypical and anaplastic meningiomas. For most patients, gross total resection remains the benchmark, although total surgical excision within the constraints of acceptable morbidity is not always achievable. Postoperative RT is usually recommended after subtotal resection, with several studies indicating improvements in local control up to 70% at 5 years. Similar rates have been shown after SRS; however, the latest is usually offered to patients with smaller-to-moderate recurrent tumors. Controversy exists regarding the role and the efficacy of postoperative adjuvant RT in patients receiving gross total resection. The relatively divergent results in the literature are most likely explained by the retrospective nature of the series and the relatively small number of patients evaluated. Kee** this in mind, EORTC 22042-26042 and RTOG 0539 prospective trials have already confirmed an excellent patients’ outcome, with approximately 90% progression-free survival rates at 3 years for WHO grade 2 meningioma undergoing complete resection and adjuvant high-dose RT, depending on patient- and tumor-treatment-related factors. Additional studies should better elucidate the timing, the optimal dose/fractionation, and radiation technique for these tumors. The development of a molecularly based classification of meningiomas will provide a better understanding of tumor biology and could help us predict which patients will benefit from adjuvant therapy.