Management of High-Grade Meningioma: Present, Past and Promising Future

Abstract

High-grade meningiomas have a persistent therapeutic challenge, which the World Health Organization (WHO) categorizes as grade II and III lesions, represent 10–20% and 5% of individuals with meningiomas, respectively. Although grade I meningiomas can be completely surgically removed and have long-term progression-free survival, higher grade meningiomas are more likely to return aggressively and to be resistant to conventional treatments. Recently, stereotactic radiosurgery (SRS) has offered promise for the treatment of localized tumors. The era of molecular targeted treatment is now upon us. Patients are being enrolled in clinical trials with a variety of innovative medications that target driver mutations, and these trials might result in more effective treatment plans. Alpha-interferon, vascular endothelial growth factor inhibitors, and somatostatin receptor agonists are among the medications that are advised for the medical treatment of meningiomas in addition to radiation and surgical excision. For the treatment of meningioma, efforts to find novel informative mutations and protein biomarkers have advanced. Several patient populations have shown promise for improved outcomes with EZH2 inhibition. Overall, it is hoped that targeted research and the application of those strategies, such as PRRT and TTF devices, would lead to better results in future. This chapter aims to discuss the neuroimaging features of high grade meningiomas, diagnostic and therapeutic implications of recently discovered genetic alterations and outcome. There will be a brief review focusing on ongoing clinical trials of novel therapeutic agents and future research scope in this arena.

1. Introduction

The majority of primary central nervous system (CNS) tumors (37% of cases) are meningiomas. The prognosis for low grade (I) meningiomas is generally good, with a 20-year recurrence rate of 20%. Grade II meningiomas is difficult to cure and have a high chance of coming back after treatment. However, the prognosis for anaplastic meningiomas is dismal, with a median overall survival of only 1.5 years [1, 2, 3]. Additionally, clinical professionals frequently have to make tough treatment choices in instances with complicated morphology or localization, close to important brain structures like the optic nerve, or when incidental cancers are present. Here, we have discussed the epidemiology, natural history and cytogenetics of high grade meningioma. Moreover, we have discussed current theories of diagnosis, therapy, molecular biology. Additionally, improvements in imaging, particularly positron emission tomography (PET) and molecular profiling, are likely to soon have an influence on current clinical practice and be included into existing guidelines [4, 5, 6].

2. Epidemiology

Around 70% of cases are classified as WHO grade I meningiomas, 28% as WHO grade II meningiomas, and just around 3% as WHO grade III meningiomas. Meningiomas of grades II and III are more prevalent in males than in girls, according to various studies, however some also found different findings [7]. Research among participants in USA found that the age-adjusted incidence rate for WHO grade II meningiomas is 0.26/100,000 in the male population and 0.30/100,000 in the female population. On the other hand, age-adjusted incidence rates for meningiomas of WHO grade III are 0.08 per 100,000 for men and 0.09 per 100,000 for women [8]. Black individuals are more likely than white people, Asian-Pacific Islanders, and then white people to have high grade meningiomas. With aging comes an increased chance of developing these meningiomas, which often affect adults around the age of 60 [9].

Around 90% of WHO grade II meningiomas survive after five years. The number of tissue and cell abnormalities is increased in atypical meningiomas (WHO grade II). These tumors have a larger chance of recurrence than benign meningiomas, develop more quickly than benign meningiomas, and frequently invade the brain (WHO grade I). In comparison to benign and atypical meningiomas, malignant meningiomas (WHO grade III) have more cellular abnormalities and progress more quickly. The two kinds of malignant meningiomas return more frequently than the other two and are more likely to penetrate the brain. 1.7% of meningiomas with tissue confirmation are malignant, making up the bulk of meningiomas (WHO grade III) [8, 10]. After age 65, the chance of high grade meningiomas dramatically increases with age. The least at risk age group is 0 to 14 year olds. In comparison to other ethnic groups in the United States, African Americans have been found to have greater incidence of high grade meningioma [8]. High levels of ionizing radiation exposure have been linked to an increased risk of high grade meningiomas. Additionally, there is evidence between low radiation exposures to meningiomas. The most frequent source of ionizing radiation exposure in the US is dental X-rays. Numerous studies have connected a higher risk of meningioma to the frequency of full mouth dental radiographs. It is thought that individuals with the genetic condition Neurofibromatosis type 2 (NF2) have an increased chance of developing meningioma. Additionally, meningiomas that are malignant or numerous may be more common in NF2 patients [10]. While post-menopausal women without these traits are more likely to have Grade I meningiomas, meningioma patients with past CVA and those with grade 4/4 vascularity are more likely to develop WHO Grade II-III tumors [11] (Table 1).

Characteristics		Grade-I	Grade-II & Grade-III
Somatic mutation [12, 13, 14, 15, 16]		Relatively low somatic mutation burden. TRAF7, KLF4, AKT1, SMO, PIK3CA, and RNA polymerase II subunit A (POLR2A) typically seen in grade-1 meningiomas and mostly do not coexist with NF2 mutations	High-grade meningiomas exhibit a relatively high somatic mutation burden. The mutations tended to be C > T transitions. a higher expression of miR-21 is found in WHO grade II or III meningioma.
Genomic profile [12, 13, 15]		Alterations in NF2 is less common in low-grade meningiomas	Alterations in NF2 or chromosome 22 occurred significantly more frequently in high-grade (80%) than low-grade meningiomas
Copy number alterations [13, 16]		Less frequent copy number alterations	High-grade meningiomas demonstrate frequent copy number alterations
Genomic disruption [17]		3%	19%
Loss of chromosome 22 [18]		More frequently (87%)	Less frequently (58%)
Gene Mutation [11, 19]	NF2	Yes	Yes & Yes
	TRAF7	Yes	Yes & Yes
	TERT	Yes	Yes & Yes
	SMARCB1	Yes	No & No
	PIK3CA	Yes	Yes & Yes
	POLR2A	Yes	No & No
	KLF4	Yes	No & No
	AKTI	Yes	No & No
	SMO	Yes	No & No
	SMARCEL	No	Yes & No
	BAPI	No	No & Yes
Chromosomal Alterations [19]		Loss: 22q	Grade II: Loss: 1p, 6q, 10, 14q, 18q; Gain: 1q, 9q, 12q, 15q, 17q, 20q; Grade III: Loss: 9p; Amplification: 17q

Table 1.

Cytogenetic variation of Grade-I, Grade-II and Grade-III meningioma.

3. Natural history of high-grade meningioma

The natural history of high-grade meningioma remains largely unknown. Based on the natural history of patients younger than 60 to 70 years of age and those with meningiomas characterized by surrounding brain hyperintensity on T2-weighted MRI, absence of calcification, and tumor diameter > 25–30 mm exhibit a higher risk for early recurrence [20, 21, 22, 23]. For patients with NF2 linked malignancies, which typically exhibit a saltatory growth pattern, it is extremely important to be aware of and take appropriate action in response to genetic abnormalities [24]. Because new tumors can develop in NF2 patients over their lifetime and because radiographic and symptomatic progression are unpredictable, resection may be best reserved for symptom-producing tumors, de novo, and brain edema-associated meningiomas in NF2 patients [24, 25]. Numerous investigations revealed that a number of chromosomal changes were linked to the development of cancer, and these changes may also be indicators of cancerous potential that affect tumor recurrence and a bad prognosis. Young age, lack of calcification, peritumoral edema, and high-intensity signal on T2WI were associated with clinical progression, according to Kim et al. [26] (Figure 1).

Figure 1.

Schematic picture demonstrated the natural history of an untreated high grade parasagittal meningioma. With the course of time, progressive invasion of SSS and overlying hyperostosis and/or, osteolysis occur. Later on, pial invasion and aquisition of pial feeders give to peritumoral edema, compression/effacement of ventricles and midline shifting. (1) parasagittal meningioma, (2) invasion of superior sagittal sinus, (3) hyperostosis of overlying bone, (4) peritumoral edema, (5) midline shifting, (6) effacement of lateral ventricle, (7&8) acquisition of pial feeders.

4. Diagnostic neuroimaging

4.1 X-ray

A general x-ray uses a modest quantity of radiation to provide an image of the inside organs and structures of the body. An x-ray of the head can occasionally help doctors locate a tumor, but it is insufficient to identify meningioma. By using X-Ray radiograph imaging, osteolysis and hyperostosis results may also be observed [27].

4.2 Computed tomography (CT or CAT)

A CT scan uses head x-rays to acquire photographs of the brain. A computer then combines these data to create a comprehensive, three-dimensional image that displays any anomalies or tumours, including the size of the tumours. Before a scan, a patient may get an injection of a specific dye called a contrast medium to improve the image’s clarity. The most effective method for identifying changes in the skull that a meningioma may produce is a CT scan. When individuals are not appropriate for MRI, particularly when the meningioma is completely ossified or calcified, CT is helpful. The first modality used to assess neurological indications or symptoms is frequently computed tomography (CT), which is also frequently the modality that finds an accidental injury [27]. For the presentation of tumour-induced osseous alterations such remodelling with localized hyperostosis and bone thickening or bone invasion with concomitant osteoblastic response (more rarely osteolysis) in malignant patients, CT continues to be the gold standard alongside MRI [28, 29, 30] (Figure 2).

Figure 2.

Post contrast coronal (A) and sagittal (B) CT scan of a 45 year-old lady with histopathologically proven anaplastic meningioma (WHO grade-III) demonstrated an extra-axial heterogeneously contrast enhancing right parasagittal mass, invading the superior sagittal sinus with compression and displacement of falx cerebri towards the left side. The mass had irregular margin with evidence of surrounding vasogenic edema. Beside this, no features of hyperostosis was seen.

4.3 Magnetic resonance imaging (MRI)

The preferred examination for identifying and classifying meningiomas is MRI. Instead than using x-rays, an MRI creates precise pictures of the body using magnetic fields. MRIs often reveal changes in the brain brought on by tumors, such as swelling or places where the tumor has grown, and can produce more comprehensive images than CT scans. The diagnosis may be determined with an extremely high degree of accuracy when both the look and location are usual. However, in other cases, the appearances are uncommon, necessitating careful interpretation in order to determine the proper preoperative diagnosis. Meningiomas’ T2-weighted imaging signal intensity corresponds with their histological subtypes. MRI offers excellent contrast definition, soft tissue characterization, and multiplanar reconstructions, making it the gold standard method for meningioma diagnosis and assessment [11] (Figure 3). The correlation between DWI and tumor grade is still debatable because no clear-cut statistical relationship between ADC values and tumoral behavior has yet been established. DWI has also been used to depict higher-grade meningiomas with increased cellularity, which show reduced values on corresponding apparent diffusion coefficient (ADC) maps [31, 32, 33]. Unenhanced and contrast-enhanced MR angiography are superior at identifying intra-tumoral dysplastic vasculature. While unenhanced phase-contrast MR venogram (and also black-blood MR imaging) has been shown to be a valid tool in detecting sinus invasion, MR venogram is often employed to evaluate venous sinuses invasion thrombosis or occlusion. For both diagnosis and follow-up, MRI of the spine is the preferred modality; the features are comparable to intracranial meningiomas [28, 29, 30].

Figure 3.

A lady of 35 year-old with no history of prior radiation, presented with intermittent dull aching localized headache for years. MRI of brain, T1-weighted axial (A) section demonstrated a predominantly hypointense extra-axial dural based mass measuring about 6×5 cm located along the lesser wing of the sphenoid bone. The mass became hyperintense in T2-weighted image with numerous intrinsic flow voids (B). After administration of contrast, there was intense homogenous contrast enhancement (C). Mass effect was evidenced by flattening of the underlying sulci and gyri, compression of the lateral ventricle and midline shifting. However, histopathology demonstrated Chordoid meningioma (WHO grade-II).

4.4 Cerebral angiogram

Cerebral angiography reveals the arteries and veins in the brain with specific relationships with the tumor. After a specific dye known as a contrast medium is injected into the major arteries of the brain, CT scans are obtained. An angiography may be necessary to plan surgery because meningioma can obstruct or invade the venous sinuses or vital veins that drain blood from the brain. Additionally, the angiography might show any aberrant arteries that may be feeding the tumor (Figure 4). Sometimes, Digital subtraction angiography plays a pivotal role for pre-operative documentation of feeding arteries, involvement of veins, and to assess the extent of cross circulation. Beside this, intraoperative bleeding can be minimized by injecting sclerosing agents into feeding arteries in the same sitting [19].

Figure 4.

CT angiogram of cerebral vessels (A) with 3D reconstruction arteriogram (B) demonstrated compression and displacement of M2 and M3 segments of left middle cerebral artery(MCA). This highly vascularized grade-II meningioma was feeded by the branches from M3 and M4 segments of MCA.

4.5 Advanced techniques: Possible applications

Conventional MRI often performs well for diagnostic reasons, although it can be exceedingly difficult to differentiate between extra-axial dural-based masses or between various meningioma subtypes. The application of sophisticated imaging techniques can improve tissue characterisation, the identification of key characteristics for surgical planning, and the discovery of prognostic biomarkers.

4.5.1 Spectroscopy

Spectroscopy is an MRI method used to determine the concentration of metabolites in an area of interest. Conversely, increased alanine has been shown to be unique for meningioma but can be challenging to detect. Meningiomas have high choline and reduced N-acetylaspartate as well as decreased creatinine, a metabolic profile common to other neoplastic processes. Meningiomas have been shown to have an enhanced metabolite peak at 3.8 parts per million, which helps to distinguish them from high-grade gliomas and intracranial metastases. It has been shown that MR spectroscopy cannot distinguish between atypical and normal meningiomas [34, 35, 36, 37].

4.5.2 Perfusion imaging

The dynamic susceptibility contrast (DSC) technique and the dynamic contrast enhancement (DCE) approach, both of which call for the injection of intravenous gadolinium, as well as arterial spin labeling, are methods used in MR perfusion to measure blood flow in tissues. When making a differential diagnosis, MR perfusion can be particularly helpful in separating meningiomas from dural-based metastases and from high-grade gliomas that have invaded the dura mater. However, hypervascular metastases, such as those from melanoma, renal carcinoma, or Merkel cell carcinoma, cannot be distinguished by MR perfusion. Meningioma and dural metastases from diverse sources (breast, colon, and prostate) may be distinguished by MR perfusion (increased cerebral blood volume) [38, 39].

A primary glial neoplastic process may be distinguished from intracranial metastases and meningiomas via the analysis of the time-intensity curve. Meningioma vascularity appears to be significantly correlated with cerebral blood flow (CBF) values, and more recently, a significant correlation between CBV and VEGF expression has also been shown, raising the possibility of using perfusion MR to predict resistance to conventional treatment and potential responsiveness to anti-angiogenic therapies [40, 41].

Although peritumoral rCBV often exhibits lower values in meningiomas, probably because of peritumoral vasogenic edema, its values are greater in the case of anaplastic meningiomas (WHO Grade III) compared to the other forms. Similarly, reduced peritumoral CBF can be detected by CT perfusion, which may indicate ischemic tissue that can be salvaged following meningioma excision [42, 43].

By measuring perfusion without the confusing impact of permeability, arterial spine labeling offers the benefit of perhaps enabling the distinction between WHO Grade I and WHO Grades II and III cerebral meningiomas. Vascular permeability was directly measured using the DCE technique and had a role in the grading of meningiomas; atypical meningiomas had greater Ktrans values than benign meningiomas. Additionally, several meningioma subtypes can be distinguished with the use of MR perfusion. In comparison to meningothelial, fibrous, or anaplastic subtypes, angiomatous meningioma has shown increased tumor rCBV [43, 44].

4.5.3 Diffusion tensor imaging

Diffusion tensor imaging (DTI) has been used to distinguish between various meningioma grades due to the ability to measure the amount and directionality of water diffusion. Despite the fact that high-grade meningiomas often have lower ADC values than low-grade ones, there have been some disputed findings, particularly for the other DTI metrics. In terms of predicting preoperative consistency, DTI has demonstrated considerable possibilities. The majority of research have found that hard meningiomas had greater fractional anisotropy (FA) values than soft ones, with a few exceptions. Meningioma consistency has also been found to be predicted by signal intensity on FA and mean diffusivity maps [45, 46, 47]. Tractography, derived from DTI data, may give additional information for treatment planning of skull base meningiomas [48].

4.5.4 MR elastography

A promising new method called MR elastography (MRe) may be able to determine the consistency of a tumor and how it interacts with nearby structures. By analyzing the share wave passage through that specific tissue, it offers a measurement of the stiffness of the tissue. A substantial association between the MRe measures and the intraoperative qualitative evaluation of tumor consistency has been shown in recent investigations [36].

4.5.5 Molecular imaging

Due to strong physiological FDG uptake in the cerebral cortex and FDG buildup in inflammatory processes, the most common molecular imaging method in the area of oncology is (18F-FDG)-PET, which employs a glucose analog to identify metabolically active cells. There is no link between FDG uptake and WHO grading, MIB-1 labeling index, or tumor doubling time, despite certain studies showing its capacity to identify benign meningioma from atypical/malignant ones and to separate recurrent/growing meningiomas from static ones [48].

On the other hand, due to the enhanced expression of SSTR II in meningiomas compared to the relatively low expression in bone and brain tissue, a strong meningioma-to-background contrast can be achieved utilizing radiolabeled somatostatin receptors II (SSTR II) ligands. When compared to contrast-enhanced MRI, PET using gallium-68-labeled SSTR-ligands, such as 68Ga-DOTATOC (DOTA-(Tyr3)-octreotid) and 68Ga DOTATATE (DOTA-DPhe1-Tyr3-octreotate), has shown a better sensitivity in identifying meningiomas. When researching optic sheath meningioma, for example, SSTR-PET is helpful for differential diagnosis. Additionally, this method enables the precise delineation of meningioma extent, which is crucial for treatment planning but difficult in cases of complex localization (skull base, orbit, falx cerebri, sagittal, and cavernous sinuses), trans-osseous growth, or in cases of meningiomas that have already received treatment, when MR contrast results are constrained [36, 49, 50, 51, 52].

Additionally, SSTR-PET may distinguish between live tumor and scar tissue using a semi-quantitative data analysis since SSTR II expression as determined by immunostaining and semi-quantitative uptake values (SUV) have a strong correlation. Additionally, SSTR-PET may be used if MRI results are unclear since it has been shown to be more accurate at locating residual meningioma. The RANO-PET workgroup has put out an evidence-based recommendation for the use of molecular imaging in meningiomas, even if SSTR II imaging’s usefulness still needs to be further validated [53, 54, 55].

4.5.6 Future directions

Radiomics is a young branch of study that analyzes medical pictures and extracts several aspects from them. Following lesion segmentation, two types of features—semantic and agnostic—can be retrieved from the region of interest. Semantic characteristics, such as form, position, etc., are frequently employed in radiology to characterize a lesion in detail, but in the discipline of radiomics, they are quantified with computer aid. Because artificial intelligence is better at handling this volume of data than traditional statistics, it may be used with radiology. Artificial intelligence uses algorithms to let computers learn directly from the data and make predictions on unknown datasets [56, 57].

Radiomics and artificial intelligence have showed potential in the study of meningiomas for preoperative assessment, recurrence and outcome prediction, and radiation therapy planning. Planning and monitoring of therapy also greatly benefit from volumetric evaluation of meningiomas. The ability to predict local failure and overall survival in these patients using preoperative radiologic and radiomic characteristics such apparent diffusion coefficient and sphericity has shown to be successful. With promising findings (accuracy 90%), MR radiomics has also been used to predict early progression or recurrence, which define a subgroup of skull base meningiomas. In order to enhance the texture-based distinction of tumor from edema and to distinguish vasogenic from tumor infiltration edema, radiomics has shown effective in the determination of radiation target volume, which constitutes a crucial step in treatment planning [58, 59].

5. Management

Surgery with the aim of full excision is the traditional first-line therapy for all MNs. The recurrence rate for high grade meningiomas is considerable; up to 60% of tumors may return after 15 years following total excision. Due to a lack of available data, there are currently no recognized standard effective therapies [60, 61]. Depending on the tumor grade and the degree of tumor excision as determined by Simpson, current recommendations call for progressive treatment regimens. Treatment and follow-up based on the most recent EANO is recommended widely. For grade I tumors (Simpson grades I–III) that can be completely removed, surveillance is advised. Stereotactic radiosurgery is the adjuvant of choice when complete resection is not possible [62, 63].

The ongoing ROAM/EORTC 1308 experiment is testing whether Simpson grade I resected atypical tumors should be treated with radiation or observation. The recommended follow-up schedule is six months apart for the first five years, then yearly. Given their severe clinical history, Grade III cancers necessitate major surgery and adjuvant radiation. No matter how extensive the surgery, fractionated radiation is recommended (recommendation level B). Anaplastic meningiomas should be followed up with every three to six months. Meningioma metastasis is uncommon, even in WHO grade III malignancies (Figure 5) [64, 65].

Figure 5.

A 45 year-old lady presented with progressive left sided hemiparesis for 2 years and convulsion for several episodes for the same duration. Pre-operative MRI of brain demonstrated a fairly large (6×5×4.5 cm) lobulated T1 weighted isointense (A), T2 weighted heterogeneously hypointense mass in the right parietal parasagittal location with moderate perilesional edema. The mass showed avid contrast enhancement after administration of the gadolinium (C). Mass effect was evidenced by compression of underlying sulci, lateral ventricle and gross midline shifting (8 mm). Magnetic resonance Venogram demonstrated filling defect at middle part of SSS with development of multiple collaterals (D). Follow up CT scan of brain after 5 years demonstrated no evidence of recurrence with encephalomalachic changes (E, F).

5.1 Surgical management

The development of endoscopic transsphenoidal methods for skull base meningiomas has led to a recent progression in surgical procedures during the past few decades. Although it was quite popular, its usage is now in decline because cerebrospinal fluid leaking could result in serious local and neurological consequences [66, 67].

Total removal is not usually feasible due to the tumor’s location, infiltration of nearby tissues, and brain parenchyma. Regardless of the histological grade, post-operative Simpson grading based on the surgeon’s assessment grades removal from grade 1 (complete) to 5 (simple biopsy) and enables prediction of symptomatic recurrence at 10 years from 10% to 100%. Since it was first reported in 1957, this conclusion has drawn criticism from a number of scientists, particularly given the lack of a systematic postoperative MRI. It has been established that, for grade II meningiomas, patients who undergo Simpson 1 resection had a longer overall and progression-free survival (Figure 6) [60, 68].

Figure 6.

A 46year-old lady, known case of papillary carcinoma of thyroid, presented with progressive enlargement of palpable hard mass in the frontal region for 2 years and convulsion for several episodes for the same duration. Pre-operative MRI of brain demonstrated a fairly large (7×6×5.5 cm) irregular T1WI iso to hypointense (A) and mixed intensity (B) mass present in both frontal region, having extra and intradural extension and invasion of the brain parenchyma. Mass effect was evident by moderate perilesional edema, compression of ventricles and gross midline shifting. After administration of contrast, there was heterogenous contrast enhancement with central non enhancing necrosed area (C). Magnetic resonance Venogram demonstrated obliteration of the anterior 1/3rd of SSS with development of multiple collaterals (D). Intraoperative photograph showed evidence of bone infiltration as well as osteolysis (E). Follow up CT scan of brain after 6 months demonstrated no evidence of recurrence (F).

For grade III meningiomas selectively, the progression-free survival at 5 years is 28% after gross total resection alone, versus 0% after subtotal removal alone. Although the results all tend to favor gross total resection, this goal should not affect the patients’ immediate neurological status, and combined strategies could be used to maximize progression-free survival while reducing the neurological risks [69, 70].

Surgical resection is typically the first-line treatment for high-grade meningiomas when the tumor is in an accessible location, and the extent of surgical resection is an important prognostic factor for progression-free and overall survival (OS), with gross tumor resection (GTR) defined as Simpson grade 1–3 and subtotal tumor resection (STR) classified as Simpson grade 4 and 5. However, rates of recurrence are high, especially with STR, and radiotherapy may significantly decrease this risk. For the purposes of this review, we will exclusively focus on the role of RT for high-grade meningiomas. Interstitial brachytherapy can be an effective adjunct to surgical resection and external beam radiotherapy, especially for aggressive, recurrent, and/or large meningiomas, but is associated with high complication rates [71, 72, 73].

5.2 Radiation therapy

Radiation therapy has emerged as the first-line treatment for some meningiomas, particularly skull base lesions surrounding the vascular and nerve structures like the optic nerve sheath or the cavernous sinus. Surgery still holds a significant position because it can alleviate the tumor mass effect and establish a histological diagnosis. If imaging results are usual and surgery is not an option, radiation therapy alone may be suggested. These findings, combined with radiation-induced damage, highlight the importance of these therapies for untreatable cancers less than 3 cm. Stereotactic radiotherapy for tiny tumors has few side effects, however there have been occurrences of radionecrosis, and pituitary function must be monitored following skull base irradiation [74, 75, 76, 77, 78].

5.3 Targeted therapy

Meningiomas exhibit a modest mutation rate, and there are not many known possible molecular targets. In high-grade MN (80% of cases), NF2 is commonly changed compared to low-grade MN (40%). The majority of the genomic and regulatory changes that have been identified in high grade MN take place in the wake of NF2 protein disruption. Furthermore, the mTOR signaling cascade is one of the primary routes connected to NF2. Natural NF2 functions as a repressor of mTORC1 and mTORC2, and when it is altered, this pathway is uncontrollably activated. This has led to the identification of mTOR and several of its downstream and upstream effectors as potential targets. Research is also being done on other pathways controlled by receptor tyrosine kinases as EGFR, PDGFR, and VEGFR (angiogenesis) [79, 80].

5.4 Adjuvant treatment: Radiotherapy indications

Meningiomas of grades II and III are aggressive tumors that have greater recurrence rates. Adjuvant radiation treatment of the tumor zone could be useful for these cancers even after gross complete resection [68, 81, 82, 83]. Based on the grade, size, and location of the tumor, the best form of radiation therapy must be chosen. In the event of a small tumor, stereotactic radiation in a single or series of doses is advised. External beam irradiation is the go-to treatment option for recurring, many, or large lesions, with doses up to 70 Gy for grade II-III meningiomas, whether using 3D conformal radiotherapy or intensity-modulated radiation therapy with or without tomotherapy. Additionally helpful, proton radiation can be utilized in conjunction with photon radiotherapy [84, 85]. Tumor recurrence less likely (2%) with Stereotactic Radiotherapy compared to 12% for surgical treatment [86].

For grade III tumors, it is established that adjuvant radiation improves long-term control and overall survival, even after total gross removal. In contrast, there is conflicting evidence for its role in grade II meningiomas. It has been shown that radiation therapy improves overall and progression-free survival when the tumor has been sub-totally removed, but not after total gross resection. Indeed, reported side-effects of radiotherapy and radiosurgery are usually mild but there is also evidence that radiation increases the risk of malignant transformation [70, 87, 88, 89].

After stereotactic radiosurgery for brain malignancies, radiation necrosis is a known consequence that affects 15% of patients. No matter the type of tumor in patients having radiosurgery, large diameter and high doses were reliable independent risk factors that led to more often occurring radiation necroses. Due to the increased risk of developing radiation necrosis, other therapeutic approaches may be taken into account in lesions with a large volume and an anticipated high radiation dosage [90]. Grade III anaplastic meningiomas are malignant (cancerous) and associated with cranial radiation exposure. People with neurofibromatosis type 2 are also at increased risk for developing meningiomas [91]. Radiation exposure during childhood significantly increases the risk of second malignancy as compared to older population. Malignant transformation can occur after radiation treatment in around 2% people due to insufficient killing of cells and some of the surviving cells acquire mutations in genes, such as TP53, that can transform a benign tumour into a malignant one [92, 93].

5.5 Chemotherapy and ongoing clinical trials

In the context of meningioma, chemotherapy is regarded as experimental since there is insufficient data on most drugs or just conflicting findings. As a result, their usage is only advised in anaplastic situations and is preferred within clinical studies. With SMO- and NF2-mutant meningiomas, respectively, targeted therapy studies for SMO and FAK inhibitors are currently being conducted. Only this trial stratifies individuals according to tumor genotype and considers potential driver mutations. Regardless of molecular background, the mTOR inhibitor vistusertib is being examined in phase II research; nonetheless, there may be a benefit to mTOR inhibition in cancers that have PI3K or AKT mutations. Bevacizumab, a number of immune checkpoint inhibitors, and tumor-treating technologies are also being studied [94, 95].

The European Organization for Research and Treatment of Cancer (EORTC) oversaw a phase II research that compared adjuvant postoperative radiation treatment with observation in patients with newly diagnosed grade II or grade III meningiomas between 2008 and 2013. (NCT00626730, Switzerland). Due to significant protocol violations and inclusion issues, this experiment had to be stopped. The second study, the American RTOG 0539 (NCT00895622) trial, involved 244 patients and is still underway. It focuses on observation for low-risk meningiomas and radiation for intermediate and high-risk meningiomas. After three years, preliminary results indicate that patients with totally resected grade II and recurring grade I who received post-operative radiation had a 96% survival rate without progression [68, 96]. A phase II randomized controlled study (ROAM/EORTC-1308) comparing radiation (60 Gy in 30 fractions) with observation after surgical excision of an atypical meningioma was launched in the UK in 2015. Distinct facilities have different treatment decisions in clinical practice. In the United Kingdom, Germany, and France, radiation is administered to patients after subtotal grade II removal by 59%, 74%, and 80% of neurosurgeons, respectively, whereas following grade II gross complete resection by 45-60% of neurosurgeons, immediate adjuvant radiotherapy is recommended [64, 97, 98].

6. Challenges in meningioma management

6.1 Surgical challenges

Due to poor localization of otherwise benign tumors, such as skull base meningiomas, or invasion of healthy brain, which indicates malignancy in the first place, surgery might be challenging. While the first group’s neurosurgical procedure improves, anaplastic tumors require adjuvant treatment. It is suggested to employ advanced preoperative and postoperative imaging methods for tumor definition, determining residual tumor mass, and identifying bone or brain invasion [53, 99].

6.2 Radiotherapeutic challenges

Patients with poor clinical outcomes, tumors with complicated morphologies, or cancers in challenging sites are frequently evaluated for primary or adjuvant radiation. Planning for radiation is likewise impacted by all of these variables. It is essential to precisely assess tumor size in order to treat the tumor mass as a whole while sparing normal brain tissue and important systems like the optic nerve. PET imaging employing SSTR ligands (current data indicate 68Ga-DOTATOC) has shown to be helpful in planning the target volume in skull base cancers for stereotactic or intensity-modulated radiotherapy, and may help with both volume definition and dose sparing [100, 101, 102].

6.3 Peritumoral edema

Peritumoral edema is a symptom of meningiomas in 40–66% of cases. Particularly for the histological subtype of secretory meningiomas, which are non-NF2 tumors distinguished by the co-occurrence of KLF4 and TRAF7 mutations, life-threatening episodes of peritumoral edema have been observed. Steroids, particularly dexamethasone, are the mainstay of treatment for peritumoral edema, however antiangiogenic therapy may be used in rare circumstances where (long-term) adverse effects or inadequate effectiveness are present. Critical cases, particularly those with secretory meningioma, may necessitate treatment in an intensive care unit with sedation, mechanical breathing, and intracranial pressure monitoring [103, 104, 105].

6.4 Meningioma en plaque

En plaque meningiomas are tumors that develop along the dura in a pattern resembling a sheet. They frequently include the orbit, but mostly occur at the sphenoid wing. They often have a noticeable hyperostosis at presentation. With extensive complete resection occurring in 56–83% of cases, their surgical removal is difficult. Therefore, a combination primary strategy with adjuvant radiosurgery may be preferable over extensive resection [106, 107].

6.5 Optic nerve sheath meningioma

1-2% of meningiomas are optic nerve sheath meningiomas (ONSM). When MRI results are ambiguous, 68Ga-DOTATATE-PET molecular imaging should be considered to rule out other possible diagnoses (e.g. lymphoma, optic neuritis, metastasis). OnSM, in particular intracanalicular ONSM, might resemble ocular neuritis. Most of the time, surgery is not an option, particularly when the tumor and the optic nerve share the same blood supply. The suggested treatment of preference is stereotactic fractionated radiation [50, 108, 109].

6.6 Multiple meningiomas

The majority of multiple meningiomas are associated with neurofibromatosis type 2, which is identified by heterozygous NF2 germline inactivation. In NF2, intracranial meningiomas frequently involve numerous tumors, with a median of three tumors. Even though the majority of the evidence predates the difference between sporadic NF2-mutated meningiomas and non-NF2 sporadic cases, meningiomas with neurofibromatosis type 2 are more likely to be atypical or anaplastic than sporadic instances. Young age ( 30 years) at the time of the initial meningioma presentation should raise the possibility of a germline mutation and may call for molecular testing. Patients with suspected or confirmed neurofibromatosis should be provided genetic counseling due to the disease’s high penetrance and potential impact on family planning. Other genetic predispositions to meningioma have been identified in addition to neurofibromatosis type 2. Clear cell meningioma of the spinal cord and intracranially are predisposed by SMARCE1 mutations [25, 110, 111, 112].

7. Future research

In bigger trials that stratify between grade-2 and grade-3 meningioma, combination regimens such as ICI with targeted treatments or new therapeutics targeting immunosuppressive myeloid cells will be evaluated. Future investigations that stratify patients based on previous systemic therapies are necessary given the evidence that chemotherapy sensitizes solid tumors to ICI by increasing dendritic-cell activation and decreasing regulatory T-cell and myeloid-derived suppressor-cell responses [113, 114].

The most often used and researched adjuvant treatment for meningiomas is radiotherapy, however there are still a lot of unanswered problems. The majority of experts think that RT has no place in treating WHO grade I cancers, unless they are symptomatic primary or recurring tumors that cannot be surgically removed. Numerous phase II and randomized controlled trials are attempting to shed light on the function of radiation in WHO grade II GTR tumors, despite the fact that this involvement has not yet been completely understood. In a phase II trial (RTOG 0539), it was found that the intermediate risk group’s 3-year progression-free survival (PFS) and 3-year overall survival (OS) rates were 98.3% and 96%, respectively, for newly diagnosed WHO grade II GTR (69.2%) and recurrent WHO grade I with any resection extent (30.8%), respectively (OS). Using adjuvant RT at a high dosage of 60 Gy, WHO grade II GTR meningiomas were shown to have an 88.7% 3-year PFS and a 98.2% 3-year OS in another phase II study. Currently, grade II GTR meningiomas receiving adjuvant RT are the subject of the randomized controlled trials ns20191111, NRG-BN003, and the ROAM/EORTC-1308 study, which compares at least 5-year OS and PFS [115, 116, 117].

There are clinical trials investigating pathway-directed therapies such as MEK pathway inhibitor, selumetinib (SEL-TH-1601, NCT03095248), CDK-p16-Rb pathway inhibitor, ribociclib (LEE-011, NCT02933736), and mTOR-pathway inhibitor, everolimus (NCT01880749 and NCT01419639), and vistusertib (AZD2014, NCT03071874). The ALTREM clinical trial is investigating the co-administration of phosphoinositide 3-kinase α (PI3Kα) specific inhibitor, alpelisib, and the MEK inhibitor, trametinib (NCT03631953). The phase II CEVOREM trial demonstrated that the coadministration of everolimus and octreotide (SSTR2A agonist) had a 6-month PFS of 55%, and 6- and 12-month OS of 90% and 75%, respectively. The CEVOREM trial showed more than a 50% decrease in the growth rate at 3 months in 78% of tumors and the median tumor growth rate over 3 months decreased from 16.6% before treatment to 0.02% at 3 months and 0.48% at 6 months after treatment. The NCT02831257 trial demonstrated that patients treated with AZD2014 had a 6-month PFS of 88.9 and 5.6% (1/18) of patients experienced a decrease in tumor volume of at least 20% compared to baseline [118].

There are also clinical trials investigating immunotherapy agents such as checkpoint inhibitors PD-1 antagonist, nivolumab (NCT02648997, NCT03173950, and NCT03604978 in combination with ipilimumab), another PD-1 antagonist, pembrolizumab (NCT03279692, NCT03016091, and NCT04659811 in combination with stereotactic radiosurgery), and PD-L1 antagonist, avelumab (NCT03267836 in combination with proton radiotherapy).

The discovery of innovative treatments to combat meningioma is being driven by growing biological understanding of this disease. Additionally, prognostication and trial stratification may benefit from genomic and epigenetic characteristics. Meningioma quantitative radiomic characterizations that are still under development may offer more tumor stratification tools and early tumor behavior prediction at the time of initial diagnosis. Finally, taking into account the multidrug-resistant meningioma’s cellular heterogeneity, which cancer stem cells bestow, opens a parallel pathway for therapeutic discoveries.

8. Conclusion

Meningioma development has been linked to particular molecular changes and ionizing radiation. In many cases of high-grade meningioma, current treatment protocols using surgery and/or radiation are sufficient for tumor management. Prospective research is required to confirm potential molecular prognostic indicators and detect negative clinical trends early on. An integrated diagnostic approach can increase the precision of recurrence and outcome forecasting and assist in the development of customized treatment programs for particular patients. Despite the discovery of important mutations and signaling pathways, targeted systemic treatments are still lacking, despite the fact that several clinical studies are now being conducted.

Conflict of interest

The author of the chapter declares that, there was no conflict of interest.