Not every diagnosed meningioma has to or can be resected. The age and physical condition of patients play major roles in treatment decisions [101]. In addition, the progress of the tumor is an important clue for the nature of the tumor and should be followed. In cases where the tumor is small (under 2.5 cm), without neurological deficits, and with calcified parts [102], or is not easily accessible, a follow-up examination is usually considered. Long-term follow-ups are mostly for small or inaccessible tumors; the alternative for small or inaccessible tumors is radiation therapy. During the last two decades, radiotherapy has become the first option for small lesions or skull base meningiomas encasing important vessels [103]. Recent instances of fractionated and hypofractionated radiosurgery have shown some astonishing results in tumor control (85–100% over 5 years) [104,105].

Surgery still remains the therapy of choice in most cases. In recent years, tremendous evolution of surgical techniques has been achieved (neuronavigation, tractography, endoscopic methods, etc.). Surgeries have become faster and more accurate, with incisions smaller and complications rarer [106]. Under this prism, one would expect even more clinicians to strive for radical resection. However, radical removal is not always possible. The location of the tumor or the encasement of important vessels and nerves can sometimes lead to partial resection to avoid neurological deterioration of the patient. Furthermore, the age and clinical condition of the patient should be taken into consideration when planning long and/or complex surgery. Aggressive meningiomas (Grade 2 and 3) have high recurrence rates over five years of about 50–55% and 70–78%, respectively. Conversely, Grade 1 meningiomas have rates of only 7–23% [24]. However, these high percentages concern patients who undergo gross total resection. In cases of subtotal resection, the recurrence rates are much higher, depending on the Simpson grade of resection [24,65]. In such cases, adjuvant treatment is recommended, especially when tumor growth is suspected in follow-up examinations.

If recurrence is suspected, the patients should be treated with extra care. As most of the patients with Grade 3, as well as some with Grade 2 meningiomas, will undergo adjuvant radiotherapy after surgery, radiation possibilities in case of recurrence are exhausted [107]. Furthermore, radiation-induced brain changes after adjuvant radiotherapy are not rare and sometimes difficult to differentiate from recurrent tumors [64]. Thankfully, recent developments in neuroimaging and the expression of somatostatin receptor 2 in meningiomas help us to differentiate between healthy brain tissue, postoperative changes, and recurrent tumors [108]. DOTATATE and DOTATOC PET imaging are valuable diagnostic means that are nowadays widely used for this purpose [109,110,111]. Moreover, DOTATATE PET imaging has special importance in the diagnosis of intraosseous meningiomas and should be used, if possible, for improved detection of the tumor [112]. In case of confirmed recurrence, surgery is still the state-of-the-art management and should always be taken into consideration, if possible [64,113,114,115,116]. Lemée et al. reported a longer time-to-retreatment for patients with recurrent meningiomas which were surgically removed, than for those treated with radiation therapy, although the benefits of a surgical treatment of meningioma recurrences decrease with the number of surgeries [116]. However, the higher complication rates and neurological deterioration of the re-operated patients should be taken into consideration when deciding the right treatment for recurrent meningiomas [114,115]. If re-surgery is not possible, targeted radiosurgery, radiation (in cases without former adjuvant therapy), or re-radiation can be considered [64,107,117].

A review of the literature on the surgical results of anaplastic meningiomas identified the following outcomes: Rogers et al. [118] reported on 53 patients with total and subtotal resection of WHO 3 meningiomas, stating that the 3-year progression-free survival (PFS) was 58.8% and the overall survival (mean follow up: 4.8 years) was 78.6%. All patients received radiation therapy after resection. In WHO 2 meningiomas, the 3-year PFS was 93.8% in N = 52 patients who received surgery and radiation [119]. Another study evaluated 214 patients with WHO 2 meningiomas with a follow-up time of 53.4 months. The authors reported that patients who had a gross total resection (n = 158) had a significantly longer PFS and overall survival than patients with subtotal resection (n = 56) [120]. A fourth study analyzed 23 patients with WHO 2 and 3 meningiomas with total and subtotal excision and postsurgical radiotherapy. The authors showed PFS values of 58% for WHO 2 and 20% for WHO 3. The overall survival rates for WHO 2 and 3 were 83% and 23%, respectively [121]. In a study by Weber et al., the authors reported their results for 78 patients with WHO 2 meningiomas and resection of Simpson Grade I-III with postsurgical radiation, showing a 3-year PFS of 88.3% and a 3-year survival of 98.2% [122].

Adjuvant radiotherapy is not only important for meningiomas belonging to Grade 2 and 3 categories, as many suppose. With recurrence rates of up to 23% in spite of total resection for Grade 1 meningiomas, possible remnants should be treated [123]. Concerning aggressive meningiomas, an increased tendency for adjuvant therapy has been reported [124]. This is particularly important as recent studies show an increasing mortality and morbidity rate in these cases [125]. The type of radiation used is individually decided according to the location, size, and grade of the tumor. Fractionated external-beam radiotherapy is now a useful tool for skull base meningiomas [126] and partially resected tumors [127]. Proton and photon radiotherapy are also good options that have been shown to be beneficial when combined [128]. Adjuvant radiotherapy is also important for incompletely removed meningiomas, as it controls remnants against recurrence and improves overall survival and progression-free survival rates. A Grade 2 meningioma after Simpson I/II resection still has a recurrence rate of 30–40%, while a Grade 3 meningioma after Simpson I/II resection has a 50–80% rate over 5 years [107]. The progression-free survival rate in Grade 3 meningiomas doubles after adjuvant radiotherapy from 28 to 57% [100]. Similar results are seen in Grade 2 meningiomas, although the rates are controversial [129]. A meta-analysis in patients with atypical meningioma showed better progression-free and overall survival rates in patients who received postoperative radiotherapy, regardless of whether there was gross total or subtotal resection [130]. In patients with anaplastic meningiomas, adjuvant therapy showed improved survival rates, although there was no significant advantage in the overall survival rate [131].

However, radiation therapy is not harmless. Larger tumors need more radiation, which can reach up to 70 Gy [107,123]. This leads to complication rates of up to 23% [132], including malignant transformation and healthy brain toxicity [133,134]. Smaller lesions respond better to hypofractionated radiation therapy, and the complication rates are decreased [132]. Radiosurgery has become a good alternative therapy to surgery for small/inaccessible tumors or patients who cannot undergo surgery, such as elderly patients or patients with poor general health. Notably, in tumors with diameters under 3 cm, gamma knife therapy can achieve local control comparable to a Simpson Grade I resection [135]. Recently, two prospective non-randomized trials suggested the effectivity of radiotherapy in WHO Grade 2 meningiomas, supporting its role in progression-free survival [119,122]. However, the outcome in WHO Grade 3 meningiomas is poor due to the propensity of these tumors to invade other tissues (brain, bone) and the risk of normal tissue toxicity [118]. Further studies about the impact of radiotherapy are relatively scarce for high-grade meningiomas. An extensive review of the current evidence and future applications of radiotherapy in meningioma treatment has been provided by Chen et al. [134].

The development of pharmacological therapy against aggressive and recurrent meningiomas started many years ago. These agents are considered against refractory and/or invasive meningiomas when surgery and radiation have failed or are not possible or available [48,136]. Cytotoxic agents, like hydroxyurea, were thoroughly tested, and although they were well-tolerated, they had limited efficacy [48,136,137,138]. Hormone therapies were also intensively tested, showing rather disappointing results [136]. This has led to a need for more targeted therapy [139]. A variety of targeted therapies like tyrosine kinase inhibitors [139,140] and everolimus monotherapy [141,142], or in combination with octreotide [49,143], have shown promising results.

Immunotherapy with interferon-α has been effective against low-grade recurrent meningiomas [144,145], but in recent years, no further studies have confirmed these results. However, some newer studies have shown promising results; understanding the underlying tumorigenesis genetics and block has been utilized in modern immunotherapy to develop effective checkpoint inhibitors. Meningiomas are known to exhibit several immune checkpoint proteins. PD-L1 expression is one of the most important, not only being proportional to tumor grade but also predicting a poorer overall prognosis due to higher recurrence and tumor progression rates [146,147,148]. A Phase 2 study of pembrolizumab, a PD-1 inhibitor, delivered encouraging efficacy in patients with recurrent and residual high-grade meningiomas [149]. Further checkpoint proteins that are highly expressed in meningiomas are PD-L2, B7-H3, CTLA-4, and NY-ESO, but their role in future therapy is still under investigation [150,151,152].

Currently, more effort is being given to the development of new pharmacological therapies. In order to achieve this, many studies have concentrated on decoding the mechanism of brain invasion. As meningiomas are highly vascularized tumors, there is special interest in inhibiting angiogenesis. Several antiangiogenic agents have also been tested, mostly in patients with recurrent tumors. They were, in most cases, well tolerated; however, the efficacy of these agents, which were partially combined with chemotherapy, has still to be proven in prospective studies [153,154,155]. Canstatin, an angiogenesis inhibitor, was expressed more than twice as frequently in non-invasive meningiomas than in invasive ones [156]. Another group proposed bevacizumab, an antiangiogenic agent, as the most effective therapeutic agent [157]; however, the cohort was small, with only 23 patients [158]. Bevacizumab as a monotherapy, or in combination with everolimus and sunitinib, are currently the most promising systemic agents for patients with aggressive meningiomas where radiation has failed [159]. Furthermore, a recent study confirmed the role of CDKN2A mRNA expression as a biomarker of clinically aggressive meningiomas, especially in Grade 3 meningiomas. This could be of great help for the development of therapeutic implications [160]. Last but not least, the future could lie in gene therapy. The idea of using adenoviruses and herpes simplex virus to insert genetic material (DNA or RNA) into human cells in order to correct or compensate for a gene abnormality or defect is not new [161,162]. However, the uncontrollable insertion of mutations and the short period of therapeutic effects have led to fewer preclinical studies and more confined development than expected [48].

Some therapies that are available in the USA and are FDA-approved were scrutinized by Jungwirth et al. [163], showing very promising results for some agents like ixabepilone, a cytotoxic agent widely used in advanced and metastatic breast cancer [164,165,166]. Alpelisib, a phosphoinositide 3-kinase α (Pi3Kα) specific inhibitor, is under investigation in combination with the MEK inhibitor trametinib (NCT03631953). Especially for patients with NF 2 mutations, a phase II trial of focal adhesion kinase inhibition (GSK2256098) showed promising efficacy and met the PFS6 criteria for further evaluation [167]. Due to the novel targets identified in recent years, there are many ongoing trials of systemic therapies for progressive and/or recurrent meningiomas [140,168,169]. A complete list of current pharmacotherapy targets can be found in the systematic review of Shahbandi et al. [168].

5. Conclusions

In summary, meningiomas are mostly benign tumors but they should be approached with extraordinary care. They can occur either on the skull base or at the convexity and falx. Tumor location is important for the surgery as some tumors are more accessible than others. However, it is generally accepted that an aggressive resection should be underwent as long as it remains safe for the patient. As we cannot pre- or perioperatively predict the WHO grade of the tumor, it is of vital importance to remove most of the tumor and the neighboring infiltrated tissues in order to increase their overall survival rate and their morbidity. Of similar importance is an adjuvant therapy for meningiomas grade II and III, as well as regular follow-up examinations. Grade I tumors however tend sometimes to recur too, so follow-up examinations are recommended for all patients after meningioma resection. Chemotherapy is developing but not as fast as expected. Nevertheless, immunotherapy and gene therapy may be the future for the treatment of recurrent or/and refractory meningiomas. Simpson grading is in our opinion still up to date concerning aggressive meningiomas as it is an excellent prognosing factor of recurrence. On the other hand, complex or inaccessible meningiomas of the skull base with vessel or nerve encasement should be removed as radically as possible, without however endangering the postoperative condition of the patient.