**9. Management**

#### **9.1. Surgery**

subtype [44]. The clear cell meningioma is composed by cells with glycogen-rich clear cytoplasm andextensive collagendeposition. This subtype typically occurs in the cauda equina region and in the posterior fossa. A high recurrence rate is characteristics. The atypical meningioma has atypical features and cannot be classified as chordoid or clear cell meningi‐

An association between the survival rate and the extent of resection for atypical meningio‐ mas was confirmed by multiple studies [45, 46]. Even if a maximal resection is the first aim of the surgery, these lesions are often less well delimited and a safe resection is often incom‐ plete because of bone infiltration and vascular invasion. Many studies are actually investigat‐ ing the real role of adjuvant therapies. If fact both radiotherapy and eventually chemotherapy are not free of side effects and even if they are commonly adopted for malignant meningio‐

Anaplastic meningiomas may present directly as primary tumors or may derive from a malignant transformation of less aggressive lesions. Malignant meningiomas are character‐

Papillary meningiomas are rare and commonly found in children, characterized by a pseudo‐ papillary architecture. Rhabdoid meningiomas are formed by cells with eccentric nuclei and

Anaplastic meningiomas are associated with a high risk of recurrence and distant metasta‐ ses. The most common sites of extraneural metastases are the liver, lungs, pleura, and lymph

Surgery aiming to obtain gross total or near total surgical resection represents the first choice, and it is combined with different types of external beam radiotherapy (fractionated or stereotactic radiosurgery) [47, 48] Anaplastic meningiomas are malignant tumors with a survival limited to 1.5–3.5 years according to most of the series [49]. A better overall survival was observed in cases <60 years old and in patients receiving adjuvant radiotherapy [46]. The role of chemotherapic agents is still under investigation, and the debate is open in particular

mas, the balance benefits–risks is not yet assessed for atypical meningiomas.

**8. Anaplastic or malignant meningiomas or WHO grade III**

oma.

368 Neurooncology - Newer Developments

ized by the following [4]:

paranuclear inclusions.

for somatostatine analogues [50, 51].

nodes.



The mainstay of the treatment for symptomatic or enlarging meningiomas of every histolog‐ ical grade is the surgical excision. A complete surgical excision of the tumor and of the surrounding dural attachment is recommended and may be curative. Furthermore surgery allows a pathological diagnosis, may improve the symptoms, and relieve the mass effect. The extent of surgical resection was first classified by Simpson [52], and it is strongly associated to the recurrence rate (Table 1). The term "Simpson grade 0" was also coniated, to define a total resection of the tumor, of the infiltrated dura and of the hyperostotic bone, with a 2 cm of free margins [53]. A complete resection (Simpson I) may not always be performed because of the localization/size of the tumor and their relationship with neurovascular structures. Thus, the highest recurrence rate was described in patients with sphenoid wing meningiomas, fol‐ lowed by parasagittal meningiomas. En plaque meningiomas, with a flat extension in the subdural space, may also be difficult to resect completely. However, according to a recent study, patients with skull base meningiomas present at a younger age and lesions have often a more indolent behavior [54].


**Table 1.** Simpson grade classifying the extent of resection for meningiomas.

More aggressive meningiomas may present with associated brain invasion, venous sinuses invasion or less defined limits, thus rendering the complete resection more challenging. The minimization of postoperative neurological deficit is one of the main goals of neurosurgeons, thus respecting neurovascular structures and the extent of resection should be balanced with the risk of postoperative disability. In the most complex cases, thus, a subtotal resection may be performed and a residue is left in place, which will be followed or treated with adjuvant radiotherapy, as fractionated external beam or stereotactic radiotherapy.

The extent of resection being a key predictor of recurrence, a long-term follow-up is essen‐ tial, especially in cases of subtotal resection.

#### **9.2. Radiotherapy**

Radiotherapy has been advocated as primary therapeutic option in cases, where the surgical excision was judged too risky because of the considerable postoperative neurological mor‐ bidities or as complementary treatment after surgery [55]. Several options of radiation therapies are available to treat meningiomas, such as photon-based stereotactic radiosurgery and hypofractionated radiation therapy. Positive results with radiation therapy have been observed in cases of incomplete resection [56, 57] or recurrence [58].

Furthermore interesting results have been found with cavernous sinus meningiomas [59] or parasagittal meningiomas [60] involving the posterior third of the superior sagittal sinus. Patients treated with a combined approach (subtotal resection followed by stereotactic radiosurgery) experienced a progression-free survival similarto the subgroup where GTR was achieved.

To summarize the most recent literature evidences, the adjuvant use of radiotherapy after the resection of grade III meningiomas is well established, while it is still matter of debate after gross totalresection of grade II meningiomas. Aghi et al. [61] showed how immediate adjuvant radiation therapy may improve overall survival and reduce local recurrence with atypical meningiomas. However, no randomized controlled or prospective studies exist and the level of evidence is thus low. Some authors suggest in fact that a close follow-up is sufficient after GTR of atypical meningiomas, thus avoiding the risk of side effects of radiotherapy. Sun et al. [47] suggested thatthe analysis of histopathologicalfeatures of aggressiveness, such as brain invasion and theMIB-1 index, to decide of a complementary treatment shouldbe administered.

A dose of 60 Gy is generally considered beneficial for fractionated radiotherapy after subto‐ tal resections and many centers administer hypofractionated radiotherapy, with doses of 1, 8, or 2 Gy per fraction, to diminish the risk of long-term neurotoxicity. After gross total resec‐ tions, some authors suggest the possibility to lower the doses to 54 Gy (RTOG trial N°0539). The EORTC trial N°22042-26042 is actually investigating the benefit of 60 Gy after GTR, with an additional boost of 10 Gy after STR. The same doses seem to be advantageous with protonbeam therapy [62].

Further indications for radiation therapy are as follows: As adjuvant treatment after the incomplete resection of a meningioma or with recurrent tumors whose surgicalremoval of the residue will bring important potential neurological morbidities or with inoperable lesions.

The limitation of fractionated radiotherapy and stereotactic radiosurgery are linked to the tumor size and to the radiation neurotoxicity, with a risk of necrosis, cerebral edema and damage of critical neurovascular structures with consequent cranial nerve palsy [48]. Recent progresses in the field of conformational radiotherapy and stereotactic radiotherapy allow a better definition of the target, thus limiting the dose to the normal tissue and delivering a more focused dose on the resection bed/residual meningioma.

Other radiation-induced complications described in literature are the risk of secondary malignancy or of tumor progression [63, 64].

## **9.3. Chemotherapy**

The extent of resection being a key predictor of recurrence, a long-term follow-up is essen‐

Radiotherapy has been advocated as primary therapeutic option in cases, where the surgical excision was judged too risky because of the considerable postoperative neurological mor‐ bidities or as complementary treatment after surgery [55]. Several options of radiation therapies are available to treat meningiomas, such as photon-based stereotactic radiosurgery and hypofractionated radiation therapy. Positive results with radiation therapy have been

Furthermore interesting results have been found with cavernous sinus meningiomas [59] or parasagittal meningiomas [60] involving the posterior third of the superior sagittal sinus. Patients treated with a combined approach (subtotal resection followed by stereotactic radiosurgery) experienced a progression-free survival similarto the subgroup where GTR was

To summarize the most recent literature evidences, the adjuvant use of radiotherapy after the resection of grade III meningiomas is well established, while it is still matter of debate after gross totalresection of grade II meningiomas. Aghi et al. [61] showed how immediate adjuvant radiation therapy may improve overall survival and reduce local recurrence with atypical meningiomas. However, no randomized controlled or prospective studies exist and the level of evidence is thus low. Some authors suggest in fact that a close follow-up is sufficient after GTR of atypical meningiomas, thus avoiding the risk of side effects of radiotherapy. Sun et al. [47] suggested thatthe analysis of histopathologicalfeatures of aggressiveness, such as brain invasion and theMIB-1 index, to decide of a complementary treatment shouldbe administered.

A dose of 60 Gy is generally considered beneficial for fractionated radiotherapy after subto‐ tal resections and many centers administer hypofractionated radiotherapy, with doses of 1, 8, or 2 Gy per fraction, to diminish the risk of long-term neurotoxicity. After gross total resec‐ tions, some authors suggest the possibility to lower the doses to 54 Gy (RTOG trial N°0539). The EORTC trial N°22042-26042 is actually investigating the benefit of 60 Gy after GTR, with an additional boost of 10 Gy after STR. The same doses seem to be advantageous with proton-

Further indications for radiation therapy are as follows: As adjuvant treatment after the incomplete resection of a meningioma or with recurrent tumors whose surgicalremoval of the residue will bring important potential neurological morbidities or with inoperable lesions.

The limitation of fractionated radiotherapy and stereotactic radiosurgery are linked to the tumor size and to the radiation neurotoxicity, with a risk of necrosis, cerebral edema and damage of critical neurovascular structures with consequent cranial nerve palsy [48]. Recent progresses in the field of conformational radiotherapy and stereotactic radiotherapy allow a better definition of the target, thus limiting the dose to the normal tissue and delivering a more

focused dose on the resection bed/residual meningioma.

observed in cases of incomplete resection [56, 57] or recurrence [58].

tial, especially in cases of subtotal resection.

**9.2. Radiotherapy**

370 Neurooncology - Newer Developments

achieved.

beam therapy [62].

The development of new medical options for recurrent or aggressive meningiomas is strongly dependent from progresses made in the understanding of molecular pathways. The role of classic chemotherapic agents is disappointing [65]. Temozolomide showed no efficacy on refractory meningiomas according to Chamberlain et al. [66], and its efficacy seems to be linked to the functionality of the enzyme O6-methylguanine-DNA-methyltransferase [67]. Hydrox‐ yurea showed preliminary favorable results in recurrent and radiation refractory meningio‐ mas [68], but the study was conducted in a limited number of patients. The study of Chamberlain et al. [69] on the contrary showed a limited efficacy. Contrasting results exist on the efficacy of irinotecan on preclinical studies [70].

Multiple targeted therapies have been tried in preclinical and clinical trials. In the animal model, the use of mTOR inhibitors such as temsirolimus and everolimus showed a reduced growth rate in meningioma cells [71]. On the contrary, the application of EGFR inhibitors (gefitinib and erlotinib) did not show a significant benefit in patients with refractory menin‐ giomas [72]. The most famous monoclonal antibody binding VEGFB, bevacizumab, was also investigated by Lou et al. [73] in a population of recurrent/progressive meningiomas, and a positive response was obtained in recurrent meningiomas. The benefit of this therapy was, however, not clearin the study of Nunes et al. [74]. Two ongoing trials will evaluate the efficacy of bevacizumab in a phase II trial (NCT01125046) and its association with everolimus in a cohort of recurrent/progressive meningiomas (NCT00972335). In preclinical studies suniti‐ nib, a PDGFRB inhibitor may inhibit cellular migration in vitro [75]. Encouraging results from the use of sunitinib were also obtained in a cohort of patients with malignant meningiomas [50].

Hormonal therapies have been widely investigated as cytostatic therapies after the discov‐ ery of the association between meningioma incidence and hyperestrogenic and hyperproges‐ tinic conditions [18]. Mifepristone (RU-486) is an antagonist of progesterone receptors, and it is the most widely investigated agent in the oncologic field. Clinical studies on its efficacy show, however, contrasting results [7, 76, 77], and only minor evidences exist to recommend mifepristone with inoperable progressive meningiomas, after consideration of the histologi‐ cal grade of the tumor and progesterone receptor expression [78]. Positive preliminary results were obtained with diffuse meningiomatosis [79].

Immunohistochemical studies showed a high prevalence of somatostatin receptor (SSTR) expression in meningiomas, in particular of SSTR2A. The sandostatin LAR was tested in a prospective trial including recurrent menngiomas, with a partial radiological response in one third of patients [80]. However, pasireotide, an analogue with a wider affinity for multiple subtypes of SSTR, showed no benefit in recurrent meningiomas [51].

In conclusion, up to date chemotherapeutic agents and hormonal therapies shows a limited efficacy in the management of recurrent/progressive and more aggressive meningiomas and the field of investigation remains large. The nanotechnology, combined with the most recent

targeted therapies, may actually represent a revolution in the targeting, transport and delivering of chemotherapeutic agents [81], thus opening new ways for the treatment of these tumors.
