Recent advances in the management of atypical meningiomas

Neurochirurgie 62 (2016) 213–222

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General review

Recent advances in the management of atypical meningiomas M. Messerer a,∗ , B. Richoz b , G. Cossu b , F. Dhermain c , A.F. Hottinger d , F. Parker a , M. Levivier b , R.T. Daniel b a Department of neurosurgery, faculty of medicine - Paris Sud, Kremlin-Bicêtre university hospital, 78, rue du Général-Leclerc, 94270 Le Kremlin-Bicêtre, France b Department of clinical neurosciences, service of neurosurgery, faculty of medicine and biology of Lausanne, Lausanne university hospital, 46, rue du Bugnon, 1011 Lausanne, Switzerland c Department of radiation oncology, institut Gustave-Roussy university hospital, 114, rue Edouard-Vaillant, 94805 Villejuif, France d Neuro-oncology unit, department of clinical neurosciences & oncology, Lausanne university hospital, faculty of medicine and biology of Lausanne, 46, rue du Bugnon, 1011 Lausanne, Switzerland

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Article history: Received 1st October 2015 Received in revised form 17 January 2016 Accepted 26 February 2016 Available online 28 June 2016 Keywords: Atypical meningioma WHO grade II meningioma Management Genetics Molecular biology Radiology Surgery Adjuvant radiotherapy Stereotactic radiosurgery Conventional external beam radiotherapy

a b s t r a c t Based on the 2007 WHO classification, the proportion of atypical meningiomas has steeply increased. Complete resection is usually considered curative, however, the recurrence rate remains high. The treatment of more aggressive meningiomas remains problematic. We performed a literature review via the PubMed database with specific attention to radiological, pathological, genetic and molecular aspects particular to WHO grade II meningiomas and current therapeutic strategies. We also reviewed the role of surgery and summarized the results of the principal studies dealing with adjuvant strategies based on the most recent evidence. Adjuvant radiotherapy, administered as stereotactic radiosurgery or conventional external beam irradiation, should be strongly considered in selected cases. Limited data exist regarding the role of hormonal treatment or chemotherapy as adjunct therapy. A target therapy modulating the altered molecular balance may be the key to revolutionize the prognosis of these patients. © 2016 Elsevier Masson SAS. All rights reserved.

1. Introduction Meningiomas represent the most common primary brain tumor [1]. They account for 20% and 38% of all primary intracranial neoplasms in males and in females, respectively, with an incidence of 4–6 per 100 000 persons [2]. Based on the 2007 World Health Organization (WHO) classification system [3], meningiomas are classified into three categories according to specific histological criteria: benign (WHO grade I), atypical (WHO grade II) and malignant or anaplastic (WHO grade III) meningiomas. Classically, most meningiomas were considered benign; currently, the incorporation of the criteria of brain invasion into the 2007 WHO grading system has noticeably increased the incidence of atypical meningiomas and they now constitute between 20 and 35% of newly diagnosed meningiomas [1,4]. This classification is the most accurate predictor of tumor recurrence and survival rate

∗ Corresponding author. Department of neurosurgery, centre hospitalier universitaire Vaudois, 1011 Lausanne, Switzerland. E-mail address: [email protected] (M. Messerer). http://dx.doi.org/10.1016/j.neuchi.2016.02.003 0028-3770/© 2016 Elsevier Masson SAS. All rights reserved.

[5]. At 5 years following surgical excision, the recurrence rate is approximately 3% for WHO grade I meningiomas [6], 41% for WHO grade II [7], and between 70 and 91% for WHO grade III meningiomas [8]. When compared to benign meningiomas, atypical meningiomas also show a statistically significant increased risk of mortality [9]. In addition to the histological grade, the recurrence rate is also related to the completeness of resection [10,11]. Epidemiological studies have shown how the female gender is a risk factor for developing meningioma, with a female to male ratio of 3:1 [12]. However, women are more prone to benign meningiomas, whereas atypical and malignant meningiomas show a slight male predominance [13]. Hormonal therapy and hormone dependent conditions like breast cancer [14], pregnancy [15] and obesity [16] were associated with an incidence of meningiomas, higher than expected in the general population. Cranial irradiation is also a recognized risk factor to develop meningiomas and radiation-induced meningiomas usually show higher histological grades, especially when presenting in younger age groups [3]. Convexity localization and age > 65 are other risk factors for highergrade meningioma [17].

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In atypical meningiomas, early diagnosis and treatment are therefore of paramount importance to achieve the best outcome. Adjuvant treatments, like radiotherapy or chemotherapy should be considered in selected cases. Although the benefit of these treatments is clearly established for malignant meningiomas, atypical meningiomas still remain a subject of debate. A heterogeneous behavior is in fact often observed within the class of atypical meningiomas: a better stratification is necessary in order to delineate the appropriate management strategies. The aim of this article is to review the existing literature regarding the recent advances in the field of atypical meningiomas and to summarize the best evidence for decision-making in the management of these tumors. 2. Pathology Meningiomas are thought to arise from the meningothelial cells of the arachnoid layer. They present with evidence of epithelial as well as mesenchymal lining. WHO grade II meningiomas are defined as tumors with increased mitotic activity (4 or more mitoses within any 10 consecutive high-power fields) [9] and/or brain invasion and/or three of the following characteristics [3]: • • • • •

sheet- or pattern-less growth; foci of spontaneous necrosis; increased cellularity; prominent nucleoli; small cells with high nuclear to cytoplasmic ratio.

High mitotic count is the most important criteria for predicting WHO grade II meningiomas. Apoptosis and nuclear pleomorphism are not considered as WHO criteria. However, as stated by Backer-Grondahl et al. [18], a correlation was found between apoptosis, nuclear pleomorphism, higher tumor grade and poorer survival. For this reason, when apoptosis is observed, highergrade meningioma should be sought. Increased vascularization and hemosiderin deposits were not correlated with tumor grade. At the contrary, classical psammomatous bodies have been found to be a protective factor [18,19]. Four subtypes of WHO grade II meningiomas have been described [3]:

• chordoid meningioma: it presents with trabeculae of eosinophilic epithelioid cells, a mucin-rich stroma and clear vacuoles resembling physaliferous cells. This pattern is usually mixed with meningothelial or transitional tumor areas. It is more often found supratentorially and it is histologically similar to chordoma; • clear cell meningioma: sheets of polygonal cells with glycogenrich clear cytoplasm and extensive perivascular and interstitial collagen deposition characterize this subtype. Typical meningioma features, as psammomatous bodies and whorl formation, are rare. This type typically occurs in the cauda equina region and in the posterior fossa in younger patients. A high recurrence rate is associated to this subtype; • atypical meningioma: it may not be classified as chordoid or clear cell meningioma because of its atypical features, however, it includes features of the WHO criteria to be defined as grade II meningiomas; • brain invasive meningioma: defined by a protrusion of tumor cells with infiltration of brain parenchyma. Since 2007, any meningioma harboring brain invasion should be considered at least as WHO grade II. Brain invasion is highly linked to a higher recurrence rate even after gross total resection. Immunohistochemical markers may help in assessing the proliferative potential of meningiomas. Although MIB-1 staining is not included in the WHO grading system, it may have a prognostic value: increased MIB-1 index correlates with increased regrowth after gross total resection [20]. Some authors have suggested considering MIB-1 index above 5% as a diagnostic marker for WHO II meningiomas [20]. 3. Genetics 3.1. Cytogenetic profile The theory of clonal evolution is commonly used to explain the progressive gain in aggressiveness and malignancy in most neoplasms [21]. Less than 2% of benign meningiomas progress to more aggressive variants [22] but the prevalence is significantly higher with recurrent tumors (between 14 and 28,5%) [23]. According to the study of Weber et al. [24] and Lee et al. [25], the number of accumulated genetic alterations and allelic imbalances is correlated with the histopathologic classification (Fig. 1).

Fig. 1. Cascade of genetic alterations and allelic imbalances correlating with the WHO histologic grade. Modified and adapted from Weber et al. [24] and Lee et al. [25].

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resulting in an uncontrolled cell cycle [34]. Additionally, the PI3 K/Akt, the MAPK pathways [9] and the WNT/beta-catenin pathway [35] are constitutively activated without the need of external stimuli. 4.2. Disruption in cell interaction and adhesion

Fig. 2. Representation of the prevalence of the most frequent genetic alterations according to the histologic grade of the meningioma.

Meningioma was the first solid tumor in which a genetic substratum was characterized. The most common genetic abnormality is represented by loss of the allelic region or deletion of the long arm of chromosome 22 (22q) [26] or monosomy of chromosome 22 [27] and it is believed to be a key-event in the early pathogenesis of meningiomas. The neurofibromatosis type 2 gene (NF2 gene or the tumor suppressor gene merlin) is located on chromosome 22q12.2 and seems to be implicated in the tumorigenesis of sporadic meningiomas. However, the frequency of NF2 gene mutation or loss depends on the subtype of meningioma. In atypical and anaplastic meningiomas, NF2 mutations are found in about 70% of cases [28]. Loss of chromosome 1p, 14q and 10q and genetic instability were recorded more specifically in atypical and malignant meningiomas. Loss of 1p represents a decisive step in meningioma progression [29] and, together with deletion of 14q, was associated with a worse prognosis in terms of disease-free survival and recurrence [30]. Loss of heterozygosis on 10q was observed in more than one third of atypical meningiomas [24,31] and the PTEN tumor suppressor gene, located at 10q23.3, may be involved in tumor progression (Fig. 2). Less frequent are losses on 6q and 18q. Other loci of genomic instability are 9q, 12q, 15q, 17q and 20q [9,32]. Amplification of chromosome 17q23 was identified in anaplastic meningiomas [24]. Al-Mefty et al. [33] showed results contrasting the hypothesis of clonal evolution. According to their study in fact, aggressive meningiomas may originate directly from cells having more complex karyotypes and not from a progressive accumulation of mutations. In these cases, meningiomas may present a more aggressive behavior and a closer follow-up from the diagnosis is advisable. 4. Molecular biology Multiple pathways seem to be implicated in meningioma pathogenesis and malignant progression. Many studies concentrated on the identification of these alterations leading to deregulated cell growth and proliferation, abnormal cell migration, angiogenesis and apoptosis. The understanding of these cascades is in first line important in the management of aggressive and atypical meningiomas, where radical surgery and radiotherapy do not allow controlling the disease. A targeted therapy modulating the hyperactive or inhibited loop may be the key to revolutionize the prognosis of these critical patients. 4.1. Disruption in the balance controlling cell cycle Atypical and anaplastic meningiomas show mutations in modulators of pRB dependent and p53 dependent pathways, thus

E-cadherin is lost in one third of meningiomas [35] and genetic instabilities of the E-cadherin gene seem to have a role in meningiomas development and progression [36]. Some studies showed how this membranous glycoprotein belonging to adherent junctions is down-regulated in malignant and atypical meningiomas, while its expression was normal in benign meningiomas [36]. According to some authors, E-cadherin may be used as a predictive molecule: an elevated expression is related to limited invasiveness and recurrence [35] and its down-regulation is associated with increased tumor cell proliferation [37]. However, contrasting results are reported: E-cadherin expression seems to be independent from histological grade in different studies [38,39]. E-cadherin may further act as tumor suppressor through the modulation of the WNT/beta-catenin cascade. Beta-catenin may activate the transcription of target genes promoting the cell cycle and it may be upregulated according to the histological grade [36]. NF2 gene may modulate the activity of E-cadherin but the argument still remains controversial. Brunner et al. [38] failed to show a relationship between deletion of chromosome 22 and an altered localization of E-cadherin and beta-catenin. 4.3. Disruption in autocrine loops The most famous autocrine and paracrine loops acting in tumorigenesis are mediated by Platelet derived growth factor (PDGF), Epidermal growth factor (EGF), Transforming growth factor (TGF) and Vasoactive endothelial growth factor (VEGF). The expression of the PDGF subunit BB (PDGFBB) and of the correspondent receptor (PDGFR) beta are related to the aggressiveness of meningioma [40]. An autocrine loop is activated and cell growth may be stimulated either directly [41] or through the production of connective tissue and neoangiogenesis [42]. Normal arachnoid cells do not express the EGF receptor (EGFR) but this receptor was isolated in meningioma cells [43]. Wernicke et al. [44] showed a significant difference in expression of EGFR between benign, atypical and malignant meningiomas, with the more aggressive subtype having the lowest expression. An autocrine loop inducing cell proliferation might be thus mediated by TGF alpha through EGFR stimulation and its expression was correlated with a more rapid growth [40]. In tumors other than meningiomas, EGFR overexpression was found to be correlated with responsiveness to radiotherapy and this may be the case also for meningiomas. Multiple studies have demonstrated VEGF upregulation in meningiomas [45,46]. VEGF is determinant in neoangiogenesis and it is related to tumor progression, increased vascular permeability and cerebral edema [47]. The real association between VEGF expression and tumor vascularity or biological behavior remains to be established [46]. Similarly, the correlation between VEGF and VEGFR levels and histological grade remains controversial [45,48,49]. VEGF may further act as paracrine factor as stimulator of cell proliferation through the interaction with PDGFR beta [50]. Other proteins that may influence meningioma progression are bone morphogenetic proteins (BMPs) and their receptors, which may represent an aberrant stimulus for meningioma cell proliferation [49]. Also, HER-2 could play a role in meningioma progression [51]. On the contrary, the TGF pathway seems to limit meningioma growth [40].

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Fig. 3. A T1-weighted cerebral MRI with contrast enhancement shows a lesion of the left occipital lobe on the axial (right panel) and sagittal plane (left panel). The heterogeneous enhancement, the perilesional edema and the not well-defined limits were more in favor of an aggressive lesion. The pathology confirmed an atypical meningioma.

5. Clinical findings Small meningiomas are mostly asymptomatic and discovered with imaging performed for unrelated symptoms [52]. Their natural history is commonly marked by a progressive enlargement having as clinical translation the onset of epileptic seizures, partial, complex partial or generalized in nature, or the onset of neurological deficit, in accordance with meningioma location. The pathogenesis of epileptic seizures is still unclear but determining factors may be the convexity location and perilesional oedema [53,54]. A direct compression may be responsible for focal neurological deficits as cranial nerve palsies with parasellar meningiomas, hemisyndrome with calvarial lesions or behavioral disturbances with anterior skull base meningiomas. Atypical meningiomas may become symptomatic earlier than benign meningiomas of the same size due to brain invasion and/or to the more rapid growth. Furthermore, large tumors or tumors with major associated peritumoral oedema may cause symptoms of intracranial hypertension or even obstructive hydrocephalus. These clinical features are not characteristics for atypical meningiomas. However, according to Zhao et al. [55], the preoperative Karnofsky performance status scale (KPS) may be associated to the WHO histological grade. 6. Radiology A correlation between radiological features and histological grade may be established and histological aggressiveness may be often predicted on the basis of imaging findings (Fig. 3, Table 1). According to Kane et al. [17], extensive and multifocal non skull base tumors, were more likely to be high-grade meningiomas. Peritumoral edema has been observed in approximately 79% of meningiomas [56] and its correlation with histological grade Table 1 Simpson grade classifying the extent of resection for meningiomas. Simpson grade

Extent of resection

1

Total removal of the tumor, dural attachment and infiltrated bone Total removal of the tumor, dural attachment coagulated Total removal of the tumor, without resection nor coagulation of the dura/infiltrated bone Partial resection of the tumor Decompression (biopsy)

2 3 4 5

remains controversial. Several studies have attributed the peritumoral edema to a vasogenic mechanism and it may be correlated with pial blood supply [56]. However, several studies failed to show a relationship between peritumoral oedema and WHO histological grade [56–58]. In fact, WHO grade I meningiomas may be highly vascularized lesions. Restricted diffusion, lower apparent diffusion coefficient (ADC) values and higher fractional anisotropy are common MRI findings in atypical meningiomas [59]. These modifications may be related to the increased cellularity of the tumor matrix and to the presence of fibrous and gliotic tissues [60]. Using ADC values, it is possible to predict 96% of atypical/malignant meningiomas and 83% of benign meningiomas. A normal ADC has a positive predictive value of between 96% and 100% for benign meningiomas [60]. Increased cerebral blood volume (CBV) values may predict higher-grade meningiomas [59]. Enokizono et al. [61] found that in non-enhanced 3D Flair MRI sequences, a tumoral rim with a low intensity was more frequent in atypical than in benign meningiomas. Adjacent bone destruction or ill-defined borders have been found to be present in both benign and higher-grade meningiomas, with no statistically significant difference [60]. It is not unusual to find hyperostosis on routine imaging of meningiomas [62]. However, the histological subtypes did not seem to correlate to the grade of bone reaction, neither for hyperostosis nor for bone destruction [57]. Arterial encasement was not different between the histological subgroups [57]. Analogously, cystic and necrotic regions, heterogeneous enhancement, as well as size, were not associated to histological malignancy [60]. On the contrary, Hsu et al. [57] showed how intratumoral cystic changes and extracranial tumor extension through skull-base foramina were more prevalent in higher-grade meningiomas. On MRI spectroscopy, a high Cho/Cr ratio and a low N-acetylaspartate peak are more indicative for atypical and anaplastic meningiomas. [59]. Spectral features may thus help to distinguish the atypical nature of meningiomas. 7. Surgery Surgery remains the primary treatment option for meningiomas of each histological grade. It allows tumor removal ranging from subtotal to gross total resection; it alleviates mass effect and thereby neurological symptoms and allows tumor grading. Whenever possible, a gross total resection (GTR) should be the aim of the surgery, with resection of the adjacent bone and dura, as GTR harbors significantly lower rates of recurrences [63,64]. To state

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the extent of resection, the Simpson classification is commonly adopted [63] (Table 1). The term GTR commonly encompasses the Simpson grades I and II, while the STR is used for Simpson grade IV and V. Although the benefit of obtaining a GTR versus a STR is well established from an oncological prospective, the advantage of achieving a Simpson grade I resection versus a Simpson grade II or III has not yet been established [65,66]. Palma et al. [67] showed an association between the survival rate and the Simpson grade in atypical meningiomas (P < 0.0003). Hammouche et al. [10] showed how Simpson grade I patients had a relapse-free survival rate of 97 and 74% at 1 and 5 years respectively, compared with 88 and 32% in Simpson grades II to IV. Durand et al. [68] confirmed in their retrospective analysis how a Simpson I resection is associated with a longer overall survival in grade II meningiomas (P = 0.005) and the extent of resection was also predictive of recurrence. In contrast, for Pasquier et al. [69], the extent of resection was not a significant prognostic factor. However, in the statistical analysis of this study, grade II and grade III meningiomas were pooled together. According to Hardesty et al. [70] and Sun et al. [71], no differences in terms of PFS were found after Simpson grade I-II or I-III resection. Faced with these contrasting results, it is clear that a limited consensus exists and, even in cases of GTR, the risk of recurrence remains high. More aggressive meningiomas are often invasive and with not well defined limits. In common practice, the resection of lesions adherent to the cortical surface, involving venous sinuses or with large cranial base implants, as is the case for most of atypical meningiomas, may be challenging. In these cases, a surgical approach with the aim of achieving a GTR would imply an increase in neurological and vascular morbidity and a subtotal resection would represent the surgical goal. Although stereotactic radiosurgery (SRS) may represent an interesting alternative in these difficult cases, the tumor volume may often be too large to upfront SRS and furthermore, primary irradiation does not allow a pathological diagnosis. A combined approach (planned subtotal resection followed by SRS) may be used in such instances, typically with voluminous petroclival meningiomas, with lesions invading the cavernous sinus, the posterior third of the superior sagittal sinus or the transverse sinus [11,72,73]. The aim of the surgery, coupled to an intraoperative electrophysiological monitoring, is to decrease the tumor volume and minimize the risk of lesions to critical neurovascular structures. Neuromonitoring may constitute an important part of the procedure, especially when the meningioma invades eloquent areas or surrounds cranial nerves. Most cranial nerves (CN) of interest are monitored according to their motor functions using bipolar electrodes positioned in their innervated muscles (V CN: masseter, VII CN: frontalis, orbicularis oris, orbicularis oculi, depressor labii inferioris, IX CN: soft palate, X CN: contact endotracheal tube, XI CN: trapezes and XII CN: tongue). The direct nerve stimulation elicits a large compound motor potential (CAMP) in the corresponding muscles, while the nerve mechanical traction generated a train of bursts. The ocular motility is monitored following ocular saccades after direct nerve stimulation (III, IV, VI CN) using electrodes positioned close to extraocular muscles [74]. Parts of the meningioma deemed too risky to be removed are left behind for complementary SRS. In order to keep an optimal distance between important cranial base structures for subsequent SRS treatment, fat grafts can be interposed if structures at risks are in contact with the tumor (f.i. chiasmopexy or hypophysopexy) [75,76]. Postoperative SRS can then be undertaken on meningioma residue delivering the adequate radiation dose and at a safe distance from surrounding structures. Combined approaches have shown to produce good tumor control of benign cavernous sinus meningiomas [72]. However, evidence regarding the treatment of skull-base atypical meningiomas with combined approaches are still sparse. Wang et al. [11] have

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recently reported comparable PFS rates in patients with skull-base atypical meningiomas between the subgroup in which STR was performed with adjuvant therapy and the subgroup in which GTR was achieved. This may suggest that STR combined with adjuvant radiation therapy can be a substitute of GTR alone with the advantage of minimizing the risk of postoperative neurological deficits, according to the accessibility of the tumor. Further studies are however necessary. The combined approach is also applicable to large parasagittal meningiomas involving the posterior third of the superior sagittal sinus [73]. When the involvement of the sagittal sinus is present and when a partial permeability is still present, a treatment is represented by a complete excision of the meningioma with a secondary reconstruction of the sinus. This procedure however includes significant morbidity and mortality rates [77]. Combined approaches for the treatment of atypical meningioma have proven to be a valid treatment option in order to maximize local tumor control as well as minimizing neurological morbidity and should be part of the armamentarium of treatments for this pathology [78,79] (Figs. 4 and 5). 8. Adjuvant therapy Achieving local control for patients with atypical meningiomas is a paramount endpoint. When local control is not achievable, different modalities of adjuvant treatment are available. Indeed, there is a high risk for patients with recurrent atypical meningiomas to die from their tumor despite aggressive salvage therapy [80]. 8.1. Radiation therapy (RT) The role of RT is controversial in atypical meningiomas. Different forms of RT have been used for atypical meningiomas after subtotal resection, including SRS and conformal external beam RT (EBRT) [81]. Even following GTR, some authors have recommended “immediate” adjuvant RT, while others advocate a close follow-up. Below, we review and describe the specific characteristics that need to be taken into account when using these therapeutic modalities, separately for SRS and for EBRT. The evidence in choosing between SRS or EBRT is low and further clinical trials may help to better understand the relative role of these 2 approaches in the course of the management of atypical meningiomas. 8.1.1. SRS: tumour coverage, total dose and treatment timing matter Most reports of SRS in atypical meningiomas are in the settings of STR [80,82,83], in the majority of cases after recurrence. Reported local control at 2 years spans in a large range from 50% to 80%. The role of SRS after GTR in atypical meningiomas remains a debated question. All studies using SRS for atypical meningiomas strongly suggest that three elements could influence outcomes: total cumulative dose, target volume and treatment timing. 8.1.1.1. Total cumulative dose. The margin dose may range from 14 to 20 Gy [84]. However, higher margin doses allow better results. Kano et al. showed that the 5-year progression-free survival was only 29.4% for atypical meningiomas treated with less than 20 Gy versus 68% for those receiving 20 Gy [82]. 8.1.1.2. Target volume. Attia et al. [85] demonstrated the importance of the conformity index (CI = treatment volume/tumor volume) with a median dose of 14 Gy (range: 12–18) in residual or recurrent atypical meningiomas. Local failure (defined as “recurrence within 2 cm of the original tumour margin”) developed in 48% of cases at 5 years, with a median time to recurrence of 25 months. Importantly, when the CI was considered, marginal dose was not

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Fig. 4. Planning for adjuvant stereotactic radiosurgery (SRS) after subtotal resection of the atypical meningioma depicted in Fig. 3. An early SRS was performed on the residual lesion in this patient.

predictive of local control. The mean CI was significantly lower in patients who recurred versus those who did not. Furthermore, atypical meningiomas may particularly recur outside of the SRS target but yet inside the resection bed. Choi et al. [86] treated 25 patients with atypical meningiomas, with a median marginal dose of 22 Gy (range: 16–30 Gy) in one to four fractions. Nine failures were identified: one intra-cranially but outside the irradiated region, three (33%) within the targeted area (real focal recurrence), and importantly 5 others (56%) elsewhere in the resection bed. Huffmann et al. [87] in a series of 15 patients showed (median dose 16 Gy) that 6 progressed, only 1 in field, but all the others within the operative cavity. For the radiation therapist or the neurosurgeon, it means that a “large” volume beyond the residual/recurrent enhancement (defined as the “gross tumour volume” or GTV) has

to be considered “at risk”, suggesting a clinical target volume (CTV) including the entire GTV and the resection bed. 8.1.1.3. Treatment timing. Choi et al. [86] and Harris et al. [88] showed an improved local control after “immediate” postoperative SRS, when compared to delayed SRS performed at the time of recurrence or progression. The median time to progression was 61 months with “early” treatment versus 15 months after “late” SRS. Multisession SRS (“hypofractionated stereotactic radiotherapy”) has also been delivered, especially for large or critically located atypical meningiomas, where the risk of direct toxicity (optic apparatus) and of edema (sagittal sinus) more likely occurs after single-session SRS [89]. Local control seems comparable to

Fig. 5. Preoperative T1-weighted MRI with gadolinium administration showing an atypical meningioma. Coronal (left panel) and axial incidence (right panel). A fractionated stereotactic radiotherapy was planned as adjuvant treatment: 60 Gy were administered as total dose, 66 Gy as integrated boost (2 Gy/fr during 6 weeks).

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single-fraction SRS [89], with possibly lower risks of side effects [90]. 8.1.2. Fractionated EBRT: definition of “tumour target” and total dose matter A dose of 60 Gy may be beneficial, especially after STR [91]. Most of atypical meningiomas are larger than their benign counterpart and many authors have recommended fractionated EBRT, delivering lower doses per fraction (1.8 to 2 Gy), in order to minimize late neurotoxicity [92]. Others have questioned its real benefit. Goyal et al. [93] reported that EBRT did not significantly affect outcome of patients, but median dose was only 54 Gy. Mair et al. [94] suggested that EBRT was not be appropriate after GTR, advising SRS rather than EBRT, but mean dose was clearly sub-optimal (51.8 Gy in 28 fractions). Accordingly, Aghi et al. [7] published one of the largest series of 108 patients with atypical meningioma after Simpson Grade I resection. Only 8 patients underwent EBRT with a mean dose of 60.2 Gy and a “target volume” defined as 1 cm beyond the resection bed. Five-year recurrence after GTR alone was 45% versus 0% after surgery followed by EBRT. Komotar et al. [95] published a series of 45 patients with atypical meningiomas, all with Simpson Grade I-II resection. Of these, 13 patients received adjuvant EBRT (median dose 59.4 Gy, target volume defined as “the tumour cavity plus a 5 to 10 mm margin”). Recurrence was observed in 41% of the patients without EBRT (median time: 19 months) versus 8% of those who benefit from RT. The recently completed RTOG trial no. 0539 proposed to deliver 54 Gy after GTR and 60 Gy following STR or for recurrent atypical meningiomas of any resection extent. In Europe, the completed EORTC trial no. 22042-26042 recommended 60 Gy after GTR, adding a boost of 10 Gy after STR [81]. Both US and European trials closed recruitment in 2013 and first results are expected for 2016. Furthermore, proton-beam therapy was used in 15 patients with atypical meningiomas [96], delivering a cumulative total dose of 42 to 72 cobalt-Gray equivalent (CGE). Local control was significantly improved with doses greater than 60 CGE, showing a 5-year local control rate of 90% with > 60 CGE versus 0% with an inferior dose. Similarly, Boskos et al. [97] presented the outcome of 24 patients with grade II-III meningiomas treated with proton therapy, mostly after STR. Cause-specific survival at 5 years was 80% with doses greater than 60 Gy (versus 24% with inferior doses), suggesting further improvement beyond 65 Gy. 8.1.2.1. Toxicity of radiation therapy. With the recent progress of modern linear accelerators dedicated for stereotactic radiotherapy, the ability to deliver very high dose (> 60 Gy), even in large volumes (> 60 cm3) with a 1-mm precision and frameless approach, has largely increased [98]. The incidence of cerebral irradiation toxicity varies across studies from 3, 4% to 16,7% [7,69,82,93,94,96,99]. The risk of cerebral necrosis is significantly increased after adjuvant radiotherapy and occurred in 0,1% [69], 4,2% [97] and 12,5% [7] of patients. An irradiation of the optic apparatus conducted to blindness in 5% of patients receiving 50 Gy but in 50% of patients receiving 65 Gy. Further complications may include hypopituitarism and cognitive decline [69,100,101]. The side effects of radiation therapy have to be weighed with the benefits and the patient should have a clear knowledge of the associated risks. 8.1.3. Current clinical trials: an ongoing key prospective and randomized proposal Most of the studies conducted on atypical meningiomas have retrospective designs and many studies were conducted before the new 2007 WHO classification and therefore, cannot be easily

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interpreted, given the change in definition of benign and atypical meningioma. Current data support the use of adjuvant RT for atypical meningiomas, at least after STR. A real debate persists for patients with newly diagnosed atypical meningiomas after GTR. They may be managed either with a close observation or with early postoperative RT [7,10,70,94,95]. With an elevated MIB-1 index (but a clear cut-off is missing) or with a skull-base location, an early adjuvant irradiation is often preferred but the protocols of treatment are different among different centres. A prospective or randomized clinical trial should be performed, addressing the role of early adjuvant EBRT after GTR in atypical meningiomas in reducing recurrence rate when compared to an active watch and wait strategy. The phase III “ROAM/EORTC no. 1308”, a multicentre RCT, will probably answer this question: primary outcome is in fact the time to MRI evidence of local recurrence. The study is powered to detect an absolute reduction in recurrence rate from 40% (reference arm) to 20% [102]. 8.2. Chemotherapy Cytotoxic agents have shown disappointing results in the management of meningiomas. Their role has therefore remained limited. Chemotherapy is reserved for refractory meningiomas, as adjuvant treatment, and novel targeted agents are currently being evaluated in this setting. Patient series and small trials with hydroxyurea, interferon alpha 2B and Sandostatin® (octreotide) long acting release (LAR® ) have been published. In a recent review of Moazzam et al. [103], hydroxyurea showed limited effect on tumor control, with 65% of patients having ongoing tumor progression despite treatment. Cyclophosphamide, adriamycin, vincristine, isofosfamide/mesna or adriamycin/dacarbazine have also been administered in patients with atypical meningiomas, although the experience is limited to small case series [27]. Chamberlain et al. [104] investigated the effects of Sandostatin® LAR® , in a group of 16 patients. One third of patients showed a clinical response, the other third experienced a clinical stability while the last third experienced systemic progression. These authors postulated that through a screening for meningioma expression of somatostatin receptors (via octreotide scintigraphy), better results could be achieved. As meningiomas express high levels of PR in about 2/3 of cases and more rarely estrogen receptors [105], estrogen and progesterone receptor antagonists have been studied. A recent systematic review [106] showed how no clear evidence exist in recommending mifepristone for inoperable meningiomas. This might be linked to the fact that high-grade meningiomas present a poor PR expression. Analogous conclusions were drawn for tamoxifen [107]. Several EGFR inhibitors were conceived and used to control tumoral growth. Herceptin, Erbitux, Tarceva, Iressa, Maztuzumab are some antagonists blocking the cascade leading to proliferation and angiogenesis [108]. Geftinib and Erlotinib were evaluated in clinical trials by the North American brain tumor coalition (NABTC) [109] and although the treatment was well tolerated, they did not show a significant activity. Inhibitors of the Mitogen activated protein kinase [MAPK) or Phosphoinositide 3-kinase (PI3 K) pathways may be also candidate for future treatments. PDGF may act as mitogenic signal and the tyrosine-kinase imatinib may inhibit the action of PDGF-associated tyrosine kinases. A phase II study [40], however, did not show the expected results and no benefit was evident from Imatinib administration. When a protease inhibitor was added, a decrease in tumor survival, growth and colony formation was observed [110]. Sunitinib is less specific and it seems to inhibit different protein kinase receptors, including PDGFR and VEGFR and it is currently under investigation [40]. This

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molecule was shown to have significant cytostatic and antimigratory effect on human meningioma cells in vitro [111]. In a single arm phase II study [112] with recurrent meningiomas (30 atypical and 6 anaplastic), the administration of Sunitinib resulted in a median PFS and OS of 5.2 months and 24.6 months respectively, meeting the primary endpoint and warranting the extension to a phase III trial. High-grade meningiomas show up-regulation of hypoxiarelated factors and an important angiogenic activity, suggesting that antiangiogenic agents might be a valid treatment option. To date, however, the efficacy of this approach has not been confirmed in any prospective randomized trial, and they have been limited to case reports and small retrospective series [113,114]. A combination of inhibitors of multiple pathways may be the option to obtain significant responses in meningioma patients. 9. Debated issues and practical management Due to the lack of randomized controlled trials or even prospective studies, the production of guidelines and the definition of standardized protocols for the treatment for atypical meningiomas are currently not possible. We did not perform a systematic review but according to the quality of the studies presented in literature only an EBM level III evidence may be obtained. The evidence to support surgery in atypical meningiomas is in fact mainly based on retrospective studies and patients included are often diagnosed on pre-WHO 2007 criteria. A multidisciplinary collaboration among neurosurgeons, oncologists, radiotherapists, pathologists and neuroradiologists represents the first step towards a more comprehensive management. A complete resection should be attempted in cases where the surgical risks of postoperative neurological morbidities are limited [66,115] but the superiority of Simpson grade I versus grade II-III is not well defined [10,65,67,68,70,71]. The role of adjuvant therapies after GTR is still object of debate. GTR is considered sufficient in many reports [4,93,94,99,116], while some authors have advocated adjuvant radiation therapy even after GTR [7,87,88,96]. According to the algorithm illustrated by Sun et al. [65], after GTR the pathological features may represent an important step in the decisional algorithm. High-risk features consist in brain invasion, mitotic index superior or equal to 8 or cellular “sheeting” [65]. If these criteria are absent, the patient may be monitored with serial MRI with a close follow-up. On the contrary, if these features are present, adjuvant EBRT may be considered. According to Mair et al., SRS rather than EBRT would be advisable after GTR of atypical meningiomas [94]. The aspect of recurrence is highly significant in patients with atypical meningiomas, as it shorten the overall survival [66,95]. According to the review of Sun et al. [65], no evidence exists to recommend salvage surgery for recurrent atypical meningiomas versus salvage EBRT or SRS. In fact, according to the review of Rogers et al. [117], a new resection is advisable in case of recurrence of atypical meningiomas. This remains a highly debated question and every individual case should thus be considered separately on the bases of the location, the size of the residual or recurrent tumors. STR is considered insufficient for the management of atypical meningiomas and it is common opinion that STR should be followed by adjuvant radiotherapy (either as SRS [80,82,83,85] or EBRT [7,96]). 10. Conclusions Atypical meningiomas represent a clear challenge to treating physicians. Different subtypes exist within this same class of

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