ANTICANCER RESEARCH 35: 6391-6400 (2015) Review Innovative Therapeutic Strategies in the Treatment of Meningioma GERARDO CARUSO1, SAMER K. ELBABAA2, PABLO GONZALEZ-LOPEZ3, VALERIA BARRESI4, MARCELLO PASSALACQUA1 and MARIA CAFFO1 1Neurosurgical Clinic, Department of Neuroscience, and 4Department of Human Pathology, University of Messina, Messina, Italy; 2Department of Neurological Surgery, Saint Louis University School of Medicine, Saint Louis, MO, U.S.A.; 3Department of Neurosurgery, University Hospital Alicante, Miguel Hernandez University School of Medicine, Alicante, Spain Abstract. Few medical options are available for progressive/ (NF2) on chromosome 22q12.2. This gene encodes the recurrent and atypical/anaplastic meningiomas. New merlin structural protein of the membrane. Typically, developments in chemotherapeutic options for meningiomas individuals with NFT2 develop multiple meningiomas. have been explored over the past decade. We review the more About 90% of meningiomas are classified according to the recent literature to recognize studies investigating recent World Health Organization (WHO) grading system as WHO medical and chemotherapeutic agents that have been grade I (2). This group includes meningothelial, fibroblastic experienced or are currently being tested for meningiomas. and transitional meningiomas. WHO grade I meningiomas Combination therapies affecting multiple molecular targets are generally defined as benign, but, for these histotypes, are currently opening up and present significant promise as recurrence rates are in the range of 7-20% and these have a adjuvant therapeutic options. However, there is an evident clear possibility of progression to higher grades. Atypical need for new molecular studies in order to better understand meningiomas WHO grade II include 5-15% of all the biology of meningiomas and, thus, to identify new and meningiomas (3). These lesions present recurrence rates of more specific therapeutic targets. 30-40% (3). Chordoid and clear cell meningiomas have an aggressive course, with a high rate of recurrence, and are Meningiomas are the most common primary intracranial classified as grade II (4). Anaplastic or malignant neoplasm, constituting over one-third of all brain tumors (1). meningiomas are classified as WHO grade III and account Meningiomas arise from arachnoidal cells of the for 1-3% of cases (3). Grade III tumors have higher leptomeninges and may occur wherever arachnoidal cells are frequencies of local invasion, recurrence, and metastasis. located. The origin of meningioma is yet to be determined. The treatment of choice for benign meningiomas is Certainly radiation therapy used in the treatment of brain represented by total surgical resection, resulting in prolonged tumors is associated with an increased risk of meningioma. disease-free survival (5). Conversely, atypical and malignant Moreover, the presence of progesterone and estrogen meningiomas frequently recur and are associated with a receptors denotes a possible link between the development shorter overall survival (6). Treatment options for recurrence of meningioma and sex hormones. Neurofibromatosis type 2 or incomplete resection include further surgery, conventional (NFT2) is an autosomal-dominant disorder characterized by external beam irradiation, stereotactic radiosurgery and mutations of the tumor suppressor gene neurofibromin 2 systemic therapies. To date, chemotherapies and hormonal therapies have had only a very limited role and have been shown to be generally ineffective. Radiation therapy or stereotactic radiosurgery is limited by radiation neurotoxicity, Correspondence to: Gerardo Caruso, MD, Via Consolare Valeria no. tumor size, and injury to adjacent vascular or cranial nerves. 1, 98124, Messina, Italy. Tel: +39 0902217167, Fax: +39 090693714, e-mail: [email protected] Over the past decades, the use of systemic therapies in the treatment of meningiomas has been the subject of intense Key Words: Meningioma, nanomedicine, surgery, targeted therapies, research and novel promising drugs with therapeutic treatment, review. potential are now being tested in an increased number of 0250-7005/2015 $2.00+.40 6391 ANTICANCER RESEARCH 35: 6391-6400 (2015) clinical trials. Recently nanomedicine, the application of Genes of histone cluster 1 on 6p, as well as genes cyclin B1 nanotechnology to health care, holds great promise for (CCNB1) and marker of proliferation Ki-67 (MKI67) were revolutionizing medical treatments, imaging, drug delivery, shown to be overexpressed in recurrent meningiomas (13, and tissue regeneration. Nanoparticle systems in cancer 14). More, chromosomal aberrations associated with higher- therapies provide better penetration of therapeutic and grade meningioma include 1p, 6q, 10p, 10q, 14q, and 18q diagnostic agents, and a reduced risk in comparison to (15). Other markers that have been reported to correlate with conventional treatments. By using nanotechnology, it is higher-grade meningioma include the B-cell lymphoma 2 possible to deliver the drug to the targeted tissue and release (BCL2) proto-oncogene, p53, p51, alterations in tumor- the drug at a controlled rate. suppressor genes, the apoptosis antigen 1 (FAS receptor or Herein, we review the current literature for therapeutic APO1) transmembrane protein, the extracellular matrix approaches for meningiomas. In particular, after discussing protein tenascin, and five novel meningioma-expressed the standard therapy for meningiomas, including surgery and antigens (15-17). Immunohistochemical staining with the radiation therapy, we focus on novel therapeutic strategies in MIB-1 antibody (Ki-67) has consistently correlated with the treatment of recurrent and malignant meningiomas, meningioma recurrence (18). Vascular endothelial growth highlighting the emerging role of targeted molecular factor (VEGF) has also been associated with recurrence due therapies. to increased neovascularization (19). Osteopontin, a factor regulating several processes in tumor progression, is more Current Treatments highly expressed in recurrent compared to non-recurrent meningiomas and in grade II compared with grade I Surgery. Meningiomas grow by expanding, leading to meningiomas (20). However, subtotal resection alone remains compression of the adjacent structures (7). For symptomatic common in practice, and in some series of patients with 10 or progressively enlarging meningiomas, complete surgical to 20 years of follow-up, the 5-, 10-, and longer than 15-year excision of the tumor bulk, and surrounding dural progression rates following subtotal resection were 37 to attachment, is recommended. Prognostic variables predictive 47%, 55 to 63%, and greater than 70%, respectively (21). of survival in patients with meningiomas include the extent of resection, histological grade, patient’s age, and tumor Radiation therapy. The role of surgery alone, especially for location. The completeness of surgical removal is an atypical and malignant meningiomas, can sometimes be important prognostic feature (8). The best accepted factor for unsuccessful. Factors considered in the decision to use prediction of recurrence is the Simpson grading system, radiation therapy include the extent of resection, grade, and which evaluates invasion of the venous sinuses, tumor histological subtype, as well as age (in the case of pediatric nodules in adjacent dura, and infiltration of bone by meningiomas). meningothelial cells as chief causes for recurrence (9). Several types of external-beam radiation exist, including Patients with a Simpson grade 1 (complete removal) modern approaches such as photon-based stereotactic meningioma have a 10-year recurrence rate of 9% compared radiosurgery and hypofractionated radiation therapy. to patients with a Simpson grade 3 (complete removal, Treatment plans may be directed to the remaining lesion without coagulation of dural attachment or resection of following subtotal resection, or the resection cavity plus a involved sinus or hyperostotic bone) meningioma, for whom margin of approximately 1 cm following gross total resection the 10-year recurrence rate is about 29%. Kinjo et al. of higher grade tumors. Preliminary observational studies classified a more extensive resection as “grade zero”, have demonstrated that immediate postoperative radiation requiring gross total resection of the primary, any improves the outcomes in patients with WHO grade II and hyperostotic bone, and all involved dura with a 2 cm dural III meningiomas (22). Aghi and colleagues, in a series of 108 margin (10). patients with atypical meningiomas who underwent gross More factors may represent probable causes of recurrence total resection, showed that immediate postoperative in meningiomas. Extent of tumor resection, histological type radiation reduces local tumor recurrence and improves and WHO grade, and brain invasion are prognostic factors of survival of patients (23). Radiation necrosis, exacerbation of meningioma recurrence. Sphenoid wing and parasagittal peritumoral edema and cranial nerve palsy are the principle meningiomas recur most frequently because of their location complications observed in patients undergoing radiation and sinus attachments. The presence of remaining therapy (22). meningotheliomatous cells on dural strips or the presence of neoplastic dural cells around the site of craniotomy, might be Radiosurgery. Radiosurgery can represent an effective reasons for recurrence (11, 12). The possibility of a primary or adjunctive treatment for grade I meningiomas