Despite recent advances in the treatment of malignant gliomas (World Health Organization grade III and grade IV tumors- Glioblastoma Multiforme, Anaplastic Astrocytoma and Anaplastic Oligodendroglioma), the overall prognosis remains poor. Tumor recurrence in malignant glioma is inevitable, and associated with reduced overall survival (OS). Bevacizumab is approved for use in progressive GBM as a second line treatment, and is associated with improvements in progression free survival (PFS). However, all GBM patients eventually recur on bevacizumab therapy, with a very short OS after bevacizumab failure. No FDA-approved therapy is available for this clinical setting. Etoposide crosses the blood-brain barrier and has activity in recurrent malignant gliomas. The use of bevacizumab with etoposide in recurrent malignant gliomas in the setting of bevacizumab resistance is evaluated in this review. Bevacizumab and etoposide combined therapy is associated with radiographic response and effectiveness in selected patients.

NovoTTF treatment is an FDA approved treatment strategy for recurrent Glioblastoma multiforme (GBM) management which employs alternating electric fields to the region of the malignant tumor through probes on the patient's head which is thought to improve time to disease progression of GBM via cell cycle mitosis disruption. A patient is described with recurrent GBM who had disease progression following initial standard surgical treatment and concomitant chemo-radiotherapy and was found to have sarcomatous transformation after initiation of NovoTTF-100A electrical device therapy with bevacizumab. Upon tumor progression, less than two years after initial diagnosis, the patient underwent surgical resection which revealed transformation from a GFAP-positive WHO grade IV astrocytoma into a GFAP-negative, reticulin-positive sarcoma with rhabdomyoid features following histopathological evaluation. The possibility of a causal connection between the NovoTTF therapy and sarcomatous transformation needs to be further evaluated. No such case of sarcoma progression in the CNS following chemo-radiotherapy and/or electrical current treatment for Glioblastoma multiforme has been reported in the literature.

Abstract OBJECTIVE: To investigate the toxicity, tolerability and efficacy of the combination of ixazomib and standard chemoradiation therapy for newly diagnosed MGMT methylated GBM patients.

BACKGROUND

GBM is the most aggressive primary malignant brain tumor. Standard therapy with temozolomide and radiotherapy after the surgery offers limited overall survival (OS). The median OS in patients with MGMT methylation is still less than 2 years. Our recent phase II clinical trial found that the addition of bortezomib, a proteasome inhibitor, to the standard therapy, offered mild survival benefit (19 months) for the entire group of GBM patients. However, significant improvement of OS and progression free survival (PFS) were found in the MGMT methylated patients when compared to MGMT unmethylated patients (OS: 49.4 vs 15.6 months, p=0.0002; PFS: 24.7 vs 5.1 months, p=0.00004) [Kong et al. Int J Radiation Oncology Biol Phys 2018]. Ixazomib is a newer generation of proteasome inhibitor and has demonstrated similar selectivity and potency to bortezomib in biochemical and cell-based assays. While bortezomib can be administered via injection, ixazomib is taken orally, which is more convenient. HYPOTHESIS: Adding ixazomib to standard therapy improve the survival of the patients with newly diagnosed MGMT-methylated GBM compared to standard therapy. STUDY DESIGN: This is a randomized, active controlled, open label phase I/II study of Ixazomib plus standard therapy versus standard therapy. Primary and secondary endpoints are PFS, 12, 24, 36 and 48 month survival rates and response duration. The study consists of two parts: In part I, the maximum tolerated dose (MTD) is decided by using 3 + 3 design with dose limiting toxicity (DLT) method. In part II, randomize the patients to the combination therapy or the standard therapy arm. Safety will be assessed by CTCAE V4.03. We will use Kaplan-Meier estimates for survival data and a stratified log-rank test for the randomization strata.

Optune^® treatment is a US FDA-approved treatment for glioblastoma (GBM) that employs alternating electric fields. Tumor treating field (TTF) therapy can exert its effects on GBM via cell cycle mitosis disruption and cytokinesis. We describe a patient with recurrent GBM who had disease progression following standard surgical treatment and concomitant chemoradiotherapy, and was found to have sarcomatous transformation after initiation of TTF therapy with bevacizumab. Upon tumor progression, repeat surgical resection revealed transformation into a GFAP-negative, reticulin-positive sarcoma with rhabdomyoid features. The possibility of a causal connection between TTF therapy and sarcomatous transformation needs to be further evaluated. No such case of apparent sarcoma formation in the CNS following chemoradiotherapy and/or TTF treatment for GBM has been reported.

Abstract Meningioma is the most common primary intracranial tumor in adults. Thorough majority of tumors are slow growing, many patients fail first-line treatments with surgery and/or radiation. Others are poor surgical candidates for definitive surgical resection due to their age, tumor location or associated medical comorbidities. Few targeted therapies and biologics for meningioma are studied, and they have limited efficacy. This study aims to assess the efficacy and safety of Sandostatin LAR as a potential treatment for recurrent, treatment resistant meningiomas. The retrospective chart review included patients over 18 years of age and diagnosed with meningioma who were administered Sandostatin LAR from 01/01/2010 until 06/01/2017 at the University of California, Irvine (UCI). The primary endpoints were overall survival (OS) and progression-free survival (PFS). The secondary endpoint was assessing safety. There were 47 patients included in the chart review. The mean age was 64 years old and 69.6% were female. The mean KPS score was 80 (60-100). The majority of patients were diagnosed with WHO grade 1 meningioma (73.3%) compared to WHO grade 2 (11.1%) and WHO grade 3 (15.6%). Of the 47 patients, 14 experienced disease progression and 6 died. The mean overall survival times for grade 1, 2, and 3 were 4.5, 2.3, and 0.91 years respectively. Median time to progression for grade 1, 2, and 3 were 3.1, 2.3, and 0.20 years respectively. The most common AE was diarrhea which occurred in 19 out of 47 patients. Overall, Sandostatin LAR was well tolerated. This is the largest reported cohort of meningioma patients treated with Sandostatin LAR and it suggests that Sandostatin LAR can be an effective, well tolerated treatment for these patients.