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Glioblastoma (GBM) pathologically is defined as an infiltrative glioma and salvage therapy with bevacizumab is believed to increase the incidence of diffuse and distant invasion as assessed radiographically. Eighty adult patients with glioblastoma were treated with surgery followed by radiotherapy (RT) and concurrent and adjuvant temozolomide (TMZ). At first recurrence, 80 patients were treated with single agent bevacizumab. At time of progression, 57 patients were treated with bevacizumab and a cytotoxic chemotherapy, cytotoxic chemotherapy alone or on an investigational trial. Magnetic resonance imaging (MRI) were analyzed at four time points in each patient; at presentation, at first, second and third recurrence. Four patterns of radiographic disease were assessed, local (unifocal disease), distant (second lesion noncontiguous with primary lesion), multifocal (>2 lesions including leptomeningeal dissemination) and diffuse. At presentation 87.5% of glioblastoma were local, 6.25% distant, 3.75% multifocal and 2.5% diffuse. At first recurrence following progression on RT/TMZ and before initiation of bevacizumab, 80% were local, 7.5% distant, 6.25% multifocal (including 1 with CSF dissemination) and 6.25% diffuse. At second recurrence following progression on bevacizumab, 71.25% were local, 8.75% distant, 8.75% multifocal (2/7 with CSF dissemination) and 11.25% were diffuse. At third recurrence (57 patients evaluable), 71.25% were local, 7.0% distant, 7.0% multifocal and 14.0% were diffuse. Survival following progression on bevacizumab did not differ by pattern of radiographic recurrence. A majority of adult patients with GBM at diagnosis manifest MRI-defined local disease and maintain this pattern notwithstanding multiple recurrences and treatment with bevacizumab.

Temozolomide-based chemotherapy represents an incremental improvement in the treatment of patients with high-grade gliomas. Notwithstanding a survival benefit in a subset of patients with high-grade gliomas, temozolomide (TMZ; Temodar ® , Schering-Plough Pharmaceuticals, NJ, USA) is the primarily palliative treatment for the vast majority of patients. Indeed, for patients with newly diagnosed glioblastoma, the median increase in survival for treatment with TMZ and radiotherapy is only 2.5 months compared with radiotherapy alone. Additionally, recent studies suggest that 60-75% of patients with glioblastoma derive no benefit from treatment with TMZ. For the treatment of recurrent anaplastic gliomas, more than 50% of patients fail TMZ treatment with cancer progression at 6 months, demonstrating that TMZ is only a modestly effective chemotherapy. In addition, 15-20% of patients treated with TMZ develop clinically significant toxicity, which can leave further treatment unsafe. Despite the availability of TMZ, there is still a substantial need for a chemotherapeutic agent that is more effective and safe. In fact, there still remains a significant unmet need for more effective treatments of high-grade gliomas (improved palliation or cure), whether that treatment be by surgery, radiotherapy, chemotherapy or any yet to be developed type of treatment, such as 'targeted therapies'.

Treatment of leptomeningeal metastasis (LMD) remains challenging due to advanced systemic disease at presentation and limited treatment options. All patients underwent standard pre-treatment LMD evaluation including CSF assessment (cytology or flow cytometry), brain and spine MR imaging, and radioisotope CSF flow study. DepoCyt (liposomal cytarabine) was administered intraventricularly ( n  = 80) or intralumbar ( n  = 40) at 50 mg every 2 weeks ×4 and then every 4 weeks ×6 in responding patients. Dexamethasone (4 mg orally twice per day ×5 days) was co-administered with each DepoCyt treatment. Patients were seen with each DepoCyt treatment and assessed for toxicity. 120 adult patients [median age 51 years (range 33–68)] with LMD were treated with DepoCyt. DepoCyt Common Toxicity Criteria ≥Grade 3 neurotoxicity was seen in 60 cycles (11.5 %) in 28 patients (23.3 %). Toxicity included bacterial meningitis (3.75 % of ventricular treatments: 0 % of lumbar treatments); chemical meningitis (17.5:15 %); communicating hydrocephalus (3.75:5 %); conus medullaris/cauda equina syndrome (5:5 %); decreased visual acuity (5:2.5 %); encephalopathy (5:5 %); leukoencephalopathy (7.5:2.5 %); myelopathy (2.5:2.5 %); radiculopathy (1.25:5 %); and seizures (1.25:2.5 %). Distribution of toxicity was similar regardless of route of administration (ventricular vs. lumbar). Toxicities were transient in 34 episodes (57 %) and permanent in 26 (43 %). There were no treatment-related deaths however 20 treatment-related toxicities (32.2 %) required hospitalization. In this retrospective case series, DepoCyt is generally well tolerated however a subset of patients (12.5 %) not easily identified pre-treatment, develop serious treatment-related neurological complications that may be persistent and impact quality of life.

Primary spinal cord tumors constitute 2% to 4% of all central nervous system neoplasms and are characterized based on their location as intramedullary, intradural extramedullary, and extradural. A contemporary literature review of primary intradural spinal cord tumors was performed. Among intramedullary tumors, ependymomas are more common and often can be surgically resected. However, astrocytomas infiltrate the spinal cord and complete resection is rare. Intradural extramedullary tumors include schwannomas, neurofibromas, and meningiomas and are usually amenable to surgical resection. Radiotherapy is reserved for malignant variants and recurrent gliomas, whereas chemotherapy is administered for recurrent primary spinal cord tumors without surgical or radiotherapy options. Early recognition of the signs and symptoms related to primary spinal cord tumors facilitates timely discovery, treatment, potentially minimizes neurologic morbidity, and may improve outcome. Treatment consists of surgical resection, and predictors of outcome include preoperative functional status, histologic grade of tumor, and extent of surgical resection.

Despite advances in upfront therapy, the prognosis in the great majority of patients with glioblastoma (GBM) is poor as almost all recur and result in disease-related death. Glioblastoma are highly vascularized cancers with elevated expression levels of vascular endothelial growth factor (VEGF), the dominant mediator of angiogenesis. A compelling biologic rationale, a need for improved therapy, and positive results from studies of bevacizumab in other cancers led to the evaluation of bevacizumab in the treatment of recurrent GBM. Bevacizumab, a humanized monoclonal antibody that targets VEGF, has been shown to improve patient outcomes in combination with chemotherapy (most commonly irinotecan) in recurrent GBM, and on the basis of positive results in two prospective phase 2 studies, bevacizumab was granted accelerated approval by the US Food and Drug Administration (FDA) as a single agent in recurrent GBM. Bevacizumab therapy is associated with manageable, class-specific toxicity as severe treatment-related adverse events are observed in only a minority of patients. With the goal of addressing questions and controversies regarding the optimal use of bevacizumab, the objective of this review is to provide a summary of the clinical efficacy and safety data of bevacizumab in patients with recurrent GBM, the practical issues surrounding the administration of bevacizumab, and ongoing investigations of bevacizumab in managing GBM.

Until recently, the standard of care for the treatment of glioblastoma involved surgical resection followed by radiation therapy with or without nitrosourea-based chemotherapy. In 2005, a large trial established adjuvant temozolomide chemotherapy and radiotherapy as a new standard therapy. This Review summarizes new developments in the treatment of glioblastoma and speculates on possible future treatment strategies for managing this aggressive cancer. Glioblastoma is both the most common and most aggressive primary brain tumor. Until recently, the standard of care involved maximal safe surgical resection followed by radiation therapy with or without nitrosourea-based chemotherapy. In 2005, the results of a large clinical trial examining the role of adjuvant chemotherapy in management of newly diagnosed glioblastoma were published. This study created a new standard of adjuvant treatment, using concurrent and sequential temozolomide in the initial therapy of glioblastoma. A companion tumor biology study identified the prognostic role of O 6 -methylguanine-DNA methyltransferase (MGMT) status in patients with newly diagnosed glioblastoma. Several preliminary studies have been initiated to address the issue of resistance and suppression of MGMT activity, and have used alternative temozolomide dosing schedules and O 6 -guanine mimetic agents as substrates for MGMT. In addition, recent studies have attempted to define mechanisms responsible for the apparent synergy between temozolomide and radiotherapy. Lastly, an increased understanding of the molecular biology of glioblastoma has provided new leads for the adjuvant treatment of this disease. This Review summarizes new developments in treatment of glioblastoma and speculates on possible future treatment strategies for managing this aggressive cancer. Key Points Temozolomide (TMZ) as a single agent used concurrently and sequentially with radiation therapy is the new standard of care for patients with newly diagnosed glioblastoma who meet the EORTC/NCI trial pre-specified inclusion criteria TMZ-induced resistance is predominantly mediated by two DNA repair mechanisms: MGMT and DNA mismatch repair, which increase exposure to TMZ, and direct inhibition of MGMT, which might circumvent both intrinsic and acquired resistance to TMZ Synergy between TMZ and radiation therapy seems to involve an increased number of radiation-induced double-strand DNA breaks Synergies between TMZ and targeted molecular therapeutics, in particular antiangiogenic and anti-integrin therapies, are being studied and promising preliminary results have been reported

Pleomorphic xanthoastrocytoma (PXA) is a World Health Organization Grade 2 glioma that is uncommon (<1 % all adult gliomas) and seen primarily in children and young adults. PXA has been demonstrated to manifest the V600E BRAF mutation in nearly 70 % of all tumors, a mutation that constitutively activates the BRAF/MEK signaling pathway. Assess response and toxicity of a BRAF inhibitor, vemurafenib, in recurrent PXA manifesting the V600E mutation. Four adults [2 males; 2 female: median age 45 years (range 34–53)] with surgery, radiation and alkylator refractory recurrent PXA demonstrating the BRAF mutation (V600E) were treated with vemurafenib. A cycle of vemurafenib was defined as 4 weeks of continuous therapy. All toxicities seen were grade 2 and included arthralgia, photosensitivity, fatigue and nausea (1 patient each). The median number of cycles of therapy was 5 (range 2–10). Radiographic response was progressive disease in 1, stable disease in 2 and partial response in 1. Median progression free survival was 5 months (range 2–10 months). Median overall survival was 8 months (range 4–14 months). In this small retrospective series of select patients with recurrent PXA manifesting the BRAF V600E activating mutation, vemurafenib appears to have single agent activity with manageable toxicity. Confirmation in a larger series of similar patients is required.

Hydroxyurea (HU), an orally administered chemotherapy, has become the de facto standard chemotherapeutic agent in patients with surgically and radiation refractory meningiomas based on a limited literature. A retrospective case series of 35 patients with recurrent WHO Grade 2 ( n  = 22) or 3 ( n  = 13) meningioma treated with HU following progression after surgery and radiotherapy was collated with primary study objectives of overall response rate, median and progression free survival (PFS) at 6-months. Thirty-five patients (25 women; 10 men: median age 63 years, range 34–86) with recurrent high-grade meningioma were treated with HU (1,000 mg/m 2 orally divided twice per day; one cycle operationally defined as 4 weeks of daily HU). Patients had progressed radiographically after prior therapy with surgery (35/35) and radiotherapy (35/35: external beam radiotherapy 35/35; stereotactic radiotherapy 35/35). No patient received prior chemotherapy or targeted therapy before instituting HU. Patients received 0.5–7 cycles (median 2.0) of HU with modest toxicity (28.5% all grades and 8.5% grade 3+ anemia or fatigue). There were no radiographic responses, 43% of patients had stable disease and 57% manifested progressive disease at first evaluation. The overall PFS was 3.0% at 6 months (median PFS 2.0 months; 95% CI 1.6–2.4). The majority of patients (80%) following progression on HU were subsequently treated on an investigational trial. In this retrospective series, HU though well tolerated and convenient appeared to have very limited activity, raise questions of what constitutes effective salvage therapy and indicates an unmet need for alternative treatments for recurrent high-grade meningiomas.

Leptomeningeal metastasis (LM) results from metastatic spread of cancer to the leptomeninges, giving rise to central nervous system dysfunction. Breast cancer, lung cancer, and melanoma are the most frequent causes of LM among solid tumors in adults. An early diagnosis of LM, before fixed neurologic deficits are manifest, permits earlier and potentially more effective treatment, thus leading to a better quality of life in patients so affected. Apart from a clinical suspicion of LM, diagnosis is dependent upon demonstration of cancer in cerebrospinal fluid (CSF) or radiographic manifestations as revealed by neuraxis imaging. Potentially of use, though not commonly employed, today are use of biomarkers and protein profiling in the CSF. Symptomatic treatment is directed at pain including headache, nausea, and vomiting, whereas more specific LM-directed therapies include intra-CSF chemotherapy, systemic chemotherapy, and site-specific radiotherapy. A special emphasis in the review discusses novel agents including targeted therapies, that may be promising in the future management of LM. These new therapies include anti-epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors erlotinib and gefitinib in nonsmall cell lung cancer, anti-HER2 monoclonal antibody trastuzumab in breast cancer, anti-CTLA4 ipilimumab and anti-BRAF tyrosine kinase inhibitors such as vermurafenib in melanoma, and the antivascular endothelial growth factor monoclonal antibody bevacizumab are currently under investigation in patients with LM. Challenges of managing patients with LM are manifold and include determining the appropriate patients for treatment as well as the optimal route of administration of intra-CSF drug therapy.

Treatment of recurrent primary CNS lymphoma (PCNSL) though not standardized most often utilizes whole brain radiotherapy, re-challenge with high-dose methotrexate, or administration of an alkylating chemotherapy. High-dose cytarabine (HD-araC) has been advocated as an active agent in PCNSL but limited information exists regarding single agent activity in the recurrent setting. A retrospective review of 14 patients (10 males, 4 females: median age 60 years) with recurrent PCNSL treated at second recurrence with single agent HD-araC. HD-araC was administered at 3gm/m 2 over a 3-h infusion every 12 h for a total of 4 doses (defined as a cycle of therapy). GM-CSF was administered at conclusion of HD-araC. Patients were clinically and radiographically evaluated every 4-weeks. Common toxicity criteria Grade 3 or 4 toxicity included thrombocytopenia (11 patients; 79 %), anemia (10; 71 %), fatigue (8; 57 %), mucositis (8; 57 %), neutropenia (8; 57 %) and neutropenic fever (5; 36 %). No patient discontinued therapy due to toxicity nor were there any treatment-related deaths. Best response to HD-araC was stable disease in 6 patients (43 %), partial response in 5 (36 %) and progressive disease in 3 (21 %). Median progression free survival 3 months (range 2–5 months; 95 % CI 2–4 months) and progression free survival was 0 % at 6-months. Median survival after onset of HD-araC was 12 months (range 3–18+ months; 95 % CI 3–15 months). Single agent HD-araC has limited activity in recurrent PCNSL and is associated with significant toxicity in this small retrospective study.