Differential regulation of TGF-β-induced, ALK-5-mediated VEGF release by SMAD2/3 versus SMAD1/5/8 signaling in glioblastoma

Background The transforming growth factor (TGF)-β and vascular endothelial growth factor (VEGF) pathways have a major role in the pathogenesis of glioblastoma, notably immunosuppression, migration, and angiogenesis, but their interactions have remained poorly understood. Methods We characterized TGF-β pathway activity in 9 long-term glioma cell lines (LTCs) and 4 glioma-initiating cell lines (GICs) in relation to constitutive and exogenous TGF-β-induced VEGF release. Results were validated using The Cancer Genome Atlas transcriptomics data. Results Glioma cells exhibit heterogeneous patterns of constitutive TGF-β pathway activation reflected by phosphorylation not only of SMAD2 and SMAD3 but also of SMAD1/5/8. Constitutive TGF-β pathway activity depends on the type I TGF-β receptor, ALK-5, and accounts for up to 69% of constitutive VEGF release, which is positively regulated by SMAD2/3 and negatively regulated by SMAD1/5/8 signaling in a cell line-specific manner. Exogenous TGF-β induces VEGF release in most cell lines in a SMAD- and ALK-5-dependent manner. There is no correlation between the fold induction of VEGF secretion induced by TGF-β compared with hypoxia. The role of SMAD5 signaling is highly context and cell-line dependent with a VEGF inhibitory effect at low TGF-β and pSMAD2 levels and a stimulatory effect when TGF-β is abundant. Conclusions TGF-β regulates VEGF release by glioma cells in an ALK-5-dependent manner involving SMAD2, SMAD3, and SMAD1/5/8 signaling. This crosstalk between the TGF-β and VEGF pathways may open up new avenues of biomarker-driven exploratory clinical trials focusing on the microenvironment in glioblastom

Is there a world beyond bevacizumab in targeting angiogenesis in glioblastoma?

INTRODUCTION: Antiangiogenic approaches are currently the dominating experimental therapeutic strategy in glioblastoma. First enthusiasm was provoked by promising radiological response rates and an apparent clinical benefit with some of these agents. Major limitations include the modest number of durable responses, the lack of cytotoxic antitumor activity, of synergy when combined with chemotherapy and of an overall survival benefit. AREAS COVERED: We review the rationale as well as preclinical and clinical evidence for the future development of antiangiogenic agents in glioblastoma. The most prominent approach targets VEGF and includes agents such as the VEGF antibody bevacizumab, the VEGF receptor fusion protein aflibercept or the tyrosine kinase inhibitors cediranib and XL-184. Inhibition of angiogenic pathways by small molecules, for example, enzastaurin, or anti-integrin-based approaches, for example, cilengitide, represent alternative strategies. EXPERT OPINION: Enzastaurin and cediranib failed in randomized Phase III trials in recurrent glioblastoma, aflibercept in Phase II. By contrast, bevacizumab was conditionally approved in many countries. Recently completed Phase III trials for bevacizumab and cilengitide in the first-line setting will define the future role of these agents. This intense clinical trial activity reflects the hope that antiangiogenic agents will become part of the limited therapeutic options for glioblastoma

Therapeutic options in recurrent glioblastoma-An update

INTRODUCTION Standards of care are not yet defined in recurrent glioblastoma. METHODS We reviewed the literature on clinical trials for recurrent glioblastoma available in PubMed and American Society of Clinical Oncology (ASCO) abstracts until June 2015. RESULTS Evidence is limited due to the paucity of randomized controlled studies. Second surgery or re-irradiation are options for selected patients. Alkylating chemotherapy such as nitrosoureas or temozolomide and the vascular endothelial growth factor (VEGF) antibody, bevacizumab, exhibit comparable single agent activity. Phase III data exploring the benefit of combining bevacizumab and lomustine are emerging. Novel approaches in the fields of targeted therapy, immunotherapy, and tumor metabolism are coming forward. Several biomarkers are being explored, but, except for O(6)-methylguanine DNA methyltransferase (MGMT) promoter methylation, none has assumed a role in clinical practice. CONCLUSION Proper patient selection, development of predictive biomarkers and randomized controlled studies are required to develop evidence-based concepts for recurrent glioblastoma

Venous thromboembolic events in glioblastoma patients: An epidemiological study

BACKGROUND AND PURPOSE Venous thromboembolic events (VTEs) are a major complication in cancer patients, and therefore, also in brain cancer patients, anticoagulants are considered appropriate in the treatment of VTEs. METHODS Frequency, risk factors, and treatment of VTEs, as well as associated complications, were assessed in a population-based cohort of glioblastoma patients in the Canton of Zurich, Switzerland. Correlations between clinical data and survival were retrospectively analyzed using the log-rank test and Cox regression models. RESULTS Four hundred fourteen glioblastoma patients with isocitrate dehydrogenase wild-type status were identified. VTEs were documented in 65 patients (15.7%). Median time from tumor diagnosis to the occurrence of a VTE was 1.8 months, and 27 patients were diagnosed with VTEs postoperatively (within 35 days; 42.2%). History of a prior VTE was more common in patients who developed VTEs than in those who did not (p = 0.004). Bevacizumab treatment at any time during the disease course was not associated with occurrence of VTEs (p = 0.593). Most patients with VTEs (n = 61, 93.8%) were treated with therapeutic anticoagulation. Complications occurred in 14 patients (23.0%), mainly intracranial hemorrhages (n = 7, 11.5%). Overall survival did not differ between patients diagnosed with VTEs and those who had no VTE (p = 0.139). Tumor progression was the major cause of death (n = 283, 90.7%), and only three patients (1.0%) died in association with acute VTEs. CONCLUSIONS Venous thromboembolic events occurred early in the disease course, suggesting that the implementation of primary venous thromboembolism prophylaxis during first-line chemoradiotherapy could be explored in a randomized setting

Neuropathological characteristics of progression after prolonged response to bevacizumab in multifocal hemangioblastoma

Background: Antiangiogenic treatment has been explored in few patients with hemangioblastoma after failure of surgery and radiotherapy. Case Report: We present the first histopathological follow-up study of a bevacizumab-responsive hemangioblastoma that eventually progressed. For a period of 12 months, therapy with bevacizumab achieved a clinical response and radiological stabilization in a patient with progressive multifocal central nervous system (CNS) hemangioblastoma. Subsequently, selected tumor sites showed radiological progression, in particular, the formation of an intramedullary lesion of the initially predominantly leptomeningeal disease. Histology showed diffuse dural invasion by the hemangioblastoma accompanied with a relatively reduced cell density compared to the preserved vessel structures. Conclusion: The pattern of progression upon vascular endothelial growth factor (VEGF)-targeting antiangiogenic treatment in hemangioblastoma may involve increased tumor invasiveness. © 2014 S. Karger GmbH, Freiburg

A risk model for prediction of diagnosis of cancer after ischemic stroke

It remains controversial which characteristics may predict occult cancer in stroke patients. Characteristics of patients with ischemic stroke registered in the Zurich Swiss Stroke Registry (2014 to 2016) were tested for associations with cancer diagnosis after stroke with consideration of death as competing risk for cancer diagnosis. Among 1157 patients, 34 (3%) and 55 patients (5%) were diagnosed with cancer within 1 and 3 years after stroke. Levels of white blood cells (WBC) > 9,600/µl (subdistribution hazard ratio (SHR) 3.68, p = 0.014), platelets > 400,000/µl (SHR 7.71, p = 0.001), and d-dimers ≥ 3 mg/l (SHR 3.67, p = 0.007) were independently associated with cancer diagnosis within 1 year after stroke. Occurrence of ischemic lesions in ≥ 2 vascular territories not attributed to cardioembolic etiology was associated with cancer diagnosed within 1 year after stroke in univariable analysis (SHR 3.69, p = 0.001). The area under the curve of a score from these parameters (score sum 0-4) was 0.73. A score of ≥ 2 had a sensitivity of 43% and specificity of 92% for prediction of cancer diagnosis within 1 year after stroke. We suggest further validation of a score of WBC, platelets, d-dimers and multiple ischemic lesions without cardioembolic stroke etiology for prediction of cancer diagnosis after stroke

Associations of levetiracetam use with the safety and tolerability profile of chemoradiotherapy for patients with newly diagnosed glioblastoma

Background Levetiracetam (LEV) is one of the most frequently used antiepileptic drugs (AED) for brain tumor patients with seizures. We hypothesized that toxicity of LEV and temozolomide-based chemoradiotherapy may overlap. Methods Using a pooled cohort of patients with newly diagnosed glioblastoma included in clinical trials prior to chemoradiotherapy (CENTRIC, CORE, AVAglio) or prior to maintenance therapy (ACT-IV), we tested associations of hematologic toxicity, nausea or emesis, fatigue, and psychiatric adverse events during concomitant and maintenance treatment with the use of LEV alone or with other AED versus other AED alone or in combination versus no AED use at the start of chemoradiotherapy and of maintenance treatment. Results Of 1681 and 2020 patients who started concomitant chemoradiotherapy and maintenance temozolomide, respectively, 473 and 714 patients (28.1% and 35.3%) were treated with a LEV-containing regimen, 538 and 475 patients (32.0% and 23.5%) with other AED, and 670 and 831 patients (39.9% and 41.1%) had no AED. LEV was associated with higher risk of psychiatric adverse events during concomitant treatment in univariable and multivariable analyses (RR 1.86 and 1.88, P < .001) while there were no associations with hematologic toxicity, nausea or emesis, or fatigue. LEV was associated with reduced risk of nausea or emesis during maintenance treatment in multivariable analysis (HR = 0.80, P = .017) while there were no associations with hematologic toxicity, fatigue, or psychiatric adverse events. Conclusions LEV is not associated with reduced tolerability of chemoradiotherapy in patients with glioblastoma regarding hematologic toxicity and fatigue. Antiemetic properties of LEV may be beneficial during maintenance temozolomide

Amino-acid PET versus MRI guided re-irradiation in patients with recurrent glioblastoma multiforme (GLIAA) – protocol of a randomized phase II trial (NOA 10/ARO 2013-1)

Background: The higher specificity of amino-acid positron emission tomography (AA-PET) in the diagnosis of gliomas, as well as in the differentiation between recurrence and treatment-related alterations, in comparison to contrast enhancement in T1-weighted MRI was demonstrated in many studies and is the rationale for their implementation into radiation oncology treatment planning. Several clinical trials have demonstrated the significant differences between AA-PET and standard MRI concerning the definition of the gross tumor volume (GTV). A small single-center non-randomized prospective study in patients with recurrent high grade gliomas treated with stereotactic fractionated radiotherapy (SFRT) showed a significant improvement in survival when AA-PET was integrated in target volume delineation, in comparison to patients treated based on CT/MRI alone. Methods: This protocol describes a prospective, open label, randomized, multi-center phase II trial designed to test if radiotherapy target volume delineation based on FET-PET leads to improvement in progression free survival (PFS) in patients with recurrent glioblastoma (GBM) treated with re-irradiation, compared to target volume delineation based on T1Gd-MRI. The target sample size is 200 randomized patients with a 1:1 allocation ratio to both arms. The primary endpoint (PFS) is determined by serial MRI scans, supplemented by AA-PET-scans and/or biopsy/surgery if suspicious of progression. Secondary endpoints include overall survival (OS), locally controlled survival (time to local progression or death), volumetric assessment of GTV delineated by either method, topography of progression in relation to MRIor PET-derived target volumes, rate of long term survivors (> 1 year), localization of necrosis after re-irradiation, quality of life (QoL) assessed by the EORTC QLQ-C15 PAL questionnaire, evaluation of safety of FET-application in AA-PET imaging and toxicity of re-irradiation. Discussion: This is a protocol of a randomized phase II trial designed to test a new strategy of radiotherapy target volume delineation for improving the outcome of patients with recurrent GBM. Moreover, the trial will help to develop a standardized methodology for the integration of AA-PET and other imaging biomarkers in radiation treatment planning. Trial registration: The GLIAA trial is registered with ClinicalTrials.gov (NCT01252459, registration date 02.12.2010), German Clinical Trials Registry (DRKS00000634, registration date 10.10.2014), and European Clinical Trials Database (EudraCT-No. 2012-001121-27, registration date 27.02.2012)