Stefan Oberndorfer

P450 enzyme inducing and non-enzyme inducing antiepileptics in glioblastoma patients treated with standard chemotherapy

SummaryThe co-administration of antiepileptic drugs (AED) and chemotherapeutic agents in patients with glioblastoma multiforme (GBM) is common. Interactions of chemotherapeutic agents and AED have not been investigated sufficiently. The purpose of this study is to evaluate the effects of enzyme inducing (EI-AED) and non-EI-AED in patients with GBM treated with standard chemotherapeutic agents on survival and haematotoxicity. One hundred and sixty eight glioblastoma patients with standard treatment including surgery, radiotherapy and chemotherapy were retrospectively analysed. Patients were separated into three groups: Group A patients without AED (n=88), Group B patients with EI-AED (n=43), and Group C patients with non-EI-AED (n=37). CCNU was the most frequently used first-line drug in all three groups (Group A: 77%; Group B: 81%; Group C: 78%). Second line treatment, mainly temozolomide, was applicated in 58 of patients and third-line treatment in 9. Carbamazepine was the most frequently administered AED in Group B (81%) and valproic acid in Group C (85%). For statistical analysis, only patients with CCNU first line treatment were calculated. A significant difference regarding survival was detected between Group B (10.8 month) and Group C (13.9 month), as well as increased haematotoxicity for Group C. These results indicate that AED influence the pharmacokinetics of chemotherapeutic drugs in patients with GBM. Valproic acid might be responsible for increasing haematotoxicity. Whether the difference regarding survival between Group B and Group C is due to a decrease of efficacy of chemotherapeutic agents by EI-AED, or due to increased efficacy of chemotherapeutic agents caused by the enzyme inhibiting properties of valproic acid, has to be evaluated in future studies.

The End-of-Life Hospital Setting in Patients with Glioblastoma

Despite aggressive treatment, outcome of patients with glioblastoma is poor. Several distinct clinical problems arise in the terminal stage of this disease. The purpose of this study was to evaluate the end-of-life phase in a hospital setting in patients with glioblastoma. Twenty-nine consecutive patients with glioblastoma, who died in our department, were included in this analysis regarding symptoms, medication, diagnostics, and interventional procedures. The patients were comparable with respect to age, gender, and overall survival with data from the literature. Relevant clinical symptoms, medications, diagnostics, well as interventional procedures increased continuously toward end of life. Pain, epileptic seizures, and symptoms of brain edema were the most frequent clinical symptoms. According to this, most patients were on antiepileptic drugs (AED), steroids, and analgesics. In the last phase, symptoms from brain edema, fever, decrease of vigilance, dysphagia, and pneumonia were the prominent clinical features. Our study demonstrates that the end of life in patients with glioblastoma has several periods with different clinical aspects with respect to symptoms and treatment.

A single-arm phase II Austrian/German multicenter trial on continuous daily sunitinib in primary glioblastoma at first recurrence (SURGE 01-07)

BACKGROUND Due to the redundancy of molecular pathways simultaneously involved in glioblastoma growth and angiogenesis, therapeutic approaches intervening at multiple levels seem particularly appealing. METHODS This prospective, multicenter, single-arm phase II trial was designed to evaluate the antitumor activity of sunitinib, an oral small-molecule inhibitor of several receptor tyrosine kinases, in patients with first recurrence of primary glioblastoma using a continuous once-daily dosing regimen. Patients received a starting dose of sunitinib 37.5 mg, followed by a maintenance dose between 12.5 mg and 50 mg depending on drug tolerability. The primary endpoint was a 6-month progression-free survival (PFS) rate. Secondary endpoints included median PFS, overall survival (OS), safety/toxicity, quality of life, and translational studies on the expression of sunitinib target molecules. RESULTS Forty participants were included in this study, and no objective responses were detected. PFS6 was 12.5%, median PFS 2.2 months, and median OS 9.2 months. Five participants (12.5%) showed prolonged stable disease ≥6 months with a median PFS of 16.0 months (range, 6.4-41.4 mo) and a median OS of 46.9 months (range, 21.2-49.2 mo) for this subgroup. c-KIT expression in vascular endothelial cells (n = 14 participants) was associated with improved PFS. The most common toxicities were fatigue/asthenia, mucositis/dermatitis, dysesthesias, gastrointestinal symptoms, cognitive impairment, leukoctopenia, and thrombocytopenia. Two participants (5%) terminated treatment due to toxicity. CONCLUSION Continuous daily sunitinib showed minimal antiglioblastoma activity and substantial toxicity when given at higher doses. High endothelial c-KIT expression may define a subgroup of patients who will benefit from sunitinib treatment by achieving prolonged PFS. ClinicalTrials.gov Identifier: NCT00535379.

Current approaches to the treatment of paraneoplastic encephalitis

Paraneoplastic neurological syndromes (PNSs) cover a wide range of diseases and involve both the central nervous system (CNS) and peripheral nervous system. Paraneoplastic encephalitis comprises several diseases such as paraneoplastic cerebellar degeneration (PCD), limbic encephalitis (LE), paraneoplastic encephalomyelitis (PEM), brainstem encephalitis, opsomyoclonus syndrome, in addition to other even less frequently occurring entities. LE was the first historically identified CNS PNS, and similarities between other temporal lobe diseases such as herpes encephalitis have been elucidated. In the past few decades several autoantibodies have been described in association with LE. These encompass the classical ‘onconeuronal’ antibodies (abs) such as Hu, Yo, Ri and others, and now additionally abs towards either ion channels or surface antigens. The clinical core findings in LE are various mental changes such as amnesia or confusion, often associated with seizures. Careful characterization of psychiatric manifestations and/or associated neurological signs can help to characterize the syndrome and type of ab. The treatment options in LE depend on the aetiology. In LE caused by onconeuronal abs, the treatment options are poor. In two types of abs associated with LE, abs against ion channels and surface antigens (e.g. NMDA), immunomodulatory treatments seem effective, making these types of LE treatable conditions. However, LE can also occur without being associated with cancer, in which case only immunomodulation is required. Despite effective treatments, some patients’ residual deficits remain, and recurrences have also been described.

European Association for Neuro-Oncology (EANO) guidelines for palliative care in adults with glioma

Patients with glioma present with complex palliative care needs throughout their disease trajectory. The life-limiting nature of gliomas and the presence of specific symptoms related to neurological deterioration necessitate an appropriate and early palliative care approach. The multidisciplinary palliative care task force of the European Association of Neuro-Oncology did a systematic review of the available scientific literature to formulate the best possible evidence-based recommendations for the palliative care of adult patients with glioma, with the aim to reduce symptom burden and improve the quality of life of patients and their caregivers, particularly in the end-of-life phase. When recommendations could not be made because of the scarcity of evidence, the task force either used evidence from studies of patients with systemic cancer or formulated expert opinion. Areas of palliative care that currently lack evidence and thus deserve attention for further research are fatigue, disorders of behaviour and mood, interventions for the needs of caregivers, and timing of advance care planning.

The Last 10 Days of Patients With Glioblastoma Assessment of Clinical Signs and Symptoms as well as Treatment

Background: High-grade gliomas are the most frequent primary brain tumors. Despite improvement in diagnostics and treatment, survival is still poor and quality-of-life issues are of major importance. Little is known regarding the clinical signs and symptoms of dying patients with glioblastoma. Objective: The aim of this study was to investigate signs and symptoms as well as therapeutic strategies in patients with glioblastoma in the end-of-life phase in order to improve end-of-life care. Methods: In this prospective single-center study, clinical data were obtained using a standardized protocol. We descriptively analyzed signs, symptoms, and therapeutic strategies on a daily basis. Results: A total of 57 patients, who died due to glioblastoma in a hospital setting, were included. The most frequent signs and symptoms in the last 10 days before death were decrease in level of consciousness (95%), fever (88%), dysphagia (65%), seizures (65%), and headache (33%). Concerning medication, 95% received opioids. There was a high need for nonsteroidal anti-inflammatory drugs (77%) and anticonvulsants (75%). Steroids were given to 56%. Conclusion: Due to a decrease in level of consciousness and cognitive impairment, assessment of clinical signs and symptoms such as headache at the end of life is difficult. Based on the signs and symptoms in the last days before death in patients with glioblastoma, supportive drug treatment remains challenging. Our study emphasizes the importance of standardized guidelines for end-of-life care in patients with glioblastoma.

Relative survival of patients with non-malignant central nervous system tumours: a descriptive study by the Austrian Brain Tumour Registry

Background:Unlike malignant primary central nervous system (CNS) tumours outcome data on non-malignant CNS tumours are scarce. For patients diagnosed from 1996 to 2002 5-year relative survival of only 85.0% has been reported. We investigated this rate in a contemporary patient cohort to update information on survival.Methods:We followed a cohort of 3983 cases within the Austrian Brain Tumour Registry. All patients were newly diagnosed from 2005 to 2010 with a histologically confirmed non-malignant CNS tumour. Vital status, cause of death, and population life tables were obtained by 31 December 2011 to calculate relative survival.Results:Overall 5-year relative survival was 96.1% (95% CI 95.1–97.1%), being significantly lower in tumours of borderline (90.2%, 87.2–92.7%) than benign behaviour (97.4%, 96.3–98.3%). Benign tumour survival ranged from 86.8 for neurofibroma to 99.7% for Schwannoma; for borderline tumours survival rates varied from 83.2 for haemangiopericytoma to 98.4% for myxopapillary ependymoma. Cause of death was directly attributed to the CNS tumour in 39.6%, followed by other cancer (20.4%) and cardiovascular disease (15.8%).Conclusion:The overall excess mortality in patients with non-malignant CNS tumours is 5.5%, indicating a significant improvement in survival over the last decade. Still, the remaining adverse impact on survival underpins the importance of systematic registration of these tumours.

Trigeminal Neuralgia in Two Patients With Glioblastoma

Headache in glioblastoma patients often indicates raised intracranial pressure by either tumor edema or tumor progression. We report local glioblastoma growth causing cranial nerve lesions as well as trigeminal neuralgia, and highlight pain management in these patients.

MR Imaging–derived Oxygen Metabolism and Neovascularization Characterization for Grading and IDH Gene Mutation Detection of Gliomas

Purpose To explore the diagnostic performance of physiological magnetic resonance (MR) imaging of oxygen metabolism and neovascularization activity for grading and characterization of isocitrate dehydrogenase (IDH) gene mutation status of gliomas. Materials and Methods This retrospective study had institutional review board approval; written informed consent was obtained from all patients. Eighty-three patients with histopathologically proven glioma (World Health Organization [WHO] grade II-IV) were examined with quantitative blood oxygen level-dependent imaging and vascular architecture mapping. Biomarker maps of neovascularization activity (microvessel radius, microvessel density, and microvessel type indicator [MTI]) and oxygen metabolism (oxygen extraction fraction [OEF] and cerebral metabolic rate of oxygen [CMRO2]) were calculated. Receiver operating characteristic analysis was used to determine diagnostic performance for grading and detection of IDH gene mutation status. Results Low-grade (WHO grade II) glioma showed areas with increased OEF (+18%, P < .001, n = 20), whereas anaplastic glioma (WHO grade III) and glioblastoma (WHO grade IV) showed decreased OEF when compared with normal brain tissue (-54% [P < .001, n = 21] and -49% [P < .001, n = 41], respectively). This allowed clear differentiation between low- and high-grade glioma (area under the receiver operating characteristic curve [AUC], 1) for the patient cohort. MTI had the highest diagnostic performance (AUC, 0.782) for differentiation between gliomas of grades III and IV among all biomarkers. CMRO2 was decreased (P = .037) in low-grade glioma with a mutated IDH gene, and MTI was significantly increased in glioma grade III with IDH mutation (P = .013) when compared with the IDH wild-type counterparts. CMRO2 showed the highest diagnostic performance for IDH gene mutation detection in low-grade glioma (AUC, 0.818) and MTI in high-grade glioma (AUC, 0.854) and for all WHO grades (AUC, 0.899) among all biomarkers. Conclusion MR imaging-derived oxygen metabolism and neovascularization characterization may be useful for grading and IDH mutation detection of gliomas and requires only 7 minutes of extra imaging time.

Magnetic resonance imaging biomarkers for clinical routine assessment of microvascular architecture in glioma.

Knowledge about the topological and structural heterogeneity of the microvasculature is important for diagnosis and monitoring of glioma. A vessel caliber and type-dependent temporal shift in the magnetic resonance imaging signal forms the basis for vascular architecture mapping. This study introduced a clinically feasible approach for assessment of vascular pathologies in gliomas using vascular architecture mapping. Sixty consecutive patients with known or suspected gliomas were examined using vascular architecture mapping as part of the routine magnetic resonance imaging protocol. Maps of microvessel radius and density, which adapted to the vasculature-dependent temporal shift phenomenon, were calculated using a costume-made software tool. Microvessel radius and density were moderately to severely elevated in a heterogeneous, inversely correlated pattern within high-grade gliomas. Additionally, three new imaging biomarkers were introduced: Microvessel type indicator allowing differentiation between supplying arterial and draining venous microvasculature in high-grade gliomas. Vascular-induced bolus peak time shift may presumably be sensitive for early neovascularization in the infiltration zone. Surprisingly, curvature showed significant changes in peritumoral vasogenic edema which correlated with neovascularization in the tumor core of high-grade gliomas. These new magnetic resonance imaging biomarkers give insights into complexity and heterogeneity of vascular changes in glioma; however, histological validations in more well-defined patient populations are required.