Summary Background Radiotherapy is the standard care in elderly patients with malignant astrocytoma and the role of primary chemotherapy is poorly defined. We did a randomised trial to compare the ...efficacy and safety of dose-dense temozolomide alone versus radiotherapy alone in elderly patients with anaplastic astrocytoma or glioblastoma. Methods Between May 15, 2005, and Nov 2, 2009, we enrolled patients with confirmed anaplastic astrocytoma or glioblastoma, age older than 65 years, and a Karnofsky performance score of 60 or higher. Patients were randomly assigned 100 mg/m2 temozolomide, given on days 1–7 of 1 week on, 1 week off cycles, or radiotherapy of 60·0 Gy, administered over 6–7 weeks in 30 fractions of 1·8–2·0 Gy. The primary endpoint was overall survival. We assessed non-inferiority with a 25% margin, analysed for all patients who received at least one dose of assigned treatment. This trial is registered with ClinicalTrials.gov , number NCT01502241. Findings Of 584 patients screened, we enrolled 412. 373 patients (195 randomly allocated to the temozolomide group and 178 to the radiotherapy group) received at least one dose of treatment and were included in efficacy analyses. Median overall survival was 8·6 months (95% CI 7·3–10·2) in the temozolomide group versus 9·6 months (8·2–10·8) in the radiotherapy group (hazard ratio HR 1·09, 95% CI 0·84–1·42, pnon-inferiority =0·033). Median event-free survival (EFS) did not differ significantly between the temozolomide and radiotherapy groups (3·3 months 95% CI 3·2–4·1 vs 4·7 4·2–5·2; HR 1·15, 95% CI 0·92–1·43, pnon-inferiority =0·043). Tumour MGMT promoter methylation was seen in 73 (35%) of 209 patients tested. MGMT promoter methylation was associated with longer overall survival than was unmethylated status (11·9 months 95% CI 9·0 to not reached vs 8·2 months 7·0–10·0; HR 0·62, 95% CI 0·42–0·91, p=0·014). EFS was longer in patients with MGMT promoter methylation who received temozolomide than in those who underwent radiotherapy (8·4 months 95e% CI 5·5–11·7 vs 4·6 4·2–5·0), whereas the opposite was true for patients with no methylation of the MGMT promoter (3·3 months 3·0–3·5 vs 4·6 months 3·7–6·3). The most frequent grade 3–4 intervention-related adverse events were neutropenia (16 patients in the temozolomide group vs two in the radiotherapy group), lymphocytopenia (46 vs one), thrombocytopenia (14 vs four), raised liver-enzyme concentrations (30 vs 16), infections (35 vs 23), and thromboembolic events (24 vs eight). Interpretation Temozolomide alone is non-inferior to radiotherapy alone in the treatment of elderly patients with malignant astrocytoma. MGMT promoter methylation seems to be a useful biomarker for outcomes by treatment and could aid decision-making. Funding Merck Sharp & Dohme.
Abstract Objective Well-defined risk factors for the identification of meningioma patients who might benefit from preoperative or early postoperative seizure prophylaxis are unknown. We investigated ...and quantified risk factors to determine individual risks of seizure occurrence in meningioma patients. Methods A total of 634 adult meningioma patients were included in this retrospective cohort study. Patient gender and age, tumor location, grade and volume, usage of antiepileptic drugs (AEDs) and extent of resection were determined. Results Preoperative and early postoperative seizures occurred in 15% (97) and 5% (21) of the patients, respectively. Overall, 502 and 418 patients were eligible for multivariate logistic regression analyses of preoperative and early postoperative seizures, respectively. Male gender (OR 2.06, P = .009), a non-skull base location (OR 4.43, P < .001) and a tumor volume of >8 cm3 (OR 3.05, P = .002) were associated with a higher risk of preoperative seizures and were used to stratify the patients into three prognostic groups. The high-risk subgroup of meningioma patients demonstrated a seizure rate of >40% (OR 9.8, P < .001). Only a non-skull base tumor location (OR 2.61, P = .046) was identified as a significant risk factor for early postoperative seizures. AEDs did not reduce early postoperative seizure occurrence. Conclusions Seizure prophylaxis might be considered for patients at high risk of developing seizures who are for other reasons being considered for watchful waiting instead of resection. In contrast, our data do not provide any evidence of the efficacy of perioperative AEDs in meningioma patients.
SummaryBackgroundThe CeTeG/NOA-09 trial showed significantly longer overall survival with combined lomustine–temozolomide therapy compared with standard temozolomide for patients with glioblastoma ...with methylated MGMT promoter. The trial also aimed to investigate the effect of lomustine–temozolomide therapy on health-related quality of life (HRQOL) and neurocognitive function, which we report here. MethodsIn this randomised, multicentre, open-label, phase 3 trial, newly diagnosed, chemoradiotherapy-naive patients with MGMT-methylated glioblastoma, aged 18–70 years, with a Karnofsky performance score of 70% or higher, were recruited and enrolled at 17 university hospitals in Germany. Patients received standard radiotherapy (60 Gy) and were randomly assigned (1:1, stratified by centre by allocating complete blocks of six to a centre, without masking) to either six 6-week courses of oral combined lomustine (100 mg/m 2 on day 1) plus temozolomide (100–200 mg/m 2 on days 2–6) or standard oral temozolomide (75 mg/m 2 daily during radiotherapy plus six 4-week courses of temozolomide 150–200 mg/m 2 on days 1–5, every 4 weeks). The primary endpoint was overall survival. HRQOL, assessed using the European Organisation for Research and Treatment of Cancer (EORTC) quality of life questionnaire core-30 and the EORTC brain cancer module (BN20); and neurocognitive function, assessed using the Mini Mental State Examination (MMSE), plus a neurocognitive test battery (NOA-07), including Trail Making Test A and B (TMT-A and B), working memory tests, and tests for lexical (Controlled Oral Word Association COWA) and semantic verbal fluency, were secondary endpoints analysed in the modified intention-to-treat population (mITT; all randomly assigned patients who received at least one dose of study chemotherapy). We used linear mixed-model analyses to investigate differences between treatment groups regarding HRQOL (clinically relevant ≥10 points) and MMSE scores (clinically relevant ≥3 points). The trial is registered with ClinicalTrials.gov, NCT01149109. FindingsBetween June 17, 2011 and April 8, 2014, 141 patients were randomly assigned and 129 patients began treatment and were included in the mITT population (63 in the temozolomide and 66 in the lomustine–temozolomide group). Median follow-up for HRQOL (the item global health) was 19·4 months (IQR 7·8–38·6), for MMSE was 15·3 months (4·1–29·6), and for COWA was 11·0 months (0–27·5). We found no significant impairment regarding any item of HRQOL in the lomustine–temozolomide group (difference between the groups for global health 0·30 95% CI −0·23 to 0·83; p=0·26). Differences in MMSE were in favour of the temozolomide group (difference −0·11 95% CI −0·19 to −0·03; p=0·0058) but were not clinically relevant (1·76/30 points over 4 years). We found no significant difference between the groups in any subtest of the neurocognitive test battery (difference for COWA 0·04 95% CI −0·01 to 0·09; p=0·14). InterpretationThe absence of systematic and clinically relevant changes in HRQOL and neurocognitive function combined with the survival benefit of lomustine–temozolomide versus temozolomide alone suggests that a long-term net clinical benefit exists for patients with newly diagnosed glioblastoma with methylation of the MGMT promoter and supports the use of lomustine–temozolomide as a treatment option for these patients. FundingGerman Federal Ministry of Education and Research.
Glioblastoma multiforme (GBM) is the most lethal primary intracranial malignant neoplasm in adults and most resistant to treatment. Integration of gene therapy and chemotherapy, chemovirotherapy, has ...the potential to improve treatment. We have introduced an intravenous bacteriophage (phage) vector for dual targeting of therapeutic genes to glioblastoma. It is a hybrid AAV/phage, AAVP, designed to deliver a recombinant adeno‐associated virus genome (rAAV) by the capsid of M13 phage. In this vector, dual tumor targeting is first achieved by phage capsid display of the RGD4C ligand that binds the αvβ3 integrin receptor. Second, genes are expressed from a tumor‐activated and temozolomide (TMZ)‐induced promoter of the glucose‐regulated protein, Grp78. Here, we investigated systemic combination therapy using TMZ and targeted suicide gene therapy by the RGD4C/AAVP‐Grp78. Firstly, in vitro we showed that TMZ increases endogenous Grp78 gene expression and boosts transgene expression from the RGD4C/AAVP‐Grp78 in human GBM cells. Next, RGD4C/AAVP‐Grp78 targets intracranial tumors in mice following intravenous administration. Finally, combination of TMZ and RGD4C/AAVP‐Grp78 targeted gene therapy exerts a synergistic effect to suppress growth of orthotopic glioblastoma.
Synopsis
Following intravenous administration, the RGD4C/AAVP‐Grp78 vector delivers the therapeutic AAV genome into GBM via binding to integrins. Treatment with temozolomide (TMZ) induces the Grp78 promoter activity and subsequently the therapeutic gene expression resulting in synergistic anti‐tumor action.
RGD4C/AAVP‐Grp78‐HSVtk binds to αvβ3 integrin in GBM, leading to vector internalisation and delivery of the recombinant rAAV genome in the nucleus to generate expression of the HSVtk.
Expression of HSVtk results in phosphorylation of ganciclovir (GCV) within GBM and subsequent tumor destruction.
Administration of TMZ induces the Grp78 promoter activity through the UPR pathway, resulting in further expression of the HSVtk and subsequent phosphorylation of GCV.
Consequently combination of TMZ with targeted intravenous RGD4C/AAVP‐Grp78‐HSVtk/GCV gene therapy results in synergistic destruction of GBM.
Following intravenous administration, the RGD4C/AAVP‐Grp78 vector delivers the therapeutic AAV genome into GBM via binding to integrins. Treatment with temozolomide (TMZ) induces the Grp78 promoter activity and subsequently the therapeutic gene expression resulting in synergistic anti‐tumor action.
Meningiomas are the most common primary intracranial tumors in adults and are increasing in incidence due to the aging population and the rising availability of neuroimaging. While most exhibit ...non-malignant behaviour, a subset of meningiomas are biologically aggressive and lead to significant neurological morbidity and mortality. In recent years, meaningful advances in our understanding of the biology of these tumors have led to the incorporation of molecular biomarkers into their grading and prognostication. However, unlike other central nervous system tumors, a unified molecular taxonomy for meningiomas has not yet been established and remains an overarching goal of the Consortium to Inform Molecular and Practical Approaches to CNS Tumor Taxonomy-Not Official WHO (cIMPACT-NOW) working group. There also remains clinical equipoise on how specific meningioma cases and patient populations should be optimally managed. To address these existing gaps, members of the International Consortium on Meningiomas (ICOM) including field-leading experts, have prepared a comprehensive consensus narrative review directed towards clinicians, researchers, and patients. Included in this manuscript are detailed overviews of proposed molecular classifications, novel biomarkers, contemporary treatment strategies, trials on systemic therapies, health-related quality of life studies, and management strategies for unique meningioma patient populations. In each section we discuss the current state of knowledge as well as ongoing clinical and research challenges to road map future directions for further investigation.
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