methods Patients with newly diagnosed, histologically confirmed glioblastoma were randomly assigned to receive radiotherapy alone (fractionated focal irradiation in daily fractions of 2 Gy given 5 days per week for 6 weeks, for a total of 60 Gy) or radiotherapy plus continuous daily temozolomide (75 mg per square meter of body-surface area per day, 7 days per week from the first to the last day of radiotherapy), followed by six cycles of adjuvant temozolomide (150 to 200 mg per square meter for 5 days during each 28-day cycle). The primary end point was overall survival. results A total of 573 patients from 85 centers underwent randomization. The median age was 56 years, and 84 percent of patients had undergone debulking surgery. At a median follow-up of 28 months, the median survival was 14.6 months with radiotherapy plus temozolomide and 12.1 months with radiotherapy alone. The unadjusted hazard ratio for death in the radiotherapy-plus-temozolomide group was 0.63 (95 percent confidence interval, 0.52 to 0.75; P<0.001 by the log-rank test). The two-year survival rate was 26.5 percent with radiotherapy plus temozolomide and 10.4 percent with radiotherapy alone. Concomitant treatment with radiotherapy plus temozolomide resulted in grade 3 or 4 hematologic toxic effects in 7 percent of patients.

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Radiotherapy plus Concomitant and Adjuvant Temozolomide for Glioblastoma

The Central Brain Tumor Registry of the United States (CBTRUS), in collaboration with the Centers for Disease Control (CDC) and National Cancer Institute (NCI), is the largest population-based registry focused exclusively on primary brain and other central nervous system (CNS) tumors in the United States (US) and represents the entire US population. This report contains the most up-to-date population-based data on primary brain tumors (malignant and non-malignant) and supersedes all previous CBTRUS reports in terms of completeness and accuracy. All rates (incidence and mortality) are age-adjusted using the 2000 US standard population and presented per 100,000 population. The average annual age-adjusted incidence rate (AAAIR) of all malignant and non-malignant brain and other CNS tumors was 23.79 (Malignant AAAIR=7.08, non-Malignant AAAIR=16.71). This rate was higher in females compared to males (26.31 versus 21.09), Blacks compared to Whites (23.88 versus 23.83), and non-Hispanics compared to Hispanics (24.23 versus 21.48). The most commonly occurring malignant brain and other CNS tumor was glioblastoma (14.5% of all tumors), and the most common non-malignant tumor was meningioma (38.3% of all tumors). Glioblastoma was more common in males, and meningioma was more common in females. In children and adolescents (age 0-19 years), the incidence rate of all primary brain and other CNS tumors was 6.14. An estimated 83,830 new cases of malignant and non-malignant brain and other CNS tumors are expected to be diagnosed in the US in 2020 (24,970 malignant and 58,860 non-malignant). There were 81,246 deaths attributed to malignant brain and other CNS tumors between 2013 and 2017. This represents an average annual mortality rate of 4.42. The 5-year relative survival rate following diagnosis of a malignant brain and other CNS tumor was 23.5% and for a non-malignant brain and other CNS tumor was 82.4%.

CBTRUS statistical report: primary brain and central nervous system tumors diagnosed in the United States in 2007-2011.

Human cancer cells typically harbour multiple chromosomal aberrations, nucleotide substitutions and epigenetic modifications that drive malignant transformation. The Cancer Genome Atlas ( TCGA) pilot project aims to assess the value of large- scale multi- dimensional analysis of these molecular characteristics in human cancer and to provide the data rapidly to the research community. Here we report the interim integrative analysis of DNA copy number, gene expression and DNA methylation aberrations in 206 glioblastomas - the most common type of primary adult brain cancer - and nucleotide sequence aberrations in 91 of the 206 glioblastomas. This analysis provides new insights into the roles of ERBB2, NF1 and TP53, uncovers frequent mutations of the phosphatidylinositol- 3- OH kinase regulatory subunit gene PIK3R1, and provides a network view of the pathways altered in the development of glioblastoma. Furthermore, integration of mutation, DNA methylation and clinical treatment data reveals a link between MGMT promoter methylation and a hypermutator phenotype consequent to mismatch repair deficiency in treated glioblastomas, an observation with potential clinical implications. Together, these findings establish the feasibility and power of TCGA, demonstrating that it can rapidly expand knowledge of the molecular basis of cancer.

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Comprehensive genomic characterization defines human glioblastoma genes and core pathways

BACKGROUND: In 2004, a randomised phase III trial by the European Organisation for Research and Treatment of Cancer (EORTC) and National Cancer Institute of Canada Clinical Trials Group (NCIC) reported improved median and 2-year survival for patients with glioblastoma treated with concomitant and adjuvant temozolomide and radiotherapy. We report the final results with a median follow-up of more than 5 years. METHODS: Adult patients with newly diagnosed glioblastoma were randomly assigned to receive either standard radiotherapy or identical radiotherapy with concomitant temozolomide followed by up to six cycles of adjuvant temozolomide. The methylation status of the methyl-guanine methyl transferase gene, MGMT, was determined retrospectively from the tumour tissue of 206 patients. The primary endpoint was overall survival. Analyses were by intention to treat. This trial is registered with Clinicaltrials.gov, number NCT00006353. FINDINGS: Between Aug 17, 2000, and March 22, 2002, 573 patients were assigned to treatment. 278 (97%) of 286 patients in the radiotherapy alone group and 254 (89%) of 287 in the combined-treatment group died during 5 years of follow-up. Overall survival was 27.2% (95% CI 22.2-32.5) at 2 years, 16.0% (12.0-20.6) at 3 years, 12.1% (8.5-16.4) at 4 years, and 9.8% (6.4-14.0) at 5 years with temozolomide, versus 10.9% (7.6-14.8), 4.4% (2.4-7.2), 3.0% (1.4-5.7), and 1.9% (0.6-4.4) with radiotherapy alone (hazard ratio 0.6, 95% CI 0.5-0.7; p<0.0001). A benefit of combined therapy was recorded in all clinical prognostic subgroups, including patients aged 60-70 years. Methylation of the MGMT promoter was the strongest predictor for outcome and benefit from temozolomide chemotherapy. INTERPRETATION: Benefits of adjuvant temozolomide with radiotherapy lasted throughout 5 years of follow-up. A few patients in favourable prognostic categories survive longer than 5 years. MGMT methylation status identifies patients most likely to benefit from the addition of temozolomide. FUNDING: EORTC, NCIC, Nelia and Amadeo Barletta Foundation, Schering-Plough.

https://www.thelancet.com/pdfs/journals/lanonc/PIIS1470-2045(09)70025-7.pdf

Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phase III study: 5-year analysis of the EORTC-NCIC trial

background Epigenetic silencing of the MGMT (O 6 -methylguanine–DNA methyltransferase) DNArepair gene by promoter methylation compromises DNA repair and has been associated with longer survival in patients with glioblastoma who receive alkylating agents. methods We tested the relationship between MGMT silencing in the tumor and the survival of patients who were enrolled in a randomized trial comparing radiotherapy alone with radiotherapy combined with concomitant and adjuvant treatment with temozolomide. The methylation status of the MGMT promoter was determined by methylation-specific polymerase-chain-reaction analysis. results The MGMT promoter was methylated in 45 percent of 206 assessable cases. Irrespective of treatment, MGMT promoter methylation was an independent favorable prognostic factor (P<0.001 by the log-rank test; hazard ratio, 0.45; 95 percent confidence interval, 0.32 to 0.61). Among patients whose tumor contained a methylated MGMT promoter, a survival benefit was observed in patients treated with temozolomide and radiotherapy; their median survival was 21.7 months (95 percent confidence interval, 17.4 to 30.4), as compared with 15.3 months (95 percent confidence interval, 13.0 to 20.9) among those who were assigned to only radiotherapy (P=0.007 by the log-rank test). In the absence of methylation of the MGMT promoter, there was a smaller and statistically insignificant difference in survival between the treatment groups. conclusions Patients with glioblastoma containing a methylated MGMT promoter benefited from temozolomide, whereas those who did not have a methylated MGMT promoter did not have such a benefit.

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MGMT Gene Silencing and Benefit from Temozolomide in Glioblastoma

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Clinical trials in neuro-oncology: one step forward, two steps back?

Gliomas are the most common primary brain tumors in adults. Only grade I glioma occurring exclusively in children can be cured by surgery only, while grade II, grade III and grade IV glioma occurring in adults are diffusely infiltrative diseases that invariably recur despite the most radical surgery. Malignant glioma (grade III, anaplastic astrocytoma and grade IV, glioblastoma, GBM) may arise from a prior lower grade lesion as a result from sequential accumulation of genetic aberrations and deregulated signaling pathways (Fig. 1) [1]. Most aggressive gliomas, however will present as a rapidly growing and debilitating disease de novo. Although indistinguishable by histopathology, these tumors will differ on a molecular level. Better insights into glioma genesis, identification of aberrant pathways, mutations and identification of characteristic molecular defects of certain glioma subtypes have given rise to expectations that molecularly driven therapy may also improve outcome of patients suffering from glioma. Over the last decade targeted therapies have changed the perspective of many solid tumors. However, despite compelling preclinical data in malignant glioma, controlled clinical trials have failed to demonstrate an unequivocal benefit from the addition of novel targeted agents. Primary brain tumors are highly heterogeneous, and multiple pathways may be dysregulated (Fig. 2) [1] and responsible for glioma development. Redundancy of signaling pathways demands therapeutic inhibition of more than only one key pathway to be eventually successful. Thus pharmacological inhibition with a single agent may not suffice to demonstrate a clinically measurable effect. There are additional challenges to be surmounted when treating malignant glioma. The blood-brain barrier, although in part disrupted in glioma, may hamper adequate delivery of many chemotherapeutics or targeted treatment agents to the brain. Peritumoral edema and increased interstial pressure will limit passive diffusion. Due to the localization of the disease in the brain, repeat biopsies with analysis of drug levels in the tumor and evaluation of the presumed drug target are inherently difficult. Innovative and presurgical trial designs are needed, ideally coupled with novel radiological techniques and biomarker evaluation in the blood and cerebro-spinal fluid. Finally, pharmacologic interactions (→ enzyme inducing antiepileptics, steroids) may increase drug metabolism and thus further lower the exposure to many agents. Overexpression and/or activation of the epidermal growth factor receptor (EGFR) pathway is present in nearly 50% of glioblastoma. Small molecule inhibitors specific for the tyrosine kinase of the EGFR have failed to demonstrate clinical antitumor activity in recurrent glioma. Strategies are underway S. Hofer Department of Oncology, University Hospital Zurich, Ramistrasse 100, 8091 Zurich, Switzerland e-mail: Silvia.Hofer@usz.ch

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Targeted therapies on the horizon for malignant glioma

Neoadjuvant treatment does not influence PD-L1 expression in stage III non-small-cell lung cancer: a retrospective analysis of tumor samples from the trials SAKK 16/96, 16/00, 16/01, and 16/14.

Management of lymphoma in the 1990s: Introduction to the Proceedings of the Fifth International Conference on Malignant Lymphoma

Background Patients with both primary and metastatic brain tumors have significant seizure burden due to their tumor The management of tumor-related epilepsy (TRE) and optimizing antiepileptic drug (AED) regimens requires collaboration between neurologists and seizure specialists, which is facilitated by seizure documentation in clinic notes We aim to describe seizure incidence in patients seen in neuro-oncology clinical practice Further, in the subset of those patients with TRE, we aim to analyze seizure documentation Methods This is a retrospective review of patients with a primary or metastatic brain tumor seen in a neuro-oncology clinic in October 2019 Patients with TRE were included in the analysis of seizure documentation These notes were analyzed for inclusion of seizure descriptors, terminology, AED regimens, and changes in management Results Of the full cohort of 356 patients, 199 (559%) had TRE Anaplastic astrocytomas had the highest percentage of patients with TRE The analysis of seizure documentation in patients with TRE revealed that the majority of notes (909%) mentioned seizures Fewer notes (396%) provided additional descriptions of the seizures or commented on AED regimens (583%) In notes for patients who had seizures within the previous 6 months, seizure descriptors were more likely Conclusions This study defines the TRE burden in a cohort of patients seen in neuro-oncology clinic Among patients with TRE, our study shows that documentation of many aspects of the characteristics and management of patient seizures can be improved, which would facilitate further analysis of impact on patient care as well as future research

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Roger Stupp

Papers

Clinical trials in neuro-oncology: one step forward, two steps back?

Targeted therapies on the horizon for malignant glioma

Neoadjuvant treatment does not influence PD-L1 expression in stage III non-small-cell lung cancer: a retrospective analysis of tumor samples from the trials SAKK 16/96, 16/00, 16/01, and 16/14.

Management of lymphoma in the 1990s: Introduction to the Proceedings of the Fifth International Conference on Malignant Lymphoma

Tumor type, epilepsy burden, and seizure documentation: experiences at a single center neuro-oncology clinic.