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.

/pdf/radiotherapy-plus-concomitant-and-adjuvant-temozolomide-for-421wvfhcfx.pdf

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.

/pdf/comprehensive-genomic-characterization-defines-human-42mc06vlka.pdf

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

https://www.genome.gov/Pages/Newsroom/Webcasts/2010ScienceReportersWorkshop/Panel5_integrated_genome_analysis_subtypes_of_glio.pdf

Integrated Genomic Analysis Identifies Clinically Relevant Subtypes of Glioblastoma Characterized by Abnormalities in PDGFRA, IDH1, EGFR, and NF1

This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited. © The Author(s) 2020. Published by Oxford University Press, the Society for Neuro-Oncology and the European Association of Neuro-Oncology. Brief Communication

/pdf/conditional-relative-survival-in-primary-central-nervous-5g4x0a566v.pdf

Conditional relative survival in primary central nervous system lymphoma: a population-based study in the Netherlands


 
 
 The efficacy of rituximab in Primary CNS Lymphoma (PCNSL) is still under debate. We performed an international randomized phase III study to investigate the efficacy of rituximab when added to methotrexate, BCNU, teniposide and prednisolone (MBVP) in PCNSL. The primary endpoint, event-free survival (EFS) at one year, was similar in both treatment groups and was previously reported (Bromberg et al, Lancet Oncology 2019; 20: 216-228). Here we present long-term follow up results after a median follow-up of 82 months.
 
 
 
 between August 2010 and May 2016 200 newly-diagnosed, non-immunocompromised patients with PCNSL aged 18-70 years and WHO performance status 0-3 were randomized between treatment with MBVP chemotherapy with (arm B) or without (arm A) rituximab. The rituximab was given weekly in the first MBVP cycle, fortnightly in the second (in total 6 rituximab administrations). Responsive patients received consolidation with high-dose cytarabine, and patients aged ≤ 60 were subsequently treated with low-dose WBRT if in CR/CRu; in case of PR with an additional boost on the tumor. Patients > 60 were not irradiated. All patients gave written informed consent.
 
 
 
 The modified intention-to-treat (m-ITT) population consisted of 199 eligible patients, 55% were men. The median age was 61 yrs (range 26-70), the median WHO performance status 1 (range 0-3). The primary endpoint EFS at one year was 49% (95% CI 39-58)(MBVP) vs 55% (95% CI 44-64) (R-MBVP). The EFS at 5 years was 25% (17-34) vs 36% (27-46) respectively, hazard ratio (HR) 0.85, 95% CI 0.61-1.18, p=0.33 (adjusted for age and WHO performance status). The progression-free survival (PFS) at one and 5 years were 58% (47-67) and 29% (21-39) (MBVP) and 65% (54-73) and 43% (33-53) (R-MBVP) ) (HR 0.73, 95% CI 0.52-1.02, p=0.07). 80 patients were still alive. Overall survival (OS) at 5 years for MBVP and R-MBVP was 49% (39-59) and 53% (43-63) respectively. A total of 111 patients had progression or relapse, 63 after MBVP and 48 after R-MBVP. 79% of these patients received further treatment. The median OS after progression/relapse was 9.7 months (5.9-19.9) in the MBVP arm, and 6.1 months (2.4-13.1) in the R-MBVP arm (HR 1.25, 95% CI 0.83-1.87, p=0.29). 119 patients died, 64 in the MBVP arm and 55 in the R-MBVP arm. Causes of death were PCNSL in 69% of the patients (both arms), complication of treatment (6% vs 5%), secondary malignancy (5% vs 2%) and other or unknown causes (20% vs 24%). Age was the strongest prognostic factor for EFS, PFS and OS in multivariate analysis.
 
 
 
 in the modified-ITT population we found no statistically significant benefit of the addition of rituximab to MBVP on EFS, PFS and OS in patients with PCNSL, even after a long follow-up of median 82 months. Therefore, the results of this study do not support the use of rituximab with MBVP in the treatment of primary CNS lymphoma.


https://academic.oup.com/neuro-oncology/article-pdf/24/Supplement_2/ii12/45691386/noac174.038.pdf

OS03.6.A Rituximab in primary CNS lymphoma - long term follow-up of the phase III HOVON 105/ALLG NHL 24 Study

Until some 15 years ago, the diagnosis of an anaplastic oligodendroglioma (AOD) or anaplastic oligoastrocytoma (AOA) was merely a pathological entity. The only clinically relevant meaning of this histological diagnosis was the observation that in general the prognosis of OD was better than that of astrocytic tumors of similar grade. This changed with the recognition of the marked sensitivity of these tumors to procarbazine, lomustine, and vincristine (PCV) chemotherapy [1,2]. A major step forward was the identification of the combined loss of the short arm of chromosome 1 (1p) and the long arm of chromosome 19 (19q) as the typical genetic lesions of OD, followed by the recognition that in particular these 1p/19q co-deleted tumors have an excellent response to chemotherapy [3–5]. It is now clear that AOD and AOA with this combined loss of 1p/19q do not only have a better response to chemotherapy, but they also have a more indolent clinical behavior and a longer lasting response to radiotherapy (RT).

Jacoline E C Bromberg

Papers

Conditional relative survival in primary central nervous system lymphoma: a population-based study in the Netherlands

OS03.6.A Rituximab in primary CNS lymphoma - long term follow-up of the phase III HOVON 105/ALLG NHL 24 Study

Anaplastic Oligodendrogliomas and Mixed Gliomas