Joint Final Report of EORTC 26951 and RTOG 9402: Phase III Trials With Procarbazine, Lomustine, and Vincristine Chemotherapy for Anaplastic Oligodendroglial Tumors

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Abstract

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the basis of the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.

Anaplastic oligodendroglial tumors (AOTs) are chemotherapy-sensitive brain tumors. We report the final very long-term survival results from European Organization for the Research and Treatment of Cancer 26951 and Radiation Therapy Oncology Group 9402 phase III trials initiated in 1990s, which both studied radiotherapy with/without neo/adjuvant procarbazine, lomustine, and vincristine (PCV) for newly diagnosed anaplastic oligodendroglial tumors. The median follow-up duration in both was 18-19 years. For European Organization for the Research and Treatment of Cancer 26951, median, 14-year, and probable 20-year overall survival rates without versus with PCV were 2.6 years, 13.4%, and 10.1% versus 3.5 years, 25.1%, and 16.8% (N = 368 overall; hazard ratio [HR] 0.78; 95% CI, 0.63 to 0.98; P = .033), with 1p19q codeletion 9.3 years, 26.2%, and 13.6% versus 14.2 years, 51.0%, and 37.1% (n = 80; HR 0.60; 95% CI, 0.35 to 1.03; P = .063), respectively. For Radiation Therapy Oncology Group 9402, analogous results were 4.8 years, 16.5%, and 11.2% versus 4.8 years, 29.1%, and 24.6% (N = 289 overall; HR 0.79; 95% CI, 0.61 to 1.03; P = .08), with codeletion 7.3 years, 25.0%, and 14.9% versus 13.2 years, 46.1%, and 37% (n = 125; HR 0.61; 95% CI, 0.40 to 0.94; P = .02), respectively. With that, the studies show similar long-term survival even without tumor recurrence in a significant proportion of patients after first-line treatment with radiotherapy/PCV.

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David N Louis, Arie Perry, Pieter Wesseling … (2021)

The fifth edition of the WHO Classification of Tumors of the Central Nervous System (CNS), published in 2021, is the sixth version of the international standard for the classification of brain and spinal cord tumors. Building on the 2016 updated fourth edition and the work of the Consortium to Inform Molecular and Practical Approaches to CNS Tumor Taxonomy, the 2021 fifth edition introduces major changes that advance the role of molecular diagnostics in CNS tumor classification. At the same time, it remains wedded to other established approaches to tumor diagnosis such as histology and immunohistochemistry. In doing so, the fifth edition establishes some different approaches to both CNS tumor nomenclature and grading and it emphasizes the importance of integrated diagnoses and layered reports. New tumor types and subtypes are introduced, some based on novel diagnostic technologies such as DNA methylome profiling. The present review summarizes the major general changes in the 2021 fifth edition classification and the specific changes in each taxonomic category. It is hoped that this summary provides an overview to facilitate more in-depth exploration of the entire fifth edition of the WHO Classification of Tumors of the Central Nervous System.

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Epigenetic silencing of the MGMT (O6-methylguanine-DNA methyltransferase) DNA-repair gene by promoter methylation compromises DNA repair and has been associated with longer survival in patients with glioblastoma who receive alkylating agents. 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. 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. 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. Copyright 2005 Massachusetts Medical Society.

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Author and article information

Journal

Journal ID (nlm-ta): J Clin Oncol

Journal ID (iso-abbrev): J Clin Oncol

Journal ID (hwp): jco

Journal ID (publisher-id): JCO

Title: Journal of Clinical Oncology

Publisher: Wolters Kluwer Health

ISSN (Print): 0732-183X

ISSN (Electronic): 1527-7755

Publication date (Print): 10 August 2022

Publication date (Electronic): 22 June 2022

Volume: 40

Issue: 23

Pages: 2539-2545

Affiliations

[ ¹ ]Division of Neuro-Oncology, Department of Neurology, Columbia University Vagelos College of Physicians and Surgeons, New York, NY

[ ² ]Herbert Irving Comprehensive Cancer Center, New York, NY

[ ³ ]NewYork-Presbyterian Hospital, New York, NY

[ ⁴ ]AP-HP, Sorbonne Université, Hôpitaux Universitaires La Pitié Salpêtrière - Charles Foix, Service de Neurologie 2, Paris, France

[ ⁵ ]NRG Oncology Statistics and Data Management Center, Philadelphia, PA

[ ⁶ ]Department of Medical Oncology, AUSL/IRCCS Institute of Neurological Sciences, Bologna, Italy

[ ⁷ ]Charbonneau Cancer Institute, University of Calgary, Calgary, Canada

[ ⁸ ]Department of Pathology, Erasmus MC Cancer Institute, University Medical Center, Rotterdam, the Netherlands

[ ⁹ ]Barrow Neurological Institute, Phoenix, AZ

[ ¹⁰ ]Department of Neurology, Leiden University Medical Center, Leiden, the Netherlands

[ ¹¹ ]Department of Neurology, Haaglanden Medical Center, the Hague, the Netherlands

[ ¹² ]Department of Radiation Oncology, McGill University, Montreal, Quebec, Canada

[ ¹³ ]Mayo Clinic Accruals for Rochester Methodist Hospital, Rochester, MN

[ ¹⁴ ]Department of Neurology, Amsterdam Universities Medical Centers, location VUmc, Amsterdam, the Netherlands

[ ¹⁵ ]Baylor University Medical Center, Houston, TX

[ ¹⁶ ]Department of Neurology, Erasmus MC Cancer Institute, Rotterdam, the Netherlands

[ ¹⁷ ]London Regional Cancer Program, Western University, London, Canada (RT)

[ ¹⁸ ]EORTC, Brussels, Belgium

[ ¹⁹ ]Miami Cancer Institute, Miami, FL

Author notes

Martin J. van den Bent, MD, The Brain Tumor Center, Erasmus MC Cancer Institute, Erasmus University Hospital, Dr Molenwaterplein 40, Rotterdam 3015GD, the Netherlands; e-mail: m.vandenbent@ 123456erasmusmc.nl .