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August 31, 2011
Letter to the Editor

Prolonged survival with valproic acid use in the EORTC/NCIC temozolomide trial for glioblastoma

M. Weller, MD, T. Gorlia, MSc, PhD, J.G. Cairncross, MD, M.J. van den Bent, MD, W. Mason, MD, K. Belanger, MD, A.A. Brandes, MD, … Show All … , U. Bogdahn, MD, D.R. Macdonald, MD, P. Forsyth, MD, A.O. Rossetti, MD, D. Lacombe, MD, R.-O. Mirimanoff, MD, C.J. Vecht, MD, and R. Stupp, MDAuthors Info & Affiliations
September 20, 2011 issue
77 (12) 1156-1164
https://doi.org/10.1212/WNL.0b013e31822f02e1
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Abstract

Objective:

This analysis was performed to assess whether antiepileptic drugs (AEDs) modulate the effectiveness of temozolomide radiochemotherapy in patients with newly diagnosed glioblastoma.

Methods:

The European Organization for Research and Treatment of Cancer (EORTC) 26981–22981/National Cancer Institute of Canada (NCIC) CE.3 clinical trial database of radiotherapy (RT) with or without temozolomide (TMZ) for newly diagnosed glioblastoma was examined to assess the impact of the interaction between AED use and chemoradiotherapy on survival. Data were adjusted for known prognostic factors.

Results:

When treatment began, 175 patients (30.5%) were AED-free, 277 (48.3%) were taking any enzyme-inducing AED (EIAED) and 135 (23.4%) were taking any non-EIAED. Patients receiving valproic acid (VPA) only had more grade 3/4 thrombopenia and leukopenia than patients without an AED or patients taking an EIAED only. The overall survival (OS) of patients who were receiving an AED at baseline vs not receiving any AED was similar. Patients receiving VPA alone (97 [16.9%]) appeared to derive more survival benefit from TMZ/RT (hazard ratio [HR] 0.39, 95% confidence interval [CI] 0.24–0.63) than patients receiving an EIAED only (252 [44%]) (HR 0.69, 95% CI 0.53–0.90) or patients not receiving any AED (HR 0.67, 95% CI 0.49–0.93).

Conclusions:

VPA may be preferred over an EIAED in patients with glioblastoma who require an AED during TMZ-based chemoradiotherapy. Future studies are needed to determine whether VPA increases TMZ bioavailability or acts as an inhibitor of histone deacetylases and thereby sensitizes for radiochemotherapy in vivo.

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Supplementary Material

File (figure_e-1.pdf)
File (table_e-1.doc)
File (table_e-2.doc)

ACKNOWLEDGMENT

The authors thank the patients treated at 85 centers, the local investigators, nurses, and data managers for participation and care and colleagues, and collaborators at the EORTC headquarters for their support, data, and database management and acknowledge editorial support by Frances Godson, administrative secretary to the EORTC Brain Tumor and Radiation Oncology Groups.

Study Funding

The original clinical trial was supported by an unrestricted educational grant and drug supply by Schering-Plough, Kenilworth, NJ. The EORTC-NCIC trial was an academic trial conducted under EORTC leadership with Dr. Stupp as the Principal Investigator. This publication was supported by the National Cancer Institute (grants 5U10 CA011488-26 through 5U10 CA11488-32). This analysis was conducted with financial support from grants by the Schweizerische Krebsliga (Switzerland) to the EORTC Charitable Trust. The content of this article is solely the responsibility of the authors and does not necessarily reflect the official views of the National Cancer Institute.

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Letters to the Editor
28 October 2011
Reply from the authors
Michael Weller, Chairman, University Hospital Zurich
Roger Strupp (Lausanne, Switzerland)

Our colleagues raise interesting ideas regarding the possible mechanisms mediating a preferential benefit of temozolomide-treated glioblastoma patients coexposed to valproic acid. However, we have no further data to support or challenge these hypopotheses.

For disclosures, please contact the editorial office at [email protected].

27 October 2011
Valproate and Glioblastoma: Role for Melatonin and Vitamin D3
George Anderson, Head of Research
Moses Rodriguez, Department Neurology and Immunology, Mayo Clinic College of Medicine, Rochester, MN,
Weller et al [1] and Wed [2] discuss the efficacy of valproate in the treatment of glioblastoma. Did the authors consider variations in melatonin and vitamin D3 as modulators of valproate effects? Valproate increases melatonin receptors in C6 glioma [3] and increases vitamin D3 chaperones BAG-1 and hsp70 in CNS cells, potentiating vitamin D3 effects. Both are anti-proliferative, with melatonin commonly used in glioma radiotherapy. This could suggest valproate modulation by endogenous melatonin and vitamin D3. Also the addition of melatonin and vitamin D3 may contribute to the efficacy of valproate. Valproate induced thrombocytopenia and leucopenia can be prevented by the co-administration of melatonin or vitamin D3 in many conditions. Where p53 is mutated, vitamin D3 may be anti-apoptotic in tumors. [4] The addition or vitamin D3 to valproate may have different consequences depending on the mutational status of p53. Vitamin D3 and melatonin synergistically inhibit breast cancer proliferation [5] and on their own may be beneficial to glioblastoma treatment. Potentiation of their effects by valproate could at the very least protect against valproate side effects, and possibly alleviate this devastating condition.

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For disclosures, contact editorial office at [email protected].

Information & Authors

Information

Published In

Neurology®
Volume 77 • Number 12 • September 20, 2011
Pages: 1156-1164
PubMed: 21880994

Copyright

Copyright © 2011 by AAN Enterprises, Inc.

Publication History

Received: January 3, 2011
Accepted: April 20, 2011
Published online: August 31, 2011
Published in issue: September 20, 2011

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Disclosure

Dr. Weller serves on scientific advisory boards for Roche, Merck Serono, Merck & Co., Inc., OncoMethylome Sciences, Exelixis Inc., and Bristol-Myers Squibb; received funding for travel or speaker honoraria from Roche, Merck Serono, Schering Plough Corp., and Merck & Co., Inc.; serves as European Editor for Neuro-Oncology and on the editorial boards of Glia, Journal of Neuro-Oncology, Journal of Neurochemistry, and Cellular Physiology & Biochemistry; and receives research support from Roche, Merck Serono, Schering-Plough Corp., and Merck & Co., Inc. Dr. Gorlia reports no disclosures. Dr. Cairncross served on scientific advisory boards for Schering-Plough Corp. and Merck Serono; has received funding for travel from Schering-Plough Corp.; serves on the editorial board of Annals of Neurology; receives publishing royalties for Neurological Therapeutics: Principles and Practice (Informa Healthcare, 2006); and receives research support from Alberta Cancer Foundation Research, Alberta Cancer Research Institute, and Grant in Aid Brain Tumor Foundation of Canada. Dr. van den Bent served on scientific advisory boards for Bristol-Myers Squibb, Exelixis, Merck & Co, Inc., Merck Serono, Antisense Therapeutics Limited, Exelixis Inc., OncoMethylome Sciences, Roche, Schering-Plough Corp., Siena Biotech S.p.A., and Ark Therapeutics; received funding for travel from Merck & Co, Inc.; serves on the editorial boards of the European Journal of Cancer, Neuro-Oncology, and Lancet Oncology; receives publishing royalties from Up-To-Date; serves on the speakers' bureau of Schering-Plough Corp.; and receives research support from Roche, Novartis, Schering-Plough Corp., and the Dutch Cancer Society. Dr. Mason serves on a scientific advisory board for Roche; serves on the speakers' bureau for Merck & Co., Inc.; has received speaker honoraria from Schering-Plough Corp. and Merck & Co., Inc.; and served as a consultant for Schering-Plough Corp., Merck & Co., Inc., Roche, AstraZeneca and Exelixis Inc. Dr. Bélanger served on a scientific advisory board for Schering-Plough Corp. Dr. Brandes serves on scientific advisory boards for Roche and Schering-Plough Corp.; has received funding for travel and speaker honoraria from GlaxoSmithKline and Schering-Plough Corp.; and served as a consultant for Bristol-Myers Squibb and OncoMethylome Sciences. Dr. Bogdahn serves on scientific advisory boards for Antisense Therapeutics Limited, Schering-Plough Corp., Merck Serono, and Roche; has received funding for travel or speaker honoraria from Merck & Co., Inc. and Novartis; is author on a patent re: Melanoma Inhibiting Activity (licensed to Roche); treats patients with brain tumors (10% clinical effort) for the Brain Tumor Therapy Center, University of Regensburg, Germany; receives research support from Siemens AG; and has provided expert legal advice to Schering-Plough Corp. Dr. Macdonald has served on scientific advisory boards for Schering-Plough Corp., Roche, AstraZeneca, Merck Serono, and Boehringer Ingelheim; has received speaker honoraria from Merck Serono and Schering-Plough Corp. and funding for travel from Merck Serono, Schering-Plough Corp., Roche, and EMD Serono, Inc.; served as a consultant for Merck Serono, Schering-Plough Corp., Roche, and EMD Serono, Inc.; serves on speakers' bureaus for Merck Serono and Schering-Plough Corp.; receives research support from Roche, EMD Serono, Inc., Schering-Plough Corp., the National Cancer Institute of Canada (NCIC), and Radiation Therapy Oncology Group (RTOG). Dr. Forsyth served on scientific advisory boards for Merck Serono, Schering-Plough Corp., and Jennerex Inc. and receives research support from ACF, #25023, CCSRI, CIHR, Ivy Foundation, the National Cancer Institute of Canada, and the Ben and Catherine Ivy Foundation. Dr. Rossetti served on scientific advisory boards for Eisai Inc., Janssen, GlaxoSmithKline, and UCB and receives research support from Pfizer Inc and UCB. Dr. Lacombe reports no disclosures. Dr. Mirimanoff served on scientific advisory boards for Merck & Co., Inc., Schering-Plough Corp., and Think Tank Accuray. Dr. Vecht has served on scientific advisory boards for and received speaker honoraria from Eisai Inc., Janssen, GlaxoSmithKline, and UCB; serves on the editorial board of Clinical Neurology and Neurosurgery; and receives research support from Pfizer Inc, GlaxoSmithKline, and UCB. Dr. Stupp served on scientific advisory boards for Roche, Schering-Plough Corp, OncoMethylome Sciences, Exelixis Inc., Merck Serono, Merck & Co., Inc., Bristol-Myers Squibb; and serves on the editorial boards of Neuro-Oncology, the Journal of Clinical Oncology, and the European Journal of Oncology.

Authors

Affiliations & Disclosures

M. Weller, MD
From the Department of Neurology (M.W.), University Hospital Tübingen, Tübingen, Germany, and University Hospital Zurich, Zurich, Switzerland; European Organisation for Research and Treatment of Cancer (T.G., D.L.), Brussels, Belgium; Department of Clinical Neurosciences and Clark H. Smith Brain Tumour Centre (J.G.C.), University of Calgary, Calgary, Canada; Department of Neuro-Oncology (M.J.v.d.B.), Daniel den Hoed Cancer Center/Erasmus Medical Centre, Rotterdam, the Netherlands; Princess Margaret Hospital (W.M.), University of Toronto, Toronto, Canada; CHUM-Hôpital Notre Dame (K.B.), Montreal, Canada; Department of Medical Oncology (A.A.B.), Bellaria Hospital, Bologna, Italy; Department of Neurology (U.B.), University Hospital, Regensburg, Germany; Division of Medical Oncology (D.R.M.), London Regional Cancer Program, University of Western Ontario, London, Canada; Clark H. Smith Brain Tumour Centre and Tom Baker Cancer Centre (P.F.), Calgary, Canada; Departments of Neurology (O.A.R.), Radiation Oncology (R.-O.M.), and Neurosurgery (R.S.), Centre Hospitalier Universitaire Vaudois and University of Lausanne, Lausanne, Switzerland; and Neuro-oncology Unit and Department of Neurology (C.J.V.), Medical Centre, The Hague, the Netherlands.
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T. Gorlia, MSc, PhD
From the Department of Neurology (M.W.), University Hospital Tübingen, Tübingen, Germany, and University Hospital Zurich, Zurich, Switzerland; European Organisation for Research and Treatment of Cancer (T.G., D.L.), Brussels, Belgium; Department of Clinical Neurosciences and Clark H. Smith Brain Tumour Centre (J.G.C.), University of Calgary, Calgary, Canada; Department of Neuro-Oncology (M.J.v.d.B.), Daniel den Hoed Cancer Center/Erasmus Medical Centre, Rotterdam, the Netherlands; Princess Margaret Hospital (W.M.), University of Toronto, Toronto, Canada; CHUM-Hôpital Notre Dame (K.B.), Montreal, Canada; Department of Medical Oncology (A.A.B.), Bellaria Hospital, Bologna, Italy; Department of Neurology (U.B.), University Hospital, Regensburg, Germany; Division of Medical Oncology (D.R.M.), London Regional Cancer Program, University of Western Ontario, London, Canada; Clark H. Smith Brain Tumour Centre and Tom Baker Cancer Centre (P.F.), Calgary, Canada; Departments of Neurology (O.A.R.), Radiation Oncology (R.-O.M.), and Neurosurgery (R.S.), Centre Hospitalier Universitaire Vaudois and University of Lausanne, Lausanne, Switzerland; and Neuro-oncology Unit and Department of Neurology (C.J.V.), Medical Centre, The Hague, the Netherlands.
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J.G. Cairncross, MD
From the Department of Neurology (M.W.), University Hospital Tübingen, Tübingen, Germany, and University Hospital Zurich, Zurich, Switzerland; European Organisation for Research and Treatment of Cancer (T.G., D.L.), Brussels, Belgium; Department of Clinical Neurosciences and Clark H. Smith Brain Tumour Centre (J.G.C.), University of Calgary, Calgary, Canada; Department of Neuro-Oncology (M.J.v.d.B.), Daniel den Hoed Cancer Center/Erasmus Medical Centre, Rotterdam, the Netherlands; Princess Margaret Hospital (W.M.), University of Toronto, Toronto, Canada; CHUM-Hôpital Notre Dame (K.B.), Montreal, Canada; Department of Medical Oncology (A.A.B.), Bellaria Hospital, Bologna, Italy; Department of Neurology (U.B.), University Hospital, Regensburg, Germany; Division of Medical Oncology (D.R.M.), London Regional Cancer Program, University of Western Ontario, London, Canada; Clark H. Smith Brain Tumour Centre and Tom Baker Cancer Centre (P.F.), Calgary, Canada; Departments of Neurology (O.A.R.), Radiation Oncology (R.-O.M.), and Neurosurgery (R.S.), Centre Hospitalier Universitaire Vaudois and University of Lausanne, Lausanne, Switzerland; and Neuro-oncology Unit and Department of Neurology (C.J.V.), Medical Centre, The Hague, the Netherlands.
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M.J. van den Bent, MD
From the Department of Neurology (M.W.), University Hospital Tübingen, Tübingen, Germany, and University Hospital Zurich, Zurich, Switzerland; European Organisation for Research and Treatment of Cancer (T.G., D.L.), Brussels, Belgium; Department of Clinical Neurosciences and Clark H. Smith Brain Tumour Centre (J.G.C.), University of Calgary, Calgary, Canada; Department of Neuro-Oncology (M.J.v.d.B.), Daniel den Hoed Cancer Center/Erasmus Medical Centre, Rotterdam, the Netherlands; Princess Margaret Hospital (W.M.), University of Toronto, Toronto, Canada; CHUM-Hôpital Notre Dame (K.B.), Montreal, Canada; Department of Medical Oncology (A.A.B.), Bellaria Hospital, Bologna, Italy; Department of Neurology (U.B.), University Hospital, Regensburg, Germany; Division of Medical Oncology (D.R.M.), London Regional Cancer Program, University of Western Ontario, London, Canada; Clark H. Smith Brain Tumour Centre and Tom Baker Cancer Centre (P.F.), Calgary, Canada; Departments of Neurology (O.A.R.), Radiation Oncology (R.-O.M.), and Neurosurgery (R.S.), Centre Hospitalier Universitaire Vaudois and University of Lausanne, Lausanne, Switzerland; and Neuro-oncology Unit and Department of Neurology (C.J.V.), Medical Centre, The Hague, the Netherlands.
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W. Mason, MD
From the Department of Neurology (M.W.), University Hospital Tübingen, Tübingen, Germany, and University Hospital Zurich, Zurich, Switzerland; European Organisation for Research and Treatment of Cancer (T.G., D.L.), Brussels, Belgium; Department of Clinical Neurosciences and Clark H. Smith Brain Tumour Centre (J.G.C.), University of Calgary, Calgary, Canada; Department of Neuro-Oncology (M.J.v.d.B.), Daniel den Hoed Cancer Center/Erasmus Medical Centre, Rotterdam, the Netherlands; Princess Margaret Hospital (W.M.), University of Toronto, Toronto, Canada; CHUM-Hôpital Notre Dame (K.B.), Montreal, Canada; Department of Medical Oncology (A.A.B.), Bellaria Hospital, Bologna, Italy; Department of Neurology (U.B.), University Hospital, Regensburg, Germany; Division of Medical Oncology (D.R.M.), London Regional Cancer Program, University of Western Ontario, London, Canada; Clark H. Smith Brain Tumour Centre and Tom Baker Cancer Centre (P.F.), Calgary, Canada; Departments of Neurology (O.A.R.), Radiation Oncology (R.-O.M.), and Neurosurgery (R.S.), Centre Hospitalier Universitaire Vaudois and University of Lausanne, Lausanne, Switzerland; and Neuro-oncology Unit and Department of Neurology (C.J.V.), Medical Centre, The Hague, the Netherlands.
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K. Belanger, MD
From the Department of Neurology (M.W.), University Hospital Tübingen, Tübingen, Germany, and University Hospital Zurich, Zurich, Switzerland; European Organisation for Research and Treatment of Cancer (T.G., D.L.), Brussels, Belgium; Department of Clinical Neurosciences and Clark H. Smith Brain Tumour Centre (J.G.C.), University of Calgary, Calgary, Canada; Department of Neuro-Oncology (M.J.v.d.B.), Daniel den Hoed Cancer Center/Erasmus Medical Centre, Rotterdam, the Netherlands; Princess Margaret Hospital (W.M.), University of Toronto, Toronto, Canada; CHUM-Hôpital Notre Dame (K.B.), Montreal, Canada; Department of Medical Oncology (A.A.B.), Bellaria Hospital, Bologna, Italy; Department of Neurology (U.B.), University Hospital, Regensburg, Germany; Division of Medical Oncology (D.R.M.), London Regional Cancer Program, University of Western Ontario, London, Canada; Clark H. Smith Brain Tumour Centre and Tom Baker Cancer Centre (P.F.), Calgary, Canada; Departments of Neurology (O.A.R.), Radiation Oncology (R.-O.M.), and Neurosurgery (R.S.), Centre Hospitalier Universitaire Vaudois and University of Lausanne, Lausanne, Switzerland; and Neuro-oncology Unit and Department of Neurology (C.J.V.), Medical Centre, The Hague, the Netherlands.
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A.A. Brandes, MD
From the Department of Neurology (M.W.), University Hospital Tübingen, Tübingen, Germany, and University Hospital Zurich, Zurich, Switzerland; European Organisation for Research and Treatment of Cancer (T.G., D.L.), Brussels, Belgium; Department of Clinical Neurosciences and Clark H. Smith Brain Tumour Centre (J.G.C.), University of Calgary, Calgary, Canada; Department of Neuro-Oncology (M.J.v.d.B.), Daniel den Hoed Cancer Center/Erasmus Medical Centre, Rotterdam, the Netherlands; Princess Margaret Hospital (W.M.), University of Toronto, Toronto, Canada; CHUM-Hôpital Notre Dame (K.B.), Montreal, Canada; Department of Medical Oncology (A.A.B.), Bellaria Hospital, Bologna, Italy; Department of Neurology (U.B.), University Hospital, Regensburg, Germany; Division of Medical Oncology (D.R.M.), London Regional Cancer Program, University of Western Ontario, London, Canada; Clark H. Smith Brain Tumour Centre and Tom Baker Cancer Centre (P.F.), Calgary, Canada; Departments of Neurology (O.A.R.), Radiation Oncology (R.-O.M.), and Neurosurgery (R.S.), Centre Hospitalier Universitaire Vaudois and University of Lausanne, Lausanne, Switzerland; and Neuro-oncology Unit and Department of Neurology (C.J.V.), Medical Centre, The Hague, the Netherlands.
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U. Bogdahn, MD
From the Department of Neurology (M.W.), University Hospital Tübingen, Tübingen, Germany, and University Hospital Zurich, Zurich, Switzerland; European Organisation for Research and Treatment of Cancer (T.G., D.L.), Brussels, Belgium; Department of Clinical Neurosciences and Clark H. Smith Brain Tumour Centre (J.G.C.), University of Calgary, Calgary, Canada; Department of Neuro-Oncology (M.J.v.d.B.), Daniel den Hoed Cancer Center/Erasmus Medical Centre, Rotterdam, the Netherlands; Princess Margaret Hospital (W.M.), University of Toronto, Toronto, Canada; CHUM-Hôpital Notre Dame (K.B.), Montreal, Canada; Department of Medical Oncology (A.A.B.), Bellaria Hospital, Bologna, Italy; Department of Neurology (U.B.), University Hospital, Regensburg, Germany; Division of Medical Oncology (D.R.M.), London Regional Cancer Program, University of Western Ontario, London, Canada; Clark H. Smith Brain Tumour Centre and Tom Baker Cancer Centre (P.F.), Calgary, Canada; Departments of Neurology (O.A.R.), Radiation Oncology (R.-O.M.), and Neurosurgery (R.S.), Centre Hospitalier Universitaire Vaudois and University of Lausanne, Lausanne, Switzerland; and Neuro-oncology Unit and Department of Neurology (C.J.V.), Medical Centre, The Hague, the Netherlands.
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D.R. Macdonald, MD
From the Department of Neurology (M.W.), University Hospital Tübingen, Tübingen, Germany, and University Hospital Zurich, Zurich, Switzerland; European Organisation for Research and Treatment of Cancer (T.G., D.L.), Brussels, Belgium; Department of Clinical Neurosciences and Clark H. Smith Brain Tumour Centre (J.G.C.), University of Calgary, Calgary, Canada; Department of Neuro-Oncology (M.J.v.d.B.), Daniel den Hoed Cancer Center/Erasmus Medical Centre, Rotterdam, the Netherlands; Princess Margaret Hospital (W.M.), University of Toronto, Toronto, Canada; CHUM-Hôpital Notre Dame (K.B.), Montreal, Canada; Department of Medical Oncology (A.A.B.), Bellaria Hospital, Bologna, Italy; Department of Neurology (U.B.), University Hospital, Regensburg, Germany; Division of Medical Oncology (D.R.M.), London Regional Cancer Program, University of Western Ontario, London, Canada; Clark H. Smith Brain Tumour Centre and Tom Baker Cancer Centre (P.F.), Calgary, Canada; Departments of Neurology (O.A.R.), Radiation Oncology (R.-O.M.), and Neurosurgery (R.S.), Centre Hospitalier Universitaire Vaudois and University of Lausanne, Lausanne, Switzerland; and Neuro-oncology Unit and Department of Neurology (C.J.V.), Medical Centre, The Hague, the Netherlands.
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P. Forsyth, MD
From the Department of Neurology (M.W.), University Hospital Tübingen, Tübingen, Germany, and University Hospital Zurich, Zurich, Switzerland; European Organisation for Research and Treatment of Cancer (T.G., D.L.), Brussels, Belgium; Department of Clinical Neurosciences and Clark H. Smith Brain Tumour Centre (J.G.C.), University of Calgary, Calgary, Canada; Department of Neuro-Oncology (M.J.v.d.B.), Daniel den Hoed Cancer Center/Erasmus Medical Centre, Rotterdam, the Netherlands; Princess Margaret Hospital (W.M.), University of Toronto, Toronto, Canada; CHUM-Hôpital Notre Dame (K.B.), Montreal, Canada; Department of Medical Oncology (A.A.B.), Bellaria Hospital, Bologna, Italy; Department of Neurology (U.B.), University Hospital, Regensburg, Germany; Division of Medical Oncology (D.R.M.), London Regional Cancer Program, University of Western Ontario, London, Canada; Clark H. Smith Brain Tumour Centre and Tom Baker Cancer Centre (P.F.), Calgary, Canada; Departments of Neurology (O.A.R.), Radiation Oncology (R.-O.M.), and Neurosurgery (R.S.), Centre Hospitalier Universitaire Vaudois and University of Lausanne, Lausanne, Switzerland; and Neuro-oncology Unit and Department of Neurology (C.J.V.), Medical Centre, The Hague, the Netherlands.
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A.O. Rossetti, MD
From the Department of Neurology (M.W.), University Hospital Tübingen, Tübingen, Germany, and University Hospital Zurich, Zurich, Switzerland; European Organisation for Research and Treatment of Cancer (T.G., D.L.), Brussels, Belgium; Department of Clinical Neurosciences and Clark H. Smith Brain Tumour Centre (J.G.C.), University of Calgary, Calgary, Canada; Department of Neuro-Oncology (M.J.v.d.B.), Daniel den Hoed Cancer Center/Erasmus Medical Centre, Rotterdam, the Netherlands; Princess Margaret Hospital (W.M.), University of Toronto, Toronto, Canada; CHUM-Hôpital Notre Dame (K.B.), Montreal, Canada; Department of Medical Oncology (A.A.B.), Bellaria Hospital, Bologna, Italy; Department of Neurology (U.B.), University Hospital, Regensburg, Germany; Division of Medical Oncology (D.R.M.), London Regional Cancer Program, University of Western Ontario, London, Canada; Clark H. Smith Brain Tumour Centre and Tom Baker Cancer Centre (P.F.), Calgary, Canada; Departments of Neurology (O.A.R.), Radiation Oncology (R.-O.M.), and Neurosurgery (R.S.), Centre Hospitalier Universitaire Vaudois and University of Lausanne, Lausanne, Switzerland; and Neuro-oncology Unit and Department of Neurology (C.J.V.), Medical Centre, The Hague, the Netherlands.
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D. Lacombe, MD
From the Department of Neurology (M.W.), University Hospital Tübingen, Tübingen, Germany, and University Hospital Zurich, Zurich, Switzerland; European Organisation for Research and Treatment of Cancer (T.G., D.L.), Brussels, Belgium; Department of Clinical Neurosciences and Clark H. Smith Brain Tumour Centre (J.G.C.), University of Calgary, Calgary, Canada; Department of Neuro-Oncology (M.J.v.d.B.), Daniel den Hoed Cancer Center/Erasmus Medical Centre, Rotterdam, the Netherlands; Princess Margaret Hospital (W.M.), University of Toronto, Toronto, Canada; CHUM-Hôpital Notre Dame (K.B.), Montreal, Canada; Department of Medical Oncology (A.A.B.), Bellaria Hospital, Bologna, Italy; Department of Neurology (U.B.), University Hospital, Regensburg, Germany; Division of Medical Oncology (D.R.M.), London Regional Cancer Program, University of Western Ontario, London, Canada; Clark H. Smith Brain Tumour Centre and Tom Baker Cancer Centre (P.F.), Calgary, Canada; Departments of Neurology (O.A.R.), Radiation Oncology (R.-O.M.), and Neurosurgery (R.S.), Centre Hospitalier Universitaire Vaudois and University of Lausanne, Lausanne, Switzerland; and Neuro-oncology Unit and Department of Neurology (C.J.V.), Medical Centre, The Hague, the Netherlands.
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R.-O. Mirimanoff, MD
From the Department of Neurology (M.W.), University Hospital Tübingen, Tübingen, Germany, and University Hospital Zurich, Zurich, Switzerland; European Organisation for Research and Treatment of Cancer (T.G., D.L.), Brussels, Belgium; Department of Clinical Neurosciences and Clark H. Smith Brain Tumour Centre (J.G.C.), University of Calgary, Calgary, Canada; Department of Neuro-Oncology (M.J.v.d.B.), Daniel den Hoed Cancer Center/Erasmus Medical Centre, Rotterdam, the Netherlands; Princess Margaret Hospital (W.M.), University of Toronto, Toronto, Canada; CHUM-Hôpital Notre Dame (K.B.), Montreal, Canada; Department of Medical Oncology (A.A.B.), Bellaria Hospital, Bologna, Italy; Department of Neurology (U.B.), University Hospital, Regensburg, Germany; Division of Medical Oncology (D.R.M.), London Regional Cancer Program, University of Western Ontario, London, Canada; Clark H. Smith Brain Tumour Centre and Tom Baker Cancer Centre (P.F.), Calgary, Canada; Departments of Neurology (O.A.R.), Radiation Oncology (R.-O.M.), and Neurosurgery (R.S.), Centre Hospitalier Universitaire Vaudois and University of Lausanne, Lausanne, Switzerland; and Neuro-oncology Unit and Department of Neurology (C.J.V.), Medical Centre, The Hague, the Netherlands.
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C.J. Vecht, MD
From the Department of Neurology (M.W.), University Hospital Tübingen, Tübingen, Germany, and University Hospital Zurich, Zurich, Switzerland; European Organisation for Research and Treatment of Cancer (T.G., D.L.), Brussels, Belgium; Department of Clinical Neurosciences and Clark H. Smith Brain Tumour Centre (J.G.C.), University of Calgary, Calgary, Canada; Department of Neuro-Oncology (M.J.v.d.B.), Daniel den Hoed Cancer Center/Erasmus Medical Centre, Rotterdam, the Netherlands; Princess Margaret Hospital (W.M.), University of Toronto, Toronto, Canada; CHUM-Hôpital Notre Dame (K.B.), Montreal, Canada; Department of Medical Oncology (A.A.B.), Bellaria Hospital, Bologna, Italy; Department of Neurology (U.B.), University Hospital, Regensburg, Germany; Division of Medical Oncology (D.R.M.), London Regional Cancer Program, University of Western Ontario, London, Canada; Clark H. Smith Brain Tumour Centre and Tom Baker Cancer Centre (P.F.), Calgary, Canada; Departments of Neurology (O.A.R.), Radiation Oncology (R.-O.M.), and Neurosurgery (R.S.), Centre Hospitalier Universitaire Vaudois and University of Lausanne, Lausanne, Switzerland; and Neuro-oncology Unit and Department of Neurology (C.J.V.), Medical Centre, The Hague, the Netherlands.
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R. Stupp, MD
From the Department of Neurology (M.W.), University Hospital Tübingen, Tübingen, Germany, and University Hospital Zurich, Zurich, Switzerland; European Organisation for Research and Treatment of Cancer (T.G., D.L.), Brussels, Belgium; Department of Clinical Neurosciences and Clark H. Smith Brain Tumour Centre (J.G.C.), University of Calgary, Calgary, Canada; Department of Neuro-Oncology (M.J.v.d.B.), Daniel den Hoed Cancer Center/Erasmus Medical Centre, Rotterdam, the Netherlands; Princess Margaret Hospital (W.M.), University of Toronto, Toronto, Canada; CHUM-Hôpital Notre Dame (K.B.), Montreal, Canada; Department of Medical Oncology (A.A.B.), Bellaria Hospital, Bologna, Italy; Department of Neurology (U.B.), University Hospital, Regensburg, Germany; Division of Medical Oncology (D.R.M.), London Regional Cancer Program, University of Western Ontario, London, Canada; Clark H. Smith Brain Tumour Centre and Tom Baker Cancer Centre (P.F.), Calgary, Canada; Departments of Neurology (O.A.R.), Radiation Oncology (R.-O.M.), and Neurosurgery (R.S.), Centre Hospitalier Universitaire Vaudois and University of Lausanne, Lausanne, Switzerland; and Neuro-oncology Unit and Department of Neurology (C.J.V.), Medical Centre, The Hague, the Netherlands.
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Notes

Study funding: Funding information is provided at the end of the article.
Address correspondence and reprint requests to Dr. Michael Weller, Department of Neurology, University Hospital Zurich, Frauenklinikstrasse 26, CH-8091 Zurich, Switzerland [email protected]

Author Contributions

The trial was designed by R. Stupp, R. Mirimanoff, D. Lacombe, and many other members of the EORTC Brain Tumour and Radiation Oncology Groups. The concept for this analysis was headed by M. Weller and R. Stupp. The statistical analysis was done by T. Gorlia. The manuscript was written by M. Weller, R. Stupp, and T. Gorlia, with substantial input and advice from J.G. Cairncross, C. Vecht, A. Rossetti, and M.J. van den Bent. M. Weller, J.G. Cairncross, M.J. van den Bent, W. Mason, A. Brandes, K. Belanger, U. Bogdahn, D. Macdonald, P. Forsyth, R.-O. Mirimanoff, C. Vecht, and R. Stupp recruited patients into the original study and provided clinical data. All authors have seen, reviewed, commented on, and approved the manuscript.

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