Wolfgang Wick1, Patrick Roth1, Christian Hartmann1, Peter Hau1, Makoto Nakamura1, Florian Stockhammer1, Michael C Sabel1, Antje Wick1, Susanne Koeppen1, Ralf Ketter1, Peter Vajkoczy1, Ilker Eyupoglu1, Rolf Kalff1, Torsten Pietsch1, Caroline Happold1, Norbert Galldiks1, Friederike Schmidt-Graf1, Michael Bamberg1, Guido Reifenberger1, Michael Platten1, Andreas von Deimling1, Christoph Meisner1, Benedikt Wiestler1, Michael Weller1. 1. Department of Neurology Clinic, University of Heidelberg, Heidelberg, Germany (W.W., A.W., M.P., B.W.); Clinical Cooperation Unit (CCU Neurooncology), German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany (W.W., B.W.); Department of Neurology, University Hospital and University of Zurich, Zurich, Switzerland (P.R., C.H., M.W.); Department of Neuropathology, Hannover Medical School, Hannover, Germany (C.H.); Department of Neurology, Regensburg University, Regensburg, Germany (P.H.); Department of Neurosurgery Clinic, Hannover Medical School, Hannover, Germany (M.N.); Department of Neurosurgery Clinic, Charité, Berlin, Germany (F.S., P.V.); Department of Neurosurgery, Heinrich Heine University, Düsseldorf, Germany (M.C.S.); Department of Neurology Clinic, Essen Medical Center, Essen, Germany (S.K.); Department of Neurosurgery Clinic, Saarland University, Homburg, Germany (R.K.); Department of Neurosurgery Clinic, University of Göttingen, Göttingen, Germany (F.S.); Department of Neurosurgery Clinic, University of Erlangen, Erlangen, Germany (I.E.); Department of Neurosurgery Clinic, University of Jena, Jena, Germany (R.K.); Department of Neurology Clinic, Cologne University, Cologne, Germany (N.G.); Department of Neurology Clinic, TU Munich, Munich, Germany (F.S.-G.); Department of Neuropathology, University of Heidelberg, Heidelberg, Germany (A.v.D.); CCU Neuropathology, (C.H., A.v.D.); CCU Brain Tumor Immunology, DKFZ, all Heidelberg, Germany (M.P.); Department of Neuropathology, Heinrich Heine University, Düsseldorf, Germany (G.R.); DKTK partner site Essen/Düsseldorf, Düsseldorf, Germany (G.R.), Department of General Neurology, Tübingen, Germany (W.W., A.W., F.S.-G., M.P., M.W.), Department of Radiation Oncology, Tübingen, Germany (M.B.), Department of Medical Biometry, University Hospital Tübingen, Tübingen, Germany (C.M.).
Abstract
BACKGROUND: Optimal treatment and precise classification for anaplastic glioma are needed. METHODS: The objective for long-term follow-up of NOA-04 is to optimize the treatment sequence for patients with anaplastic gliomas. Patients were randomized 2:1:1 to receive the standard radiotherapy (RT) (arm A), procarbazine, lomustine and vincristine (PCV) (arm B1), or temozolomide (TMZ) (arm B2). RESULTS: Primary endpoint was time-to-treatment-failure (TTF), defined as progression after 2 lines of therapy or any time before if no further therapy was administered. Exploratory analyses examined associations of molecular marker status with TTF, progression-free survival (PFS), and overall survival (OS). At 9.5 (95% CI: 8.6-10.2) years, no difference between arms (A vs B1/B2) was observed: median TTF (4.6 [3.4-5.1] y vs 4.4 [3.3-5.3) y), PFS (2.5 [1.3-3.5] y vs 2.7 [1.9-3.2] y), and OS (8 [5.5-10.3] y vs 6.5 [5.4-8.3] y). Oligodendroglial versus astrocytic histology-but more so the subgroups according to CpG island methylator phenotype (CIMP) and 1p/19q co-deletion status-revealed a strong prognostic value of CIMPpos with (CIMPcodel) versus without 1p/19 co-deletion (CIMPnon-codel) versus CIMPneg. but no differential efficacy of RT versus chemotherapy for any of the endpoints. PFS was better for PCV- than for TMZ-treated patients with CIMPcodel tumors (HR B1 vs B2 0.39 [0.17-0.92], P = .031). In CIMPneg. tumors, hypermethylation of the O6-methyl-guanyl-DNA methyltransferase promoter (MGMT) provided a risk reduction for PFS with chemotherapy. CONCLUSIONS: There is no differential activity of primary chemotherapy versus RT in any subgroup of anaplastic glioma. Molecular diagnosis is superior to histology. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00717210.
RCT Entities:
BACKGROUND: Optimal treatment and precise classification for anaplastic glioma are needed. METHODS: The objective for long-term follow-up of NOA-04 is to optimize the treatment sequence for patients with anaplastic gliomas. Patients were randomized 2:1:1 to receive the standard radiotherapy (RT) (arm A), procarbazine, lomustine and vincristine (PCV) (arm B1), or temozolomide (TMZ) (arm B2). RESULTS: Primary endpoint was time-to-treatment-failure (TTF), defined as progression after 2 lines of therapy or any time before if no further therapy was administered. Exploratory analyses examined associations of molecular marker status with TTF, progression-free survival (PFS), and overall survival (OS). At 9.5 (95% CI: 8.6-10.2) years, no difference between arms (A vs B1/B2) was observed: median TTF (4.6 [3.4-5.1] y vs 4.4 [3.3-5.3) y), PFS (2.5 [1.3-3.5] y vs 2.7 [1.9-3.2] y), and OS (8 [5.5-10.3] y vs 6.5 [5.4-8.3] y). Oligodendroglial versus astrocytic histology-but more so the subgroups according to CpG island methylator phenotype (CIMP) and 1p/19q co-deletion status-revealed a strong prognostic value of CIMPpos with (CIMPcodel) versus without 1p/19 co-deletion (CIMPnon-codel) versus CIMPneg. but no differential efficacy of RT versus chemotherapy for any of the endpoints. PFS was better for PCV- than for TMZ-treated patients with CIMPcodel tumors (HR B1 vs B2 0.39 [0.17-0.92], P = .031). In CIMPneg. tumors, hypermethylation of the O6-methyl-guanyl-DNA methyltransferase promoter (MGMT) provided a risk reduction for PFS with chemotherapy. CONCLUSIONS: There is no differential activity of primary chemotherapy versus RT in any subgroup of anaplastic glioma. Molecular diagnosis is superior to histology. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00717210.
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