Long-term analysis of the NOA-04 randomized phase III trial of sequential radiochemotherapy of anaplastic glioma with PCV or temozolomide.

Wolfgang Wick, Patrick Roth, Christian Hartmann, Peter Hau, Makoto Nakamura, Florian Stockhammer, Michael C Sabel, Antje Wick, Susanne Koeppen, Ralf Ketter, Peter Vajkoczy, Ilker Eyupoglu, Rolf Kalff, Torsten Pietsch, Caroline Happold, Norbert Galldiks, Friederike Schmidt-Graf, Michael Bamberg, Guido Reifenberger, Michael Platten, Andreas von Deimling, Christoph Meisner, Benedikt Wiestler, Michael Weller

Journal: Neuro-oncology 2017;18(11):1529-1537

PMID: 27370396

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 CIMP with (CIMP) versus without 1p/19 co-deletion (CIMP) versus CIMP. but no differential efficacy of RT versus chemotherapy for any of the endpoints. PFS was better for PCV- than for TMZ-treated patients with CIMP tumors (HR B1 vs B2 0.39 [0.17-0.92], P = .031). In CIMP. 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.

© The Author(s) 2016. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: [email protected].

Address: 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.).
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