Adjuvant procarbazine, lomustine, and vincristine chemotherapy in newly diagnosed anaplastic oligodendroglioma: long-term follow-up of EORTC brain tumor group study 26951.

PURPOSE Anaplastic oligodendroglioma are chemotherapy-sensitive tumors. We now present the long-term follow-up findings of a randomized phase III study on the addition of six cycles of procarbazine, lomustine, and vincristine (PCV) chemotherapy to radiotherapy (RT). PATIENTS AND METHODS Adult patients with newly diagnosed anaplastic oligodendroglial tumors were randomly assigned to either 59.4 Gy of RT or the same RT followed by six cycles of adjuvant PCV. An exploratory analysis of the correlation between 1p/19q status and survival was part of the study. Retrospectively, the methylation status of the methyl-guanine methyl transferase gene promoter and the mutational status of the isocitrate dehydrogenase (IDH) gene were determined. The primary end points were overall survival (OS) and progression-free survival based on intent-to-treat analysis. RESULTS A total of 368 patients were enrolled. With a median follow-up of 140 months, OS in the RT/PCV arm was significantly longer (42.3 v 30.6 months in the RT arm, hazard ratio [HR], 0.75; 95% CI, 0.60 to 0.95). In the 80 patients with a 1p/19q codeletion, OS was increased, with a trend toward more benefit from adjuvant PCV (OS not reached in the RT/PCV group v 112 months in the RT group; HR, 0.56; 95% CI, 0.31 to 1.03). IDH mutational status was also of prognostic significance. CONCLUSION The addition of six cycles of PCV after 59.4 Gy of RT increases both OS and PFS in anaplastic oligodendroglial tumors. 1p/19q-codeleted tumors derive more benefit from adjuvant PCV compared with non-1p/19q-deleted tumors.

[1]  D K Pearl,et al.  Improving diagnostic accuracy and interobserver concordance in the classification and grading of primary gliomas , 1997, Cancer.

[2]  Denis Lacombe,et al.  Adjuvant procarbazine, lomustine, and vincristine improves progression-free survival but not overall survival in newly diagnosed anaplastic oligodendrogliomas and oligoastrocytomas: a randomized European Organisation for Research and Treatment of Cancer phase III trial. , 2006, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[3]  S. Berger,et al.  IDH mutation impairs histone demethylation and results in a block to cell differentiation , 2012, Nature.

[4]  K. Hoang-Xuan,et al.  Genomic aberrations associated with outcome in anaplastic oligodendroglial tumors treated within the EORTC phase III trial 26951 , 2010, Journal of Neuro-Oncology.

[5]  P. Kleihues,et al.  IDH1 mutations are early events in the development of astrocytomas and oligodendrogliomas. , 2009, The American journal of pathology.

[6]  Caterina Giannini,et al.  Panel Review of Anaplastic Oligodendroglioma From European Organization for Research and Treatment of Cancer Trial 26951: Assessment of Consensus in Diagnosis, Influence of 1p/19q Loss, and Correlations With Outcome , 2007, Journal of neuropathology and experimental neurology.

[7]  Pieter Wesseling,et al.  IDH1 and IDH2 Mutations Are Prognostic but not Predictive for Outcome in Anaplastic Oligodendroglial Tumors: A Report of the European Organization for Research and Treatment of Cancer Brain Tumor Group , 2010, Clinical Cancer Research.

[8]  M. J. van den Bent,et al.  1p/19q loss within oligodendroglioma is predictive for response to first line temozolomide but not to salvage treatment. , 2006, European journal of cancer.

[9]  P. Burger,et al.  What is an Oligodendroglioma? , 2002, Brain pathology.

[10]  D. Louis,et al.  Survey of treatment recommendations for anaplastic oligodendroglioma. , 2007, Neuro-oncology.

[11]  P. Rothwell,et al.  External validity of randomised controlled trials: “To whom do the results of this trial apply?” , 2005, The Lancet.

[12]  M. J. van den Bent,et al.  Health-related quality of life in patients treated for anaplastic oligodendroglioma with adjuvant chemotherapy: results of a European Organisation for Research and Treatment of Cancer randomized clinical trial. , 2007, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[13]  K. Aldape,et al.  Anaplastic Oligodendroglial Tumors: Refining the Correlation among Histopathology, 1p 19q Deletion and Clinical Outcome in Intergroup Radiation Therapy Oncology Group Trial 9402 , 2008, Brain pathology.

[14]  D. Busam,et al.  An Integrated Genomic Analysis of Human Glioblastoma Multiforme , 2008, Science.

[15]  R. Mirimanoff,et al.  MGMT gene silencing and benefit from temozolomide in glioblastoma. , 2005, The New England journal of medicine.

[16]  Walter Curran,et al.  Phase III trial of chemotherapy plus radiotherapy compared with radiotherapy alone for pure and mixed anaplastic oligodendroglioma: Intergroup Radiation Therapy Oncology Group Trial 9402. , 2006, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[17]  J. Licht,et al.  Leukemic IDH1 and IDH2 mutations result in a hypermethylation phenotype, disrupt TET2 function, and impair hematopoietic differentiation. , 2010, Cancer cell.

[18]  O. G. Dodge,et al.  Histological Typing of tumours of the Central Nervous System , 1981, British Journal of Cancer.

[19]  L. Douw,et al.  Cognitive and radiological effects of radiotherapy in patients with low-grade glioma: long-term follow-up , 2009, The Lancet Neurology.

[20]  R. Mirimanoff,et al.  Molecular analysis of anaplastic oligodendroglial tumors in a prospective randomized study: A report from EORTC study 26951. , 2009, Neuro-oncology.

[21]  T. Cascino,et al.  Response criteria for phase II studies of supratentorial malignant glioma. , 1990, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[22]  T. Cascino,et al.  Chemotherapy for anaplastic oligodendroglioma. National Cancer Institute of Canada Clinical Trials Group. , 1994, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[23]  A. Twijnstra,et al.  Response rate and prognostic factors of recurrent oligodendroglioma treated with procarbazine, CCNU, and vincristine chemotherapy , 1998, Neurology.

[24]  K. Hopkins,et al.  Temozolomide versus procarbazine, lomustine, and vincristine in recurrent high-grade glioma. , 2010, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[25]  Jean-Yves Delattre,et al.  Methylation profiling identifies 2 groups of gliomas according to their tumorigenesis. , 2011, Neuro-oncology.

[26]  R. Wilson,et al.  Identification of a CpG island methylator phenotype that defines a distinct subgroup of glioma. , 2010, Cancer cell.

[27]  D. Louis,et al.  Specific genetic predictors of chemotherapeutic response and survival in patients with anaplastic oligodendrogliomas. , 1998, Journal of the National Cancer Institute.

[28]  M. J. van den Bent,et al.  MGMT promoter methylation is prognostic but not predictive for outcome to adjuvant PCV chemotherapy in anaplastic oligodendroglial tumors: a report from EORTC Brain Tumor Group Study 26951. , 2009, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[29]  M. J. van den Bent,et al.  Chromosomal anomalies in oligodendroglial tumors are correlated with clinical features , 2003, Cancer.

[30]  Pieter Wesseling,et al.  A Hypermethylated Phenotype Is a Better Predictor of Survival than MGMT Methylation in Anaplastic Oligodendroglial Brain Tumors: A Report from EORTC Study 26951 , 2011, Clinical Cancer Research.

[31]  Martin J. Bent,et al.  Interobserver variation of the histopathological diagnosis in clinical trials on glioma: a clinician’s perspective , 2010, Acta Neuropathologica.

[32]  Andrey Korshunov,et al.  Analysis of the IDH1 codon 132 mutation in brain tumors , 2008, Acta Neuropathologica.

[33]  E. Shaw,et al.  Phase III trial of chemoradiotherapy for anaplastic oligodendroglioma: long-term results of RTOG 9402. , 2013, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[34]  A. Brandes,et al.  Efficacy and feasibility of standard procarbazine, lomustine, and vincristine chemotherapy in anaplastic oligodendroglioma and oligoastrocytoma recurrent after radiotherapy , 2004, Cancer.

[35]  J. Peto,et al.  Asymptotically Efficient Rank Invariant Test Procedures , 1972 .

[36]  A. Viale,et al.  IDH1 mutation is sufficient to establish the glioma hypermethylator phenotype , 2012, Nature.

[37]  G. Reifenberger,et al.  NOA-04 randomized phase III trial of sequential radiochemotherapy of anaplastic glioma with procarbazine, lomustine, and vincristine or temozolomide. , 2009, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.