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EORTC topics in neurooncology: The long path from a focus on neurological complications of cancer towards molecularly defined trials and therapies in neurooncology
ejc supplements 10, no. 1 (2012) 20–26
EORTC topics in neurooncology: The long path from a focus on neurological complications of cancer towards molecularly defined trials and therapies in neurooncology Wolfgang Wick a, *, Martin van den Bent b , Charles Vecht c , Alba Brandes d , Denis Lacombe e , Thierry Gorlia e , Anouk Allgeier e , Brigitta G. Baumert f , Riccardo Soffietti g , Marc Sanson h , Abul B.M.F. Karim i , R´ene-Olivier Mirimanoff j , Martin Taphoorn c , Max Kros b , Monika Hegi j , Roger Stupp j , on behalf of the EORTC Brain Tumor Group a
Neurology Clinic and National Center for Tumor Diseases Heidelberg, Germany Erasmus University Medical Center, Rotterdam, The Netherlands c Medisch Centrum Haaglanden- Weseinde, Den Haag, The Netherlands d Azienda USL Bellaria − Maggiore, Bologna, Italy e EORTC Headquarters, Brussels, Belgium f Maastricht University Medical Center, Maastricht, The Netherlands g University Hospital San Giovanni Battista, Turin, Italy h Groupe Hospitalier Piti´e-Salpetri`ere, Paris, France i Vrije University Amsterdam, Amsterdam, The Netherlands j Centre Hospitalier Universitaire Vaudois (CHUV) and University of Lausanne, Lausanne, Switzerland b
article info
abstract
Keywords: Glioblastoma MGMT 1p/19q IDH1 Neurocognition
Over the past decade a series of trials of the EORTC Brain Tumor Group (BTG) has substantially influenced and shaped the standard-of-care of primary brain tumors. All these trials were coupled with biological research that has allowed for better understanding of the biology of these tumors. In glioblastoma, EORTC trial 26981/22981 conducted jointly with the National Cancer Institute of Canada Clinical Trials Group showed superiority of concomitant radiochemotherapy with temozolomide over radiotherapy alone. It also identified the first predictive marker for benefit from alkylating agent chemotherapy in glioblastoma, the methylation of the O6-methyl-guanyl-methly-transferase (MGMT) gene promoter. In another large randomized trial, EORTC 26951, adjuvant chemotherapy in anaplastic oligodendroglial tumors was investigated. Despite an improvement in progressionfree survival this did not translate into a survival benefit. The third example of a landmark trial is the EORTC 22845 trial. This trial led by the EORTC Radiation Oncology Group forms the basis for an expectative approach to patients with lowgrade glioma, as early radiotherapy indeed prolongs time to tumor progression but with no benefit in overall survival. This trial is the key reference in deciding at what time in their disease adult patients with low-grade glioma should be irradiated.
* Corresponding author. Wolfgang Wick, MD, Department of Neurooncology, Neurology Clinic & National Center for Tumor Disease, University of Heidelberg, Im Neuenheimer Feld 400, D-69120 Heidelberg, Germany. Tel.: +49 6221/56-7075; fax: +49 6221/56-7554. E-mail address: [email protected] (W. Wick). 1359-6349/$ – see front matter © 2012 European Organisation for Research and Treatment of Cancer. All rights reserved.
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Future initiatives will continue to focus on the conduct of controlled trials, rational academic drug development as well as systematic evaluation of tumor tissue including biomarker development for personalized therapy. Important lessons learned in neurooncology are to dare to ask real questions rather than merely rapidly testing new compounds, and the value of well designed trials, including the presence of controls, central pathology review, strict radiology protocols and biobanking. Structurally, the EORTC BTG has evolved into a multidisciplinary group with strong transatlantic alliances. It has contributed to the maturation of neurooncology within the oncological sciences. © 2012 European Organisation for Research and Treatment of Cancer. All rights reserved.
1. Examples of twenty-five years of Brain Tumor Group (BTG) Trials 1.1. Radiochemotherapy and MGMT in newly diagnosed glioblastoma For more than 30 years neurosurgical resection to the extent safely feasible followed by radiotherapy alone were the cornerstones of treatment for patients with glioblastoma. The most relevant prognostic parameters were age, Karnofsky performance score and extent of neurosurgical resection. Chemotherapeutic agents, with the possible exception of nitrosoureas, have shown little or no activity in malignant glioma patients. It was the EORTC 26981/22981–National Cancer Institute of Canada Clinical Trials Group (NCIC) CE.3 trial which for the first time in more than 20 years of neurooncology led to significant and relevant progress in the treatment of glioblastoma patients and has substantially influenced management of glioma in general, and future research in particular. The major results from the trial are (i) an increase in the overall survival of glioblastoma patients − at 2 years 27% of patients treated with combined radiochemotherapy remained alive compared to only 10% of patients who were initially treated with radiotherapy alone, 1 (ii) a relevant proportion of patients surviving >2−5 years 2 and (iii) the identification of a marker for benefit from temozolomide in brain tumors, promoter hypermethylation of the repair gene encoding O6-methyl-guanyl-methyl-transferase (MGMT). 3−5 Concomitant and adjuvant radiochemotherapy with temozolomide has now become the standard of care for newly diagnosed glioblastoma worldwide, and the identification of MGMT gene promoter methylation as the first predictive marker in brain tumors introduced the concept of personalized oncology into neurooncology. On a scientific level it heavily influenced design and clinical as well as basic research strategies of brain tumor trials afterwards. Several translational projects in addition to the companion project on MGMT have been successfully conducted. 6−14 From all referenced, 1−14 the health-related quality of life (HRQoL) evaluations 4 and work on a stem cell signature explaining resistance towards radiochemotherapy 8 best show the range of
science that is done within the framework of the EORTC BTG. Immediate follow-up projects that are heavily inspired by the EORTC 26981/22981 trial are the Radiation Therapy Oncology Group (RTOG) 05-25/EORTC 26052– 22053 Intergroup trial, which aimed at overcoming MGMT-mediated resistance and improving outcomes for the putatively sensitive MGMT-promoter-methylated patients by an intensified three out of four weeks dosedense temozolomide maintenance therapy regimen. This trial, including over 1100 patients in North America and Europe, failed to demonstrate an advantage in PFS or OS. 15 Importantly, the trial showed the feasibility of international collaboration and mandatory tumor tissue collection and testing of molecular markers. It allowed prospective confirmation of the prognostic value of MGMT promoter methylation. Nevertheless, until more effective treatments have been developed, outside clinical trials the EORTC regimen of radiotherapy with concomitant and adjuvant temozolomide remains the standard of care for all newly diagnosed glioblastoma. We recently completed accrual of a large randomized clinical trial adding the antiangiogenic and anti-migratory integrin inhibitor cilengitide in patients with a methylated MGMT promoter only (EORTC trial 26071/22072). When the pivotal glioblastoma trial was designed, an upper age limit of 70 years was deemed appropriate, because a prolonged course of therapy would only jeopardize the quality of life of elderly patients without sufficient prospect of meaningful benefit. However, the success of combined modality therapy in younger patients has led to revisiting this position, and the ongoing NCIC CE.6/EORTC 26062–22061 trial is investigating combined temozolomide chemotherapy in conjunction with hypofractionated radiotherapy. 1.2. Molecular subtypes in anaplastic glioma The EORTC 26951 trial investigating adjuvant procarbazine/lomustine/vincristine (PCV) chemotherapy after completion of radiotherapy in the more chemosensitive anaplastic oligodendroglioma (AOD) and oligoastrocytoma (AOA) is another example of a trial that moved the field beyond its actual result. The trials did
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not show a statistically significant difference in survival, although progression-free survival was significantly prolonged. We concluded that chemotherapy has a clear role in this disease. However, the timing of administration, initially/adjuvant or at the time of tumor recurrence or progression, appears of lesser importance, and toxicity of the chemotherapy has to be taken into account. In addition to the publication of the clinical data, 16,17 this study inspired a large series of translational research efforts which contributed to the molecular subtyping of anaplastic gliomas 16−22 Together with contemporary trials of the RTOG (94-02) 23 and the Neurooncology Working Group of the German Cancer Society (NOA-04), 24 as well as basic research from the International Cancer Genome Consortium, 25 molecular markers like MGMT, 21 isocitrate dehydrogenase 1 (IDH1) 20 and codeletion 1p/19q 16,19 have been firmly established in anaplastic gliomas. Ongoing research aims at unraveling the findings in the NOA-04 and EORTC 26951 trials indicating that MGMT methylation could predict a good response not only to alkylating chemotherapy but also to radiotherapy alone. The most recent contribution here is the strong prognostic effect of the Glioma CpG Island Methylator Phenotype (G-CIMP) in EORTC 26951 whose clinical significance is currently being further investigated. 26 So far however, all molecular markers in this trial are merely prognostic. MGMT that has been shown to be associated with benefit from temozolomide chemotherapy in glioblastoma does not hold the predictive power for alkylating chemotherapy in grade III tumors. This underscores the distinct biology of anaplastic tumors and glioblastoma. The need for a molecular classification, especially for anaplastic glioma, was also emphasized by the intrinsic typing and grading difficulties in these tumors that was addressed in a post hoc panel review for this trial. 27 This is a topic of high clinical relevance, with a major impact on ongoing trials. Recent news on the molecular markers for oligodendroglioma from US groups is the discovery of the genes located on 1p and 19q that may be the drivers for combined loss of 1p/19q in these tumors. Inactivating mutations have been identified in far-upstream element (FUSE) binding protein 1 (FUBP1) [>10% of cases], which may lead to myc activation, and in homolog of the Drosophila capicua gene (CIC) [40−50% of cases], which is a downstream target for some tyrosine kinase receptors. 25 In summary, anaplastic gliomas are regarded as an important and biologically distinct entity, in which we made rapid progress in understanding of their biology and subgroups. Radiotherapy or temozolomide chemotherapy but not the combination of both is standard or common practice within the centers of our group.
Furthermore, this trial with its companions stimulated two EORTC/RTOG (NCIC/MRC/HUB/NOA/COGNO transatlantic intergroup trials (EORTC 26053/22054 [CATNON] and EORTC 26081/22086 [CODEL]) aiming at answering another relevant question; determining how to optimally combine temozolomide chemotherapy and radiotherapy in anaplastic gliomas, in a joint and therefore more timely fashion. Clinically, the CATNON trial may also shed light on the question whether concomitant or maintenance temozolomide treatment is pivotal for the success of radiochemotherapy, and thus potentially influence treatment schedules and future trial development. In addition, these trials will provide the neurooncological community with unique biomaterial resources as both trials rely on the examination of 1p/19q deletion status as entry criterion and hence biomaterial will also be available later on for novel translational research questions. In order to conduct this important biological research, we have created a translational research platform within the EORTC. The advantages of this organized collaborative effort are evident: not only does it allow investigation of rare tumor types and subtypes with characteristic molecular aberrations, but all samples have been histopathologically reviewed, are annotated both molecularly and clinically, and patients were treated in a homogeneous manner allowing correlation of biological findings with outcome. But to successfully conduct this type of translational research, we depend on grant support from both national and international sources. Collaborations and further expansion of the translational research expertise within the BTG are key. When treating patients, quality of life is as much a concern as simple longevity. Analysis of the HRQOL data from the EORTC 26981 and 26951 trials showed that the addition of chemotherapy has no or only a limited and transient negative impact on HRQOL during and shortly following treatment. 4,17,28 Not unexpectedly, the generally well tolerated temozolomide chemotherapy had a less negative impact than the PCV regimen. Baseline HRQOL data demonstrated no additional prognostic significance compared to clinical data. Future studies should include longitudinal HRQOL measurements, especially following radiological recurrence, to establish the clinical impact of radiological progression. From the patient’s perspective, time to clinical deterioration may be a more relevant endpoint than time to progression if this progression is still asymptomatic. To meet this requirement, the validation of novel and more clinical endpoints is required. 1.3. To believe or not to believe: impact of tumor-specific treatment in low-grade glioma The last example of a landmark EORTC trial conducted jointly by the Radiation Oncology Group and the BTG is
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the EORTC trial 22845. 29−34 This trial is the key reference in determining at what time in their disease adult patients with low-grade glioma should be irradiated. The trial convincingly demonstrated that adjuvant irradiation may be delayed until subsequent disease progression without detrimental effect on overall survival despite a prolongation in progression-free survival. 29,30 To date these data, together with the set of prognostic factors that was established using data from that trial, 31 guide the decision on when to treat patients with low-grade tumors. These factors include tumor progression, age >40 years, presence of neurological deficits other than only seizures, a tumor size >5 cm or a tumor extending over the midline. As patients with low-grade gliomas have a comparably good life expectancy of >7 years and may survive relevant adverse effects of early therapies, this information is pivotal. Furthermore, this trial is one of the very few examples of completed randomized trials in that disease, in part because of the rarity and relatively good prognosis and thus long survival of these patients. Together with the work on temozolomide in glioblastoma and the increasing awareness in our group that tissue is the key for academic neurooncology, this trial also stimulated the important and timely EORTC 22033-26033 trial that has recently completed its accrual. In that trial we are asking the question whether standard first-line radiotherapy may be delayed and
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2. Towards a molecular classification of brain tumors − prime time for targeted treatments? Molecular diagnostics of gliomas allows definition of more homogeneous patient populations as exemplified in CODEL and CATNON for anaplastic gliomas with and without the 1p/19q co-deletion, respectively, the TAVAREC trial for recurrent glioma, or CENTRIC for glioblastoma with methylated MGMT. In the future, molecular diagnostics will be used to test whether specific treatments are active depending on the absence or presence of a specific molecular marker. In addition, the determination of IDH mutations is likely to gain an important role in the near future. Malignant gliomas with IDH mutations have a much better prognosis and are thought to have a different pathogenetic origin, further supported by the recent discovery of G-CIMP associated with IDH mutations. 26,36 IDH mutations have also been identified in acute myeloblastic leukemia in association with CIMP, and define a new prognostic subtype (PMID: 21130701; 20567020). Hence, gliomapatients with G-CIMP are molecularly and biologically distinct and should probably not be included in future glioblastoma trials. Biomarker research should provide guidance for clinical decision making aiming towards personalized oncology. To date, none of the molecular markers established in glioma today, e.g. p53, EGFR amplification or autoactivity, 1p/19q co-deletion, MGMT or IDH1/2, are relevantly contributing to daily decision making.
replaced by dose-dense temozolomide chemotherapy. Again tumor tissue has been collected from all patients and should ultimately allow separation of good- and poor-prognosis patients based on molecular profiles. Respective molecular signatures may also allow for identification of novel treatment targets. Until results of this trial are available, the BTG decided to pursue a new avenue by developing a trial for recurrent, poor-prognosis, contrast enhancing low-grade and anaplastic gliomas. In this trial, EORTC 26091/TAVAREC, patients are randomized at progression after initial treatment to receive temozolomide or temozolomide plus bevacizumab. With this and the companion trial 26101 on glioblastoma, the BTG is not only contributing to the first controlled trials with bevacizumab in recurrent glioma but is also paving the way for systematic academic centralized evaluation of imaging. The BTG together with the EORTC Imaging Platform have set up a standard imaging protocol for these trials, and data will be assessed centrally in order to generate pivotal data on the determination of progression also in the context of antiangiogenic therapy, recurrence patterns, and an upfront validation of the updated imaging criteria as developed by the Response Assessment in Neurooncology (RANO) Working group. 35
3. Visions in neurooncology Classification of brain tumors will no longer rely solely on morphological criteria, but invariably also include reproducible and standardized [sic!] molecular markers. For a growing number of patients in industrial countries sequencing of the full tumor genome is now available for a couple of hundred euros, and is becoming more and more affordable. However, we need to identify mutations that are actionable in glioma in order to offer appropriate treatments. A genome-wide expression analysis is done to enable classification of molecular subtypes of strong prognostic relevance. 37 These analyses are currently best performed within phase II and III clinical trials, however they are already offered commercially. Diagnostic determination of molecular signatures should assist choice of therapy and predict efficacy of established or new therapies, and will allow to enrich patient population most likely to benefit from a new treatment, thus avoiding exposure of a large number of patients to ineffective therapy. Since the EORTC is dedicated to rational academic drug development, our trials are designed with a clear focus on relevance for the patients. Too artificial inclusion and exclusion criteria are avoided, which allows an easy
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translation into daily clinical practice and with a clear focus on non-metric factors such as symptom burden, tolerance and quality of life aiming to produce relevant and just significant results. Given present demographics, future trial activities will focus on the distinct demands of elderly patients. An older age of tumor patient in general is associated with increased toxicity of many drugs, including antineoplastic agents, but increased toxicity in older patients has also been documented for targeted agents. Most likely, some of these trials will be carried out in close collaboration with other cooperative groups as successfully demonstrated in the past. This demands not only good scientific interaction but also a strong political will to facilitate these projects.
4. EORTC BTG in 2022 We will have learned to recognize and treat the tumor as an organ. We will recognize the tumor within its unique environment and interaction with the host organ. A tumor exceeds the mere assembly of tumor cells and requires a permissive milieu provided by nonmalignant cells and structures of the body to grow and spread. These are in particular vascular, immune and parenchymal cells 38 and potentially effects of intercellular plasticity. These components are different in the brain compared to other compartments of the body. The obligatory role of non-neoplastic cells is of special importance to brain tumors since all systemically given therapies need to reach the tumor cell at sufficient concentrations. In addition, immunotherapy, which needs to overcome the immunosuppressive environment in an immune-privileged organ, needs further development. However, smaller immunotherapy trials show promising molecular signals, which in the future may be translated into a clinically relevant signal, 39 for example by a future EORTC trial with an anti-EGFRvIII immunotherapy. Finally, tumor-initiating cells will be specifically targeted by the treatment. They will be characterized in many solid tumors including glioma that will foster the understanding of therapy resistance. We are prepared for a paradigm shift, as these cells may be much less susceptible to classical cytostatic/cytotoxic therapies. Approaches to modify stem cell features in brain tumors without heavy interference with physiological systems will need to be developed.
5. Conflict of interest statement Denis Lacombe, Thierry Gorlia, Anouk Allgeier, Max Kros, Charles Vecht, and ABMF Karim declare no conflicts of
interest. Riccardo Soffietti consulted for MSD, MerckSerono, Mundipharma, and consulted for and received research funds from Roche. Monika Hegi consulted for MDxHealth and MDS, and consulted for and received honoraria from Merck-Serono. Roger Stupp consulted (advisory boards) for Merck Serono, MSD/Merck & Co (formerly Schering-Plough), MDx Health, and Roche Pharma. Alba Brandes was a member of advisory boards for and received honoraria from Roche and Schering-Plough, and received honoraria from GSK. Marc Sanson consulted for and received honoraria from Merck and Roche, and received research funds from Pfizer. Martin Taphoorn received research funds from the Dutch Cancer Society, EORTC Quality of Life Group, and Jacobus Foundation The Hague. Wolfgang Wick consulted for and received honoraria and research funds from MSD, consulted for and received honoraria from Roche, consulted for Noxxon and Antisense Pharma, and received research funds from Eli Lilly and Apogenix. Martin van den Bent consulted for and received honoraria from MSD. Rene´ Olivier Mirimanoff consulted for and received honoraria and research funds from MDS and Schering-Plough. Brigitta G. Baumert consulted and received honoraria and research funds from MSD and Schering-Plough, and consulted for and received honoraria from the Institute for Quality and Efficiency in Health Care.
References
1. Stupp R, Mason WP, van den Bent MJ, et al.; European Organisation for Research and Treatment of Cancer Brain Tumor and Radiotherapy Groups; National Cancer Institute of Canada Clinical Trials Group. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 2005;352:987−96. 2. Stupp R, Hegi ME, Mason WP, et al.; European Organisation for Research and Treatment of Cancer Brain Tumour and Radiation Oncology Groups; National Cancer Institute of Canada Clinical Trials Group. Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phase III study: 5-year analysis of the EORTC-NCIC trial. Lancet Oncol 2009;10:459−66. 3. Beauchesne P, Bernier V, Carnin C, et al. Prolonged survival for patients with newly diagnosed, inoperable glioblastoma with 3-times daily ultrafractionated radiation therapy. Neuro Oncol 2010;12:595–602. 4. Taphoorn MJ, Stupp R, Coens C, et al.; European Organisation for Research and Treatment of Cancer Brain Tumour Group; EORTC Radiotherapy Group; National Cancer Institute of Canada Clinical Trials Group. Health-related quality of life in patients with glioblastoma: a randomised controlled trial. Lancet Oncol 2005;6:937−44. 5. Hegi ME, Diserens AC, Gorlia T, et al. MGMT gene silencing and benefit from temozolomide in glioblastoma. N Engl J Med 2005;352:997–1003.
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6. Ataman F, Poortmans P, Stupp R, Fisher B, Mirimanoff RO. Quality assurance of the EORTC 26981/22981; NCIC CE3 intergroup trial on radiotherapy with or without temozolomide for newly-diagnosed glioblastoma multiforme: the individual case review. Eur J Cancer 2004;40:1724−30. 7. Mirimanoff RO, Gorlia T, Mason W, et al. Radiotherapy and temozolomide for newly diagnosed glioblastoma: recursive partitioning analysis of the EORTC 26981/22981–NCIC CE3 phase III randomized trial. J Clin Oncol 2006;24:2563−9. 8. Murat A, Migliavacca E, Gorlia T, et al. Stem cell-related “self-renewal” signature and high epidermal growth factor receptor expression associated with resistance to concomitant chemoradiotherapy in glioblastoma. J Clin Oncol 2008;26:3015−24. 9. Mirimanoff RO, Gorlia T, Mason W, et al. Radiotherapy and temozolomide for newly diagnosed glioblastoma: recursive partitioning analysis of the EORTC 26981/22981–NCIC CE3 phase III randomized trial. J Clin Oncol 2006;24:2563−9. 10. Gorlia T, van den Bent MJ, Hegi ME, et al. Nomograms for predicting survival of patients with newly diagnosed glioblastoma: prognostic factor analysis of EORTC and NCIC trial 26981–22981/CE.3. Lancet Oncol 2008;9:29−38. 11. Lamers LM, Stupp R, van den Bent MJ, et al.; EORTC 26981/22981 NCI-C CE3 Intergroup Study. Costeffectiveness of temozolomide for the treatment of newly diagnosed glioblastoma multiforme: a report from the EORTC 26981/22981 NCI-C CE3 Intergroup Study. Cancer 2008;112:1337−44. 12. Preusser M, Charles Janzer R, Felsberg J, et al. AntiO6-methylguanine-methyltransferase (MGMT) immunohistochemistry in glioblastoma multiforme: observer variability and lack of association with patient survival impede its use as clinical biomarker. Brain Pathol 2008;18:520−32. 13. Wick W, Stupp R, Beule AC, et al.; European Organisation for Research and Treatment of Cancer and the National Cancer Institute of Canada Clinical Trials Group. A novel tool to analyze MRI recurrence patterns in glioblastoma. Neuro Oncol 2008;10:1019−24. 14. Weller M, Gorlia T, Cairncross JG, et al. Prolonged survival with valproic acid use in the EORTC/NCIC temozolomide trial for glioblastoma. Neurology 2011;77:1156−64. 15. Gilbert MR, Wang M, Aldape KD, et al. RTOG 0525: A randomized phase III trial comparing standard adjuvant temozolomide (TMZ) with a dose-dense (dd) schedule in newly diagnosed glioblastoma (GBM). J Clin Oncol 2011;29(Suppl): abstr 2006. 16. van den Bent MJ, Carpentier AF, Brandes AA, 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. J Clin Oncol 2006;24:2715−22. 17. Taphoorn MJ, van den Bent MJ, Mauer ME, et al.; European Organisation for Research and Treatment of Cancer. 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. J Clin Oncol 2007;25:5723−30.
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18. Mokhtari K, Ducray F, Kros JM, et al. Alphainternexin expression predicts outcome in anaplastic oligodendroglial tumors and may positively impact the efficacy of chemotherapy: European organization for research and treatment of cancer trial 26951. Cancer 2011;117:3014−26. 19. Idbaih A, Dalmasso C, Kouwenhoven M, et al. Genomic aberrations associated with outcome in anaplastic oligodendroglial tumors treated within the EORTC phase III trial 26951. J Neurooncol 2011;103:221−30. 20. van den Bent MJ, Dubbink HJ, Marie Y, 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. Clin Cancer Res 2010;16:1597–604. 21. van den Bent MJ, Dubbink HJ, Sanson M, 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. J Clin Oncol 2009;27:5881−6. 22. Kouwenhoven MC, Gorlia T, Kros JM, et al. Molecular analysis of anaplastic oligodendroglial tumors in a prospective randomized study: A report from EORTC study 26951. Neuro Oncol 2009;11:737−46. 23. Cairncross G, Berkey B, Shaw E, 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. J Clin Oncol 2006;24:2707−14. 24. Wick W, Hartmann C, Engel C, et al.; for the Neurooncology Working Group (NOA) of the German Cancer Society. NOA-04 randomized Phase III trial of sequential radiochemotherapy of anaplastic glioma with PCV or temozolomide. J Clin Oncol 2009;27:5874−80. 25. Bettegowda C, Agrawal N, Jiao Y, et al. Mutations in CIC and FUBP1 contribute to human oligodendroglioma Science 2011;333:1453−5. 26. van den Bent MJ, Gravendeel LA, Gorlia T, et al. A hypermethylated phenotype in anaplastic oligodendroglial brain tumors is a better predictor of survival than MGMT methylation in anaplastic oligodendroglioma: a report from EORTC study 26951. Clin Cancer Res 2011;17:7148−55. 27. Kros JM, Gorlia T, Kouwenhoven MC, 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. J Neuropathol Exp Neurol 2007;66:545−51. 28. Mauer ME, Taphoorn MJ, Bottomley A, et al.; EORTC Brain Cancer Group. Prognostic value of healthrelated quality-of-life data in predicting survival in patients with anaplastic oligodendrogliomas, from a phase III EORTC brain cancer group study. J Clin Oncol 2007;25:5731−7. 29. van den Bent MJ, Afra D, de Witte O, et al.; EORTC Radiotherapy and Brain Tumor Groups and the UK Medical Research Council. Long-term efficacy of early versus delayed radiotherapy for low-grade astrocytoma and oligodendroglioma in adults: the EORTC 22845 randomised trial. Lancet 2005;366:985−90. Erratum: Lancet 2006;367:1818.
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30. Karim AB, Afra D, Cornu P, et al. Randomized trial on the efficacy of radiotherapy for cerebral lowgrade glioma in the adult: European Organization for Research and Treatment of Cancer Study 22845 with the Medical Research Council study BRO4: an interim analysis. Int J Radiat Oncol Biol Phys 2002;52:316−24. 31. Pignatti F, van den Bent M, Curran D, et al.; European Organization for Research and Treatment of Cancer Brain Tumor Cooperative Group. Prognostic factors for survival in adult patients with cerebral low-grade glioma. J Clin Oncol 2002;20:2076−84. 32. Kiebert GM, Curran D, Aaronson NK, et al.; EORTC Radiotherapy Co-operative Group. Quality of life after radiation therapy of cerebral low-grade gliomas of the adult: results of a randomised phase III trial on dose response (EORTC trial 22844). Eur J Cancer 1998;34:1902−9. 33. Taphoorn MJ, Heimans JJ, van der Veen EA, Karim AB. Endocrine functions in long-term survivors of lowgrade supratentorial glioma treated with radiation therapy. J Neurooncol 1995;25:97–102. 34. Taphoorn MJ, Heimans JJ, Snoek FJ, Lindeboom J, Karim AB. Quality of life and neuropsychological
35.
36.
37.
38. 39.
functions in long-term low-grade glioma survivors. Int J Radiat Oncol Biol Phys 1994;29:1201−2. Wen PY, Macdonald DA, Reardon DA, et al. Updated response assessment criteria for high-grade gliomas: Response Assessment in Neuro-Oncology (RANO) Working Group. J Clin Oncol 2010;28:1963−72. Noushmehr H, Weisenberger DJ, Diefes K, et al.; Cancer Genome Atlas Research Network. Identification of a CpG island methylator phenotype that defines a distinct subgroup of glioma. Cancer Cell 2010;17:510−22. The Cancer Genome Atlas Research Network. Comprehensive genomic characterization defines human glioblastoma genes and core pathways. Nature 2008;455:1061−8. Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell 2011;144:646−74. Sampson JH, Heimberger AB, Archer GE, et al. Immunologic escape after prolonged progressionfree survival with epidermal growth factor receptor variant III peptide vaccination in patients with newly diagnosed glioblastoma. J Clin Oncol 2010;28:4722−9.
EORTC topics in neurooncology: The long path from a focus on neurological complications of cancer towards molecularly defined trials and therapies in neurooncology Wolfgang Wick a, *, Martin van den Bent b , Charles Vecht c , Alba Brandes d , Denis Lacombe e , Thierry Gorlia e , Anouk Allgeier e , Brigitta G. Baumert f , Riccardo Soffietti g , Marc Sanson h , Abul B.M.F. Karim i , R´ene-Olivier Mirimanoff j , Martin Taphoorn c , Max Kros b , Monika Hegi j , Roger Stupp j , on behalf of the EORTC Brain Tumor Group a
Neurology Clinic and National Center for Tumor Diseases Heidelberg, Germany Erasmus University Medical Center, Rotterdam, The Netherlands c Medisch Centrum Haaglanden- Weseinde, Den Haag, The Netherlands d Azienda USL Bellaria − Maggiore, Bologna, Italy e EORTC Headquarters, Brussels, Belgium f Maastricht University Medical Center, Maastricht, The Netherlands g University Hospital San Giovanni Battista, Turin, Italy h Groupe Hospitalier Piti´e-Salpetri`ere, Paris, France i Vrije University Amsterdam, Amsterdam, The Netherlands j Centre Hospitalier Universitaire Vaudois (CHUV) and University of Lausanne, Lausanne, Switzerland b
article info
abstract
Keywords: Glioblastoma MGMT 1p/19q IDH1 Neurocognition
Over the past decade a series of trials of the EORTC Brain Tumor Group (BTG) has substantially influenced and shaped the standard-of-care of primary brain tumors. All these trials were coupled with biological research that has allowed for better understanding of the biology of these tumors. In glioblastoma, EORTC trial 26981/22981 conducted jointly with the National Cancer Institute of Canada Clinical Trials Group showed superiority of concomitant radiochemotherapy with temozolomide over radiotherapy alone. It also identified the first predictive marker for benefit from alkylating agent chemotherapy in glioblastoma, the methylation of the O6-methyl-guanyl-methly-transferase (MGMT) gene promoter. In another large randomized trial, EORTC 26951, adjuvant chemotherapy in anaplastic oligodendroglial tumors was investigated. Despite an improvement in progressionfree survival this did not translate into a survival benefit. The third example of a landmark trial is the EORTC 22845 trial. This trial led by the EORTC Radiation Oncology Group forms the basis for an expectative approach to patients with lowgrade glioma, as early radiotherapy indeed prolongs time to tumor progression but with no benefit in overall survival. This trial is the key reference in deciding at what time in their disease adult patients with low-grade glioma should be irradiated.
* Corresponding author. Wolfgang Wick, MD, Department of Neurooncology, Neurology Clinic & National Center for Tumor Disease, University of Heidelberg, Im Neuenheimer Feld 400, D-69120 Heidelberg, Germany. Tel.: +49 6221/56-7075; fax: +49 6221/56-7554. E-mail address: [email protected] (W. Wick). 1359-6349/$ – see front matter © 2012 European Organisation for Research and Treatment of Cancer. All rights reserved.
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Future initiatives will continue to focus on the conduct of controlled trials, rational academic drug development as well as systematic evaluation of tumor tissue including biomarker development for personalized therapy. Important lessons learned in neurooncology are to dare to ask real questions rather than merely rapidly testing new compounds, and the value of well designed trials, including the presence of controls, central pathology review, strict radiology protocols and biobanking. Structurally, the EORTC BTG has evolved into a multidisciplinary group with strong transatlantic alliances. It has contributed to the maturation of neurooncology within the oncological sciences. © 2012 European Organisation for Research and Treatment of Cancer. All rights reserved.
1. Examples of twenty-five years of Brain Tumor Group (BTG) Trials 1.1. Radiochemotherapy and MGMT in newly diagnosed glioblastoma For more than 30 years neurosurgical resection to the extent safely feasible followed by radiotherapy alone were the cornerstones of treatment for patients with glioblastoma. The most relevant prognostic parameters were age, Karnofsky performance score and extent of neurosurgical resection. Chemotherapeutic agents, with the possible exception of nitrosoureas, have shown little or no activity in malignant glioma patients. It was the EORTC 26981/22981–National Cancer Institute of Canada Clinical Trials Group (NCIC) CE.3 trial which for the first time in more than 20 years of neurooncology led to significant and relevant progress in the treatment of glioblastoma patients and has substantially influenced management of glioma in general, and future research in particular. The major results from the trial are (i) an increase in the overall survival of glioblastoma patients − at 2 years 27% of patients treated with combined radiochemotherapy remained alive compared to only 10% of patients who were initially treated with radiotherapy alone, 1 (ii) a relevant proportion of patients surviving >2−5 years 2 and (iii) the identification of a marker for benefit from temozolomide in brain tumors, promoter hypermethylation of the repair gene encoding O6-methyl-guanyl-methyl-transferase (MGMT). 3−5 Concomitant and adjuvant radiochemotherapy with temozolomide has now become the standard of care for newly diagnosed glioblastoma worldwide, and the identification of MGMT gene promoter methylation as the first predictive marker in brain tumors introduced the concept of personalized oncology into neurooncology. On a scientific level it heavily influenced design and clinical as well as basic research strategies of brain tumor trials afterwards. Several translational projects in addition to the companion project on MGMT have been successfully conducted. 6−14 From all referenced, 1−14 the health-related quality of life (HRQoL) evaluations 4 and work on a stem cell signature explaining resistance towards radiochemotherapy 8 best show the range of
science that is done within the framework of the EORTC BTG. Immediate follow-up projects that are heavily inspired by the EORTC 26981/22981 trial are the Radiation Therapy Oncology Group (RTOG) 05-25/EORTC 26052– 22053 Intergroup trial, which aimed at overcoming MGMT-mediated resistance and improving outcomes for the putatively sensitive MGMT-promoter-methylated patients by an intensified three out of four weeks dosedense temozolomide maintenance therapy regimen. This trial, including over 1100 patients in North America and Europe, failed to demonstrate an advantage in PFS or OS. 15 Importantly, the trial showed the feasibility of international collaboration and mandatory tumor tissue collection and testing of molecular markers. It allowed prospective confirmation of the prognostic value of MGMT promoter methylation. Nevertheless, until more effective treatments have been developed, outside clinical trials the EORTC regimen of radiotherapy with concomitant and adjuvant temozolomide remains the standard of care for all newly diagnosed glioblastoma. We recently completed accrual of a large randomized clinical trial adding the antiangiogenic and anti-migratory integrin inhibitor cilengitide in patients with a methylated MGMT promoter only (EORTC trial 26071/22072). When the pivotal glioblastoma trial was designed, an upper age limit of 70 years was deemed appropriate, because a prolonged course of therapy would only jeopardize the quality of life of elderly patients without sufficient prospect of meaningful benefit. However, the success of combined modality therapy in younger patients has led to revisiting this position, and the ongoing NCIC CE.6/EORTC 26062–22061 trial is investigating combined temozolomide chemotherapy in conjunction with hypofractionated radiotherapy. 1.2. Molecular subtypes in anaplastic glioma The EORTC 26951 trial investigating adjuvant procarbazine/lomustine/vincristine (PCV) chemotherapy after completion of radiotherapy in the more chemosensitive anaplastic oligodendroglioma (AOD) and oligoastrocytoma (AOA) is another example of a trial that moved the field beyond its actual result. The trials did
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not show a statistically significant difference in survival, although progression-free survival was significantly prolonged. We concluded that chemotherapy has a clear role in this disease. However, the timing of administration, initially/adjuvant or at the time of tumor recurrence or progression, appears of lesser importance, and toxicity of the chemotherapy has to be taken into account. In addition to the publication of the clinical data, 16,17 this study inspired a large series of translational research efforts which contributed to the molecular subtyping of anaplastic gliomas 16−22 Together with contemporary trials of the RTOG (94-02) 23 and the Neurooncology Working Group of the German Cancer Society (NOA-04), 24 as well as basic research from the International Cancer Genome Consortium, 25 molecular markers like MGMT, 21 isocitrate dehydrogenase 1 (IDH1) 20 and codeletion 1p/19q 16,19 have been firmly established in anaplastic gliomas. Ongoing research aims at unraveling the findings in the NOA-04 and EORTC 26951 trials indicating that MGMT methylation could predict a good response not only to alkylating chemotherapy but also to radiotherapy alone. The most recent contribution here is the strong prognostic effect of the Glioma CpG Island Methylator Phenotype (G-CIMP) in EORTC 26951 whose clinical significance is currently being further investigated. 26 So far however, all molecular markers in this trial are merely prognostic. MGMT that has been shown to be associated with benefit from temozolomide chemotherapy in glioblastoma does not hold the predictive power for alkylating chemotherapy in grade III tumors. This underscores the distinct biology of anaplastic tumors and glioblastoma. The need for a molecular classification, especially for anaplastic glioma, was also emphasized by the intrinsic typing and grading difficulties in these tumors that was addressed in a post hoc panel review for this trial. 27 This is a topic of high clinical relevance, with a major impact on ongoing trials. Recent news on the molecular markers for oligodendroglioma from US groups is the discovery of the genes located on 1p and 19q that may be the drivers for combined loss of 1p/19q in these tumors. Inactivating mutations have been identified in far-upstream element (FUSE) binding protein 1 (FUBP1) [>10% of cases], which may lead to myc activation, and in homolog of the Drosophila capicua gene (CIC) [40−50% of cases], which is a downstream target for some tyrosine kinase receptors. 25 In summary, anaplastic gliomas are regarded as an important and biologically distinct entity, in which we made rapid progress in understanding of their biology and subgroups. Radiotherapy or temozolomide chemotherapy but not the combination of both is standard or common practice within the centers of our group.
Furthermore, this trial with its companions stimulated two EORTC/RTOG (NCIC/MRC/HUB/NOA/COGNO transatlantic intergroup trials (EORTC 26053/22054 [CATNON] and EORTC 26081/22086 [CODEL]) aiming at answering another relevant question; determining how to optimally combine temozolomide chemotherapy and radiotherapy in anaplastic gliomas, in a joint and therefore more timely fashion. Clinically, the CATNON trial may also shed light on the question whether concomitant or maintenance temozolomide treatment is pivotal for the success of radiochemotherapy, and thus potentially influence treatment schedules and future trial development. In addition, these trials will provide the neurooncological community with unique biomaterial resources as both trials rely on the examination of 1p/19q deletion status as entry criterion and hence biomaterial will also be available later on for novel translational research questions. In order to conduct this important biological research, we have created a translational research platform within the EORTC. The advantages of this organized collaborative effort are evident: not only does it allow investigation of rare tumor types and subtypes with characteristic molecular aberrations, but all samples have been histopathologically reviewed, are annotated both molecularly and clinically, and patients were treated in a homogeneous manner allowing correlation of biological findings with outcome. But to successfully conduct this type of translational research, we depend on grant support from both national and international sources. Collaborations and further expansion of the translational research expertise within the BTG are key. When treating patients, quality of life is as much a concern as simple longevity. Analysis of the HRQOL data from the EORTC 26981 and 26951 trials showed that the addition of chemotherapy has no or only a limited and transient negative impact on HRQOL during and shortly following treatment. 4,17,28 Not unexpectedly, the generally well tolerated temozolomide chemotherapy had a less negative impact than the PCV regimen. Baseline HRQOL data demonstrated no additional prognostic significance compared to clinical data. Future studies should include longitudinal HRQOL measurements, especially following radiological recurrence, to establish the clinical impact of radiological progression. From the patient’s perspective, time to clinical deterioration may be a more relevant endpoint than time to progression if this progression is still asymptomatic. To meet this requirement, the validation of novel and more clinical endpoints is required. 1.3. To believe or not to believe: impact of tumor-specific treatment in low-grade glioma The last example of a landmark EORTC trial conducted jointly by the Radiation Oncology Group and the BTG is
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the EORTC trial 22845. 29−34 This trial is the key reference in determining at what time in their disease adult patients with low-grade glioma should be irradiated. The trial convincingly demonstrated that adjuvant irradiation may be delayed until subsequent disease progression without detrimental effect on overall survival despite a prolongation in progression-free survival. 29,30 To date these data, together with the set of prognostic factors that was established using data from that trial, 31 guide the decision on when to treat patients with low-grade tumors. These factors include tumor progression, age >40 years, presence of neurological deficits other than only seizures, a tumor size >5 cm or a tumor extending over the midline. As patients with low-grade gliomas have a comparably good life expectancy of >7 years and may survive relevant adverse effects of early therapies, this information is pivotal. Furthermore, this trial is one of the very few examples of completed randomized trials in that disease, in part because of the rarity and relatively good prognosis and thus long survival of these patients. Together with the work on temozolomide in glioblastoma and the increasing awareness in our group that tissue is the key for academic neurooncology, this trial also stimulated the important and timely EORTC 22033-26033 trial that has recently completed its accrual. In that trial we are asking the question whether standard first-line radiotherapy may be delayed and
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2. Towards a molecular classification of brain tumors − prime time for targeted treatments? Molecular diagnostics of gliomas allows definition of more homogeneous patient populations as exemplified in CODEL and CATNON for anaplastic gliomas with and without the 1p/19q co-deletion, respectively, the TAVAREC trial for recurrent glioma, or CENTRIC for glioblastoma with methylated MGMT. In the future, molecular diagnostics will be used to test whether specific treatments are active depending on the absence or presence of a specific molecular marker. In addition, the determination of IDH mutations is likely to gain an important role in the near future. Malignant gliomas with IDH mutations have a much better prognosis and are thought to have a different pathogenetic origin, further supported by the recent discovery of G-CIMP associated with IDH mutations. 26,36 IDH mutations have also been identified in acute myeloblastic leukemia in association with CIMP, and define a new prognostic subtype (PMID: 21130701; 20567020). Hence, gliomapatients with G-CIMP are molecularly and biologically distinct and should probably not be included in future glioblastoma trials. Biomarker research should provide guidance for clinical decision making aiming towards personalized oncology. To date, none of the molecular markers established in glioma today, e.g. p53, EGFR amplification or autoactivity, 1p/19q co-deletion, MGMT or IDH1/2, are relevantly contributing to daily decision making.
replaced by dose-dense temozolomide chemotherapy. Again tumor tissue has been collected from all patients and should ultimately allow separation of good- and poor-prognosis patients based on molecular profiles. Respective molecular signatures may also allow for identification of novel treatment targets. Until results of this trial are available, the BTG decided to pursue a new avenue by developing a trial for recurrent, poor-prognosis, contrast enhancing low-grade and anaplastic gliomas. In this trial, EORTC 26091/TAVAREC, patients are randomized at progression after initial treatment to receive temozolomide or temozolomide plus bevacizumab. With this and the companion trial 26101 on glioblastoma, the BTG is not only contributing to the first controlled trials with bevacizumab in recurrent glioma but is also paving the way for systematic academic centralized evaluation of imaging. The BTG together with the EORTC Imaging Platform have set up a standard imaging protocol for these trials, and data will be assessed centrally in order to generate pivotal data on the determination of progression also in the context of antiangiogenic therapy, recurrence patterns, and an upfront validation of the updated imaging criteria as developed by the Response Assessment in Neurooncology (RANO) Working group. 35
3. Visions in neurooncology Classification of brain tumors will no longer rely solely on morphological criteria, but invariably also include reproducible and standardized [sic!] molecular markers. For a growing number of patients in industrial countries sequencing of the full tumor genome is now available for a couple of hundred euros, and is becoming more and more affordable. However, we need to identify mutations that are actionable in glioma in order to offer appropriate treatments. A genome-wide expression analysis is done to enable classification of molecular subtypes of strong prognostic relevance. 37 These analyses are currently best performed within phase II and III clinical trials, however they are already offered commercially. Diagnostic determination of molecular signatures should assist choice of therapy and predict efficacy of established or new therapies, and will allow to enrich patient population most likely to benefit from a new treatment, thus avoiding exposure of a large number of patients to ineffective therapy. Since the EORTC is dedicated to rational academic drug development, our trials are designed with a clear focus on relevance for the patients. Too artificial inclusion and exclusion criteria are avoided, which allows an easy
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translation into daily clinical practice and with a clear focus on non-metric factors such as symptom burden, tolerance and quality of life aiming to produce relevant and just significant results. Given present demographics, future trial activities will focus on the distinct demands of elderly patients. An older age of tumor patient in general is associated with increased toxicity of many drugs, including antineoplastic agents, but increased toxicity in older patients has also been documented for targeted agents. Most likely, some of these trials will be carried out in close collaboration with other cooperative groups as successfully demonstrated in the past. This demands not only good scientific interaction but also a strong political will to facilitate these projects.
4. EORTC BTG in 2022 We will have learned to recognize and treat the tumor as an organ. We will recognize the tumor within its unique environment and interaction with the host organ. A tumor exceeds the mere assembly of tumor cells and requires a permissive milieu provided by nonmalignant cells and structures of the body to grow and spread. These are in particular vascular, immune and parenchymal cells 38 and potentially effects of intercellular plasticity. These components are different in the brain compared to other compartments of the body. The obligatory role of non-neoplastic cells is of special importance to brain tumors since all systemically given therapies need to reach the tumor cell at sufficient concentrations. In addition, immunotherapy, which needs to overcome the immunosuppressive environment in an immune-privileged organ, needs further development. However, smaller immunotherapy trials show promising molecular signals, which in the future may be translated into a clinically relevant signal, 39 for example by a future EORTC trial with an anti-EGFRvIII immunotherapy. Finally, tumor-initiating cells will be specifically targeted by the treatment. They will be characterized in many solid tumors including glioma that will foster the understanding of therapy resistance. We are prepared for a paradigm shift, as these cells may be much less susceptible to classical cytostatic/cytotoxic therapies. Approaches to modify stem cell features in brain tumors without heavy interference with physiological systems will need to be developed.
5. Conflict of interest statement Denis Lacombe, Thierry Gorlia, Anouk Allgeier, Max Kros, Charles Vecht, and ABMF Karim declare no conflicts of
interest. Riccardo Soffietti consulted for MSD, MerckSerono, Mundipharma, and consulted for and received research funds from Roche. Monika Hegi consulted for MDxHealth and MDS, and consulted for and received honoraria from Merck-Serono. Roger Stupp consulted (advisory boards) for Merck Serono, MSD/Merck & Co (formerly Schering-Plough), MDx Health, and Roche Pharma. Alba Brandes was a member of advisory boards for and received honoraria from Roche and Schering-Plough, and received honoraria from GSK. Marc Sanson consulted for and received honoraria from Merck and Roche, and received research funds from Pfizer. Martin Taphoorn received research funds from the Dutch Cancer Society, EORTC Quality of Life Group, and Jacobus Foundation The Hague. Wolfgang Wick consulted for and received honoraria and research funds from MSD, consulted for and received honoraria from Roche, consulted for Noxxon and Antisense Pharma, and received research funds from Eli Lilly and Apogenix. Martin van den Bent consulted for and received honoraria from MSD. Rene´ Olivier Mirimanoff consulted for and received honoraria and research funds from MDS and Schering-Plough. Brigitta G. Baumert consulted and received honoraria and research funds from MSD and Schering-Plough, and consulted for and received honoraria from the Institute for Quality and Efficiency in Health Care.
References
1. Stupp R, Mason WP, van den Bent MJ, et al.; European Organisation for Research and Treatment of Cancer Brain Tumor and Radiotherapy Groups; National Cancer Institute of Canada Clinical Trials Group. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 2005;352:987−96. 2. Stupp R, Hegi ME, Mason WP, et al.; European Organisation for Research and Treatment of Cancer Brain Tumour and Radiation Oncology Groups; National Cancer Institute of Canada Clinical Trials Group. Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phase III study: 5-year analysis of the EORTC-NCIC trial. Lancet Oncol 2009;10:459−66. 3. Beauchesne P, Bernier V, Carnin C, et al. Prolonged survival for patients with newly diagnosed, inoperable glioblastoma with 3-times daily ultrafractionated radiation therapy. Neuro Oncol 2010;12:595–602. 4. Taphoorn MJ, Stupp R, Coens C, et al.; European Organisation for Research and Treatment of Cancer Brain Tumour Group; EORTC Radiotherapy Group; National Cancer Institute of Canada Clinical Trials Group. Health-related quality of life in patients with glioblastoma: a randomised controlled trial. Lancet Oncol 2005;6:937−44. 5. Hegi ME, Diserens AC, Gorlia T, et al. MGMT gene silencing and benefit from temozolomide in glioblastoma. N Engl J Med 2005;352:997–1003.
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6. Ataman F, Poortmans P, Stupp R, Fisher B, Mirimanoff RO. Quality assurance of the EORTC 26981/22981; NCIC CE3 intergroup trial on radiotherapy with or without temozolomide for newly-diagnosed glioblastoma multiforme: the individual case review. Eur J Cancer 2004;40:1724−30. 7. Mirimanoff RO, Gorlia T, Mason W, et al. Radiotherapy and temozolomide for newly diagnosed glioblastoma: recursive partitioning analysis of the EORTC 26981/22981–NCIC CE3 phase III randomized trial. J Clin Oncol 2006;24:2563−9. 8. Murat A, Migliavacca E, Gorlia T, et al. Stem cell-related “self-renewal” signature and high epidermal growth factor receptor expression associated with resistance to concomitant chemoradiotherapy in glioblastoma. J Clin Oncol 2008;26:3015−24. 9. Mirimanoff RO, Gorlia T, Mason W, et al. Radiotherapy and temozolomide for newly diagnosed glioblastoma: recursive partitioning analysis of the EORTC 26981/22981–NCIC CE3 phase III randomized trial. J Clin Oncol 2006;24:2563−9. 10. Gorlia T, van den Bent MJ, Hegi ME, et al. Nomograms for predicting survival of patients with newly diagnosed glioblastoma: prognostic factor analysis of EORTC and NCIC trial 26981–22981/CE.3. Lancet Oncol 2008;9:29−38. 11. Lamers LM, Stupp R, van den Bent MJ, et al.; EORTC 26981/22981 NCI-C CE3 Intergroup Study. Costeffectiveness of temozolomide for the treatment of newly diagnosed glioblastoma multiforme: a report from the EORTC 26981/22981 NCI-C CE3 Intergroup Study. Cancer 2008;112:1337−44. 12. Preusser M, Charles Janzer R, Felsberg J, et al. AntiO6-methylguanine-methyltransferase (MGMT) immunohistochemistry in glioblastoma multiforme: observer variability and lack of association with patient survival impede its use as clinical biomarker. Brain Pathol 2008;18:520−32. 13. Wick W, Stupp R, Beule AC, et al.; European Organisation for Research and Treatment of Cancer and the National Cancer Institute of Canada Clinical Trials Group. A novel tool to analyze MRI recurrence patterns in glioblastoma. Neuro Oncol 2008;10:1019−24. 14. Weller M, Gorlia T, Cairncross JG, et al. Prolonged survival with valproic acid use in the EORTC/NCIC temozolomide trial for glioblastoma. Neurology 2011;77:1156−64. 15. Gilbert MR, Wang M, Aldape KD, et al. RTOG 0525: A randomized phase III trial comparing standard adjuvant temozolomide (TMZ) with a dose-dense (dd) schedule in newly diagnosed glioblastoma (GBM). J Clin Oncol 2011;29(Suppl): abstr 2006. 16. van den Bent MJ, Carpentier AF, Brandes AA, 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. J Clin Oncol 2006;24:2715−22. 17. Taphoorn MJ, van den Bent MJ, Mauer ME, et al.; European Organisation for Research and Treatment of Cancer. 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. J Clin Oncol 2007;25:5723−30.
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18. Mokhtari K, Ducray F, Kros JM, et al. Alphainternexin expression predicts outcome in anaplastic oligodendroglial tumors and may positively impact the efficacy of chemotherapy: European organization for research and treatment of cancer trial 26951. Cancer 2011;117:3014−26. 19. Idbaih A, Dalmasso C, Kouwenhoven M, et al. Genomic aberrations associated with outcome in anaplastic oligodendroglial tumors treated within the EORTC phase III trial 26951. J Neurooncol 2011;103:221−30. 20. van den Bent MJ, Dubbink HJ, Marie Y, 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. Clin Cancer Res 2010;16:1597–604. 21. van den Bent MJ, Dubbink HJ, Sanson M, 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. J Clin Oncol 2009;27:5881−6. 22. Kouwenhoven MC, Gorlia T, Kros JM, et al. Molecular analysis of anaplastic oligodendroglial tumors in a prospective randomized study: A report from EORTC study 26951. Neuro Oncol 2009;11:737−46. 23. Cairncross G, Berkey B, Shaw E, 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. J Clin Oncol 2006;24:2707−14. 24. Wick W, Hartmann C, Engel C, et al.; for the Neurooncology Working Group (NOA) of the German Cancer Society. NOA-04 randomized Phase III trial of sequential radiochemotherapy of anaplastic glioma with PCV or temozolomide. J Clin Oncol 2009;27:5874−80. 25. Bettegowda C, Agrawal N, Jiao Y, et al. Mutations in CIC and FUBP1 contribute to human oligodendroglioma Science 2011;333:1453−5. 26. van den Bent MJ, Gravendeel LA, Gorlia T, et al. A hypermethylated phenotype in anaplastic oligodendroglial brain tumors is a better predictor of survival than MGMT methylation in anaplastic oligodendroglioma: a report from EORTC study 26951. Clin Cancer Res 2011;17:7148−55. 27. Kros JM, Gorlia T, Kouwenhoven MC, 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. J Neuropathol Exp Neurol 2007;66:545−51. 28. Mauer ME, Taphoorn MJ, Bottomley A, et al.; EORTC Brain Cancer Group. Prognostic value of healthrelated quality-of-life data in predicting survival in patients with anaplastic oligodendrogliomas, from a phase III EORTC brain cancer group study. J Clin Oncol 2007;25:5731−7. 29. van den Bent MJ, Afra D, de Witte O, et al.; EORTC Radiotherapy and Brain Tumor Groups and the UK Medical Research Council. Long-term efficacy of early versus delayed radiotherapy for low-grade astrocytoma and oligodendroglioma in adults: the EORTC 22845 randomised trial. Lancet 2005;366:985−90. Erratum: Lancet 2006;367:1818.
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30. Karim AB, Afra D, Cornu P, et al. Randomized trial on the efficacy of radiotherapy for cerebral lowgrade glioma in the adult: European Organization for Research and Treatment of Cancer Study 22845 with the Medical Research Council study BRO4: an interim analysis. Int J Radiat Oncol Biol Phys 2002;52:316−24. 31. Pignatti F, van den Bent M, Curran D, et al.; European Organization for Research and Treatment of Cancer Brain Tumor Cooperative Group. Prognostic factors for survival in adult patients with cerebral low-grade glioma. J Clin Oncol 2002;20:2076−84. 32. Kiebert GM, Curran D, Aaronson NK, et al.; EORTC Radiotherapy Co-operative Group. Quality of life after radiation therapy of cerebral low-grade gliomas of the adult: results of a randomised phase III trial on dose response (EORTC trial 22844). Eur J Cancer 1998;34:1902−9. 33. Taphoorn MJ, Heimans JJ, van der Veen EA, Karim AB. Endocrine functions in long-term survivors of lowgrade supratentorial glioma treated with radiation therapy. J Neurooncol 1995;25:97–102. 34. Taphoorn MJ, Heimans JJ, Snoek FJ, Lindeboom J, Karim AB. Quality of life and neuropsychological
35.
36.
37.
38. 39.
functions in long-term low-grade glioma survivors. Int J Radiat Oncol Biol Phys 1994;29:1201−2. Wen PY, Macdonald DA, Reardon DA, et al. Updated response assessment criteria for high-grade gliomas: Response Assessment in Neuro-Oncology (RANO) Working Group. J Clin Oncol 2010;28:1963−72. Noushmehr H, Weisenberger DJ, Diefes K, et al.; Cancer Genome Atlas Research Network. Identification of a CpG island methylator phenotype that defines a distinct subgroup of glioma. Cancer Cell 2010;17:510−22. The Cancer Genome Atlas Research Network. Comprehensive genomic characterization defines human glioblastoma genes and core pathways. Nature 2008;455:1061−8. Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell 2011;144:646−74. Sampson JH, Heimberger AB, Archer GE, et al. Immunologic escape after prolonged progressionfree survival with epidermal growth factor receptor variant III peptide vaccination in patients with newly diagnosed glioblastoma. J Clin Oncol 2010;28:4722−9.