Neue Entwicklungen in der Gliomtherapie

Zusammenfassung

Die Standardtherapie des Glioblastoms im Erwachsenenalter besteht aus operativer Resektion, Bestrahlung der erweiterten Tumorregion begleitet von einer kontinuierlichen Temozolomidtherapie, gefolgt von 6 Zyklen einer adjuvanten Temozolomidtherapie. Therapiestudien mit dem Ziel, diese Standardtherapie zu verbessern, werden derzeit mit dem Integrinantagonisten Cilengitide, mit Tyrosinkinaseinhibitoren, mit dem PKC-β-Hemmer Enzastaurin, mit Neoangiogenesehemmern und anderen durchgeführt. In der Rezidivtherapie werden intensivierte Chemotherapieprotokolle und zunehmend der Neoangiogenesehemmer Bevacizumab eingesetzt. Im Rezidiv enttäuscht haben bislang sog. targeted therapies mit „small molecules” allein oder in Kombination mit Zytostatika. Für die anaplastischen Gliome, WHO-Grad III, hat die NOA 04-Studie einen neuen Therapiestandard definiert: Diese Gliome dürfen, unabhängig von der oligodendroglialen oder astroglialen Zuordnung, primär mit einer Chemotherapie behandelt werden. Die Vorgehensweise, differenzierte Gliome bei makroskopisch kompletter Resezierbarkeit zu operieren, soweit neue neurologische Störungen vermieden werden können, wurde durch 2 große retrospektive Serien 2008 bestätigt: Beide zeigten eine deutlich verlängerte Gesamtüberlebenszeit und progressionsfreie Überlebenszeit bei nach MRT-Kriterien erzielter makroskopisch kompletter Tumorresektion.

Abstract

The standard of care in adult glioblastoma is tumour resection followed by concomitant radio- / chemotherapy with temozolomide and 6 cycles of adjuvant temozolomide. To improve this standard, clinical trials are under way to evaluate efficacy and toxicity of cilengitide, an integrin antagonist, inhibitors of tyrosine kinases, of PKC-β and of neo-angiogenesis and others. In the recurrent situation intensified chemotherapy regimens are applied and – with increasing frequency – the use of bevacizumab, an antibody to the vascular endothelial growth factor (VEGF). For recurrent glioblastoma the results with small molecules have been disappointing so far. For anaplastic glioma, WHO grade III, results of the NOA04-trial established a new standard in 2008. Regardless of an astrocytic or oligodendroglial origin, the results allow us to treat these grade III tumours postoperatively with chemotherapy alone as the first-line option. Low-grade glioma should be resected if complete tumour removal is achievable without new neurological symptoms. This guideline has gained support by 2 recent large retrospective analyses, showing a significantly better overall survival and progression-free survival in those patients whose tumour was (nearly) completely resected according to post-operative MRI measurements.

Schlüsselwörter

Glioblastoma multiforme - Chemotherapie - Strahlentherapie - Gliome

Keywords

glioblastoma multiforme - chemotherapy - radiotherapy - glioma

Literatur

• 1 Stupp R, Mason W P, van den Bent M J. et al . Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma.  N Engl J Med. 2005;  352 987-996
• 2 Wick W, Hartmann C, Engel C. et al . NOA-04 randomized phase III trial of sequential radiochemotherapy of anaplastic glioma with procarbazine, lomustine, and vincristine or temozolomide.  J Clin Oncol. 2009 (Epub 11/11/2009); 
• 3 Hegi M E, Diserens A C, Gorlia T. et al . MGMT gene silencing and benefit from temozolomide in glioblastoma.  N Engl J Med. 2005;  352 997-1003
• 4 Yan H, Parsons D W, Jin G. et al . IDH1 and IDH2 mutations in gliomas.  N Engl J Med. 2009;  360 765-773
• 5 Smith J S, Chang E F, Lamborn K R. et al . Role of extent of resection in the long-term outcome of low-grade hemispheric gliomas.  J Clin Oncol. 2008;  26 1338-1345
• 6 McGirt M J, Chaichana K L, Attenello F J. et al . Extent of surgical resection is independently associated with survival in patients with hemispheric infiltrating low-grade gliomas.  Neurosurgery. 2008;  63 700-707; author reply 707–708
• 7 Jenkins R B, Blair H, Ballman K V. et al . A t(1; 19) (q10; p10) mediates the combined deletions of 1p and 19q and predicts a better prognosis of patients with oligodendroglioma.  Cancer Res. 2006;  66 9852-9861
• 8 van den Bent M J, Carpentier A F, Brandes A A. 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 2715-2722
• 9 Smith J S, Perry A, Borell T J. et al . Alterations of chromosome arms 1p and 19q as predictors of survival in oligodendrogliomas, astrocytomas, and mixed oligoastrocytomas.  J Clin Oncol. 2000;  18 636-645
• 10 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 2707-2714
• 11 Mikeska T, Bock C, El-Maarri O. et al . Optimization of quantitative MGMT promoter methylation analysis using pyrosequencing and combined bisulfite restriction analysis.  J Mol Diagn. 2007;  9 368-381
• 12 Hartmann C, Meyer J, Balss J. et al . Type and frequency of IDH1 and IDH2 mutations are related to astrocytic and oligodendroglial differentiation and age: a study of 1,010 diffuse gliomas.  Acta Neuropathol. 2009;  118 469-474
• 13 Stupp R, Hegi M E, Mason W P. et al . 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;  10 459-466
• 14 Blumenthal D T, Won M, Mehta M P. et al . Short delay in initiation of radiotherapy may not affect outcome of patients with glioblastoma: a secondary analysis from the radiation therapy oncology group database.  J Clin Oncol. 2009;  27 733-739
• 15 Glas M, Happold C, Rieger J. et al . Long-term survival of patients with glioblastoma treated with radiotherapy and lomustine plus temozolomide.  J Clin Oncol. 2009;  27 1257-1261
• 16 Stupp R, Goldbrunner R, Neyns B. et al . Phase I / IIa trial of cilengitide (EMD121974) and temozolomide with concomitant radiotherapy, followed by temozolomide and cilengitide maintenance therapy in patients (pts) with newly diagnosed glioblastoma (GBM).  J Clin Oncol. 2007;  25
• 17 Tabatabai G, Frank B, Wick A. et al . Synergistic antiglioma activity of radiotherapy and enzastaurin.  Ann Neurol. 2007;  61 153-161
• 18 Brandes A A, Franceschi E, Tosoni A. et al . MGMT promoter methylation status can predict the incidence and outcome of pseudoprogression after concomitant radiochemotherapy in newly diagnosed glioblastoma patients.  J Clin Oncol. 2008;  26 2192-2197
• 19 Chamberlain M C, Glantz M J, Chalmers L. et al . Early necrosis following concurrent temodar and radiotherapy in patients with glioblastoma.  J Neurooncol. 2007;  82 81-83
• 20 Brandsma D, Stalpers L, Taal W. et al . Clinical features, mechanisms, and management of pseudoprogression in malignant gliomas.  Lancet Oncol. 2008;  9 453-461
• 21 Taal W, Brandsma D, de Bruin H G. et al . Incidence of early pseudo-progression in a cohort of malignant glioma patients treated with chemoirradiation with temozolomide.  Cancer. 2008;  113 405-410
• 22 Wick A, Felsberg J, Steinbach J P. et al . Efficacy and tolerability of temozolomide in an alternating weekly regimen in patients with recurrent glioma.  J Clin Oncol. 2007;  25 3357-3361
• 23 Wick A, Pascher C, Wick W. et al . Rechallenge with temozolomide in patients with recurrent gliomas.  J Neurol. 2009;  256 734-741
• 24 Brandes A A, Turazzi S, Basso U. et al . A multidrug combination designed for reversing resistance to BCNU in glioblastoma multiforme.  Neurology. 2002;  58 1759-1764
• 25 Kappelle A C, Postma T J, Taphoorn M J. et al . PCV chemotherapy for recurrent glioblastoma multiforme.  Neurology. 2001;  56 118-120
• 26 Schmidt F, Fischer J, Herrlinger U. et al . PCV chemotherapy for recurrent glioblastoma.  Neurology. 2006;  66 587-589
• 27 Happold C, Roth P, Wick W. et al . ACNU-based chemotherapy for recurrent glioma in the temozolomide era.  J Neurooncol. 2009;  92 45-48
• 28 Raymond E, Brandes A A, Dittrich C. et al . Phase II study of imatinib in patients with recurrent gliomas of various histologies: a European Organisation for Research and Treatment of Cancer Brain Tumor Group Study.  J Clin Oncol. 2008;  26 4659-4665
• 29 Reardon D A, Egorin M J, Quinn J A. et al . Phase II study of imatinib mesylate plus hydroxyurea in adults with recurrent glioblastoma multiforme.  J Clin Oncol. 2005;  23 9359-9368
• 30 Prados M D, Chang S M, Butowski N. et al . Phase II study of erlotinib plus temozolomide during and after radiation therapy in patients with newly diagnosed glioblastoma multiforme or gliosarcoma.  J Clin Oncol. 2009;  27 579-584
• 31 Sathornsumetee S, Cao Y, Marcello J E. et al . Tumor angiogenic and hypoxic profiles predict radiographic response and survival in malignant astrocytoma patients treated with bevacizumab and irinotecan.  J Clin Oncol. 2008;  26 271-278
• 32 Vredenburgh J J, Desjardins A, Herndon 2nd J E. et al . Bevacizumab plus irinotecan in recurrent glioblastoma multiforme.  J Clin Oncol. 2007;  25 4722-4729
• 33 Kreisl T N, Kim L, Moore K. et al . Phase II trial of single-agent bevacizumab followed by bevacizumab plus irinotecan at tumor progression in recurrent glioblastoma.  J Clin Oncol. 2009;  27 740-745
• 34 Friedman H S, Prados M D, Wen P Y. et al . Bevacizumab alone and in combination with irinotecan in recurrent glioblastoma.  J Clin Oncol. 2009;  27 4733-4740
• 35 Maier-Hauff K, Rothe R, Scholz R. et al . Intracranial thermotherapy using magnetic nanoparticles combined with external beam radiotherapy: results of a feasibility study on patients with glioblastoma multiforme.  J Neurooncol. 2007;  81 53-60
• 36 de Robles P, Cairncross G. Glioblastoma in the elderly: an age-old problem.  Ann Neurol. 2008;  64 597-599
• 37 Keime-Guibert F, Chinot O, Taillandier L. et al . Radiotherapy for glioblastoma in the elderly.  N Engl J Med. 2007;  356 1527-1535
• 38 Iwamoto F M, Cooper A R, Reiner A S. et al . Glioblastoma in the elderly: the Memorial Sloan-Kettering Cancer Center Experience (1997–2007).  Cancer. 2009; 
• 39 Weller M, Muller B, Koch R. et al . Neuro-Oncology Working Group 01 trial of nimustine plus teniposide versus nimustine plus cytarabine chemotherapy in addition to involved-field radiotherapy in the first-line treatment of malignant glioma.  J Clin Oncol. 2003;  21 3276-3284
• 40 Schlegel U, Weller M, Westphal M. Neuroonkologie. Second Edition ed. Stuttgart; Thieme 2003
• 41 Hau P, Jachimczak P, Schlingensiepen R. et al . Inhibition of TGF-β2 with AP 12 009 in recurrent malignant gliomas: from preclinical to phase I / II studies.  Oligonucleotides. 2007;  17 201-212
• 42 Schlingensiepen K H, Schlingensiepen R, Steinbrecher A. et al . Targeted tumor therapy with the TGF-β 2 antisense compound AP 12 009.  Cytokine Growth Factor Rev. 2006;  17 129-139
• 43 Taillibert S, Vincent L A, Granger B. et al . Bevacizumab and irinotecan for recurrent oligodendroglial tumors.  Neurology. 2009;  72 1601-1606
• 44 Ricard D, Kaloshi G, Amiel-Benouaich A. et al . Dynamic history of low-grade gliomas before and after temozolomide treatment.  Ann Neurol. 2007;  61 484-490
• 45 Kaloshi G, Benouaich-Amiel A, Diakite F. et al . Temozolomide for low-grade gliomas: predictive impact of 1p / 19q loss on response and outcome.  Neurology. 2007;  68 1831-1836