Wolfgang Wick1, Christian Hartmann1, Corinna Engel1, Mandy Stoffels1, Jörg Felsberg1, Florian Stockhammer1, Michael Sabel1, Susanne Koeppen1, Ralf Ketter1, Richard Meyermann1, Marion Rapp1, C Meisner1, Rolf‐Dieter Kortmann1, Torsten Pietsch1, Otmar D. Wiestler1, Ulrike Ernemann1, M. Bamberg1, Guido Reifenberger1, Andreas von Deimling1, Michael Weller1
1From the Department of Neurology and Hertie Institute for Clinical Brain Research, and Departments of Medical Biometry, Neuropathology, Neuroradiology, and Radiation Oncology, University of Tübingen, Tübingen; Departments of Neuropathology and Neurosurgery, Heinrich-Heine-University, Düsseldorf; Departments of Neurooncology and Neuropathology, University of Heidelberg, and Clinical Cooperation Unit Neuropathology, German Cancer Research Center, Heidelberg; Clinic of Neurosurgery, Charité...
Tóm tắt
Purpose The standard of care for anaplastic gliomas is surgery followed by radiotherapy. The NOA-04 phase III trial compared efficacy and safety of radiotherapy followed by chemotherapy at progression with the reverse sequence in patients with newly diagnosed anaplastic gliomas. Patients and Methods Patients (N = 318) were randomly assigned 2:1:1 (A:B1:B2) to receive conventional radiotherapy (arm A); procarbazine, lomustine (CCNU), and vincristine (PCV; arm B1); or temozolomide (arm B2) at diagnosis. At occurrence of unacceptable toxicity or disease progression, patients in arm A were treated with PCV or temozolomide (1:1 random assignment), whereas patients in arms B1 or B2 received radiotherapy. The primary end point was time to treatment failure (TTF), defined as progression after radiotherapy and one chemotherapy in either sequence. Results Patient characteristics in the intention-to-treat population (n = 274) were balanced between arms. All histologic diagnoses were centrally confirmed. Median TTF (hazard ratio [HR] = 1.2; 95% CI, 0.8 to 1.8), progression-free survival (PFS; HR = 1.0; 95% CI, 0.7 to 1.3, and overall survival (HR = 1.2; 95% CI, 0.8 to 1.9) were similar for arms A and B1/B2. Extent of resection was an important prognosticator. Anaplastic oligodendrogliomas and oligoastrocytomas share the same, better prognosis than anaplastic astrocytomas. Hypermethylation of the O6-methylguanine DNA-methyltransferase (MGMT) promoter (HR = 0.59; 95% CI, 0.36 to 1.0), mutations of the isocitrate dehydrogenase (IDH1) gene (HR = 0.48; 95% CI, 0.29 to 0.77), and oligodendroglial histology (HR = 0.33; 95% CI, 0.2 to 0.55) reduced the risk of progression. Hypermethylation of the MGMT promoter was associated with prolonged PFS in the chemotherapy and radiotherapy arm. Conclusion Initial radiotherapy or chemotherapy achieved comparable results in patients with anaplastic gliomas. IDH1 mutations are a novel positive prognostic factor in anaplastic gliomas, with a favorable impact stronger than that of 1p/19q codeletion or MGMT promoter methylation.
