Phase II Study of Radiotherapy and Temsirolimus versus Radiochemotherapy with Temozolomide in Patients with Newly Diagnosed Glioblastoma without MGMT Promoter Hypermethylation (EORTC 26082)
| Autor: | Michael Platten, G. Pesce, Thierry Gorlia, Kirsten Hopkins, Vassilis Golfinopoulos, Markus Kosch, Wolfgang Wick, Jean-Sebastien Frenel, Christine Marosi, Jonathan Steuve, Michael Weller, Mario Campone, Martin J. van den Bent, Antje Wick, Benoit Lhermitte, Salvador Villà, Krisztian Homicsko, Astrid Weyerbrock, Monika E. Hegi, Pierre Bady, Marie-France Hamou, Damien Ricard, Patrick Roth, Alba A. Brandes, Martin J.B. Taphoorn, Roger Stupp |
|---|---|
| Přispěvatelé: | Neurology, University of Zurich, Wick, Wolfgang |
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Oncology Male Cancer Research Phases of clinical research Kaplan-Meier Estimate 0302 clinical medicine 1306 Cancer Research Promoter Regions Genetic DNA Modification Methylases education.field_of_study Brain Neoplasms Chemoradiotherapy Middle Aged Temsirolimus 3. Good health Dacarbazine 030220 oncology & carcinogenesis 2730 Oncology Female medicine.drug Adult medicine.medical_specialty Population 610 Medicine & health 03 medical and health sciences Young Adult Internal medicine medicine Temozolomide Humans education Aged Proportional Hazards Models Brain Neoplasms/drug therapy Brain Neoplasms/mortality Brain Neoplasms/radiotherapy Chemoradiotherapy/methods DNA Methylation DNA Modification Methylases/genetics DNA Repair Enzymes/genetics Dacarbazine/administration & dosage Dacarbazine/analogs & derivatives Glioblastoma/drug therapy Glioblastoma/mortality Glioblastoma/radiotherapy Promoter Regions Genetic/genetics Sirolimus/administration & dosage Sirolimus/analogs & derivatives Tumor Suppressor Proteins/genetics Sirolimus Performance status business.industry Tumor Suppressor Proteins Surgery 10040 Clinic for Neurology 030104 developmental biology DNA Repair Enzymes 10032 Clinic for Oncology and Hematology MGMT-Unmethylated Glioblastoma business Glioblastoma |
| Zdroj: | Clinical Cancer Research, 22(19), 4797-4806. American Association for Cancer Research Inc. Clinical Cancer Research, 22(19), 4797-4806 Clinical Cancer Research Clinical cancer research, vol. 22, no. 19, pp. 4797-4806 |
| ISSN: | 1557-3265 1078-0432 |
| DOI: | 10.1158/1078-0432.ccr-15-3153 |
| Popis: | Purpose: EORTC 26082 assessed the activity of temsirolimus in patients with newly diagnosed glioblastoma harboring an unmethylated O6 methylguanine-DNA-methyltransferase (MGMT) promoter. Experimental Design: Patients (n = 257) fulfilling eligibility criteria underwent central MGMT testing. Patients with MGMT unmethylated glioblastoma (n = 111) were randomized 1:1 between standard chemo-radiotherapy with temozolomide or radiotherapy plus weekly temsirolimus (25 mg). Primary endpoint was overall survival at 12 months (OS12). A positive signal was considered >38 patients alive at 12 months in the per protocol population. A noncomparative reference arm of 54 patients evaluated the assumptions on OS12 in a standard-treated cohort of patients. Prespecified post hoc analyses of markers reflecting target activation were performed. Results: Both therapies were administered per protocol with a median of 13 cycles of maintenance temsirolimus. Median age was 55 and 58 years in the temsirolimus and standard arms, the WHO performance status 0 or 1 for most patients (95.5%). In the per protocol population, 38 of 54 patients treated with temsirolimus reached OS12. The actuarial 1-year survival was 72.2% [95% confidence interval (CI), 58.2–82.2] in the temozolomide arm and 69.6% (95% CI, 55.8–79.9) in the temsirolimus arm [hazard ratio (HR) 1.16; 95% CI, 0.77–1.76; P = 0.47]. In multivariable prognostic analyses of clinical and molecular factors, phosphorylation of mTORSer2448 in tumor tissue (HR 0.13; 95% CI, 0.04–0.47; P = 0.002), detected in 37.6%, was associated with benefit from temsirolimus. Conclusions: Temsirolimus was not superior to temozolomide in patients with an unmethylated MGMT promoter. Phosphorylation of mTORSer2448 in the pretreatment tumor tissue may define a subgroup benefitting from mTOR inhibition. Clin Cancer Res; 22(19); 4797–806. ©2016 AACR. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|