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J Clin Oncol. 2016 May 10;34(14):1611-9. doi: 10.1200/JCO.2015.63.4691. Epub 2016 Mar 14.

Bevacizumab Plus Irinotecan Versus Temozolomide in Newly Diagnosed O6-Methylguanine-DNA Methyltransferase Nonmethylated Glioblastoma: The Randomized GLARIUS Trial.

Author information

1
Ulrich Herrlinger, Niklas Schäfer, Frederic Mack, Moritz Stuplich, Sied Kebir, Torsten Pietsch, and Martin Glas, University of Bonn, Bonn; Joachim P. Steinbach and Michael W. Ronellenfitsch, University of Frankfurt, Frankfurt; Astrid Weyerbrock and Horst Urbach, University of Freiburg, Freiburg; Peter Hau and Martin Uhl, University Hospital Regensburg, Regensburg; Roland Goldbrunner and Stefan Grau, University of Cologne, Cologne; Franziska Friedrich and Rolf-Dieter Kortmann, University of Leipzig, Leipzig; Veit Rohde, University of Goettingen, Goettingen; Florian Ringel, Klinikum rechts der Isar Technical University of Munich; Oliver Schnell and Claus Belka, Ludwig Maximillian University of Munich, Munich; Uwe Schlegel, Ruhr-Universität Bochum, Bochum; Michael Sabel and Jaroslaw Maciaczyk, University of Düsseldorf, Düsseldorf; Mathias Hänel, Klinikum Chemnitz, Chemnitz; Dietmar Krex, University of Dresden, Dresden; Peter Vajkoczy, Charité, Humboldt University of Berlin, Berlin; Rüdiger Gerlach, Helios Klinikum Erfurt, Erfurt; Maximilian Mehdorn, University of Kiel, Kiel; Jochen Tüttenberg, Klinikum Idar-Oberstein, Idar-Oberstein; Regine Mayer-Steinacker, University of Ulm, Ulm; Rainer Fietkau, University of Erlangen, Erlangen; Stefanie Brehmer, University of Mannheim, Mannheim; Ralf Kohnen and Elmar Dunkl, RPS Research Germany, Nürnberg; Barbara Leutgeb and Martin Proescholdt, Roche Pharma AG, Grenzach-Wyhlen; and Walter Stummer, University of Münster, Münster, Germany ulrich.herrlinger@ukb.uni-bonn.de.
2
Ulrich Herrlinger, Niklas Schäfer, Frederic Mack, Moritz Stuplich, Sied Kebir, Torsten Pietsch, and Martin Glas, University of Bonn, Bonn; Joachim P. Steinbach and Michael W. Ronellenfitsch, University of Frankfurt, Frankfurt; Astrid Weyerbrock and Horst Urbach, University of Freiburg, Freiburg; Peter Hau and Martin Uhl, University Hospital Regensburg, Regensburg; Roland Goldbrunner and Stefan Grau, University of Cologne, Cologne; Franziska Friedrich and Rolf-Dieter Kortmann, University of Leipzig, Leipzig; Veit Rohde, University of Goettingen, Goettingen; Florian Ringel, Klinikum rechts der Isar Technical University of Munich; Oliver Schnell and Claus Belka, Ludwig Maximillian University of Munich, Munich; Uwe Schlegel, Ruhr-Universität Bochum, Bochum; Michael Sabel and Jaroslaw Maciaczyk, University of Düsseldorf, Düsseldorf; Mathias Hänel, Klinikum Chemnitz, Chemnitz; Dietmar Krex, University of Dresden, Dresden; Peter Vajkoczy, Charité, Humboldt University of Berlin, Berlin; Rüdiger Gerlach, Helios Klinikum Erfurt, Erfurt; Maximilian Mehdorn, University of Kiel, Kiel; Jochen Tüttenberg, Klinikum Idar-Oberstein, Idar-Oberstein; Regine Mayer-Steinacker, University of Ulm, Ulm; Rainer Fietkau, University of Erlangen, Erlangen; Stefanie Brehmer, University of Mannheim, Mannheim; Ralf Kohnen and Elmar Dunkl, RPS Research Germany, Nürnberg; Barbara Leutgeb and Martin Proescholdt, Roche Pharma AG, Grenzach-Wyhlen; and Walter Stummer, University of Münster, Münster, Germany.

Abstract

PURPOSE:

In patients with newly diagnosed glioblastoma that harbors a nonmethylated O(6)-methylguanine-DNA methyltransferase promotor, standard temozolomide (TMZ) has, at best, limited efficacy. The GLARIUS trial thus explored bevacizumab plus irinotecan (BEV+IRI) as an alternative to TMZ.

PATIENTS AND METHODS:

In this phase II, unblinded trial 182 patients in 22 centers were randomly assigned 2:1 to BEV (10 mg/kg every 2 weeks) during radiotherapy (RT) followed by maintenance BEV (10 mg/kg every 2 weeks) plus IRI(125 mg/m(2) every 2 weeks) or to daily TMZ (75 mg/m(2)) during RT followed by six courses of TMZ (150-200 mg/m(2)/d for 5 days every 4 weeks). The primary end point was the progression-free survival rate after 6 months (PFS-6).

RESULTS:

In the modified intention-to-treat (ITT) population, PFS-6 was increased from 42.6% with TMZ (95% CI, 29.4% to 55.8%) to 79.3% with BEV+IRI (95% CI, 71.9% to 86.7%; P <.001). PFS was prolonged from a median of 5.99 months (95% CI, 2.7 to 7.3 months) to 9.7 months (95% CI, 8.7 to 10.8 months; P < .001). At progression, crossover BEV therapy was given to 81.8% of all patients who received any sort of second-line therapy in the TMZ arm. Overall survival (OS) was not different in the two arms: the median OS was 16.6 months (95% CI, 15.4 to 18.4 months) with BEV+IRI and was 17.5 months (95% CI, 15.1 to 20.5 months) with TMZ. The time course of quality of life (QOL) in six selected domains of the European Organisation for Research and Treatment of Cancer Quality-of-Life Questionnaire (QLQ) -C30 and QLQ-BN20 (which included cognitive functioning), of the Karnofsky performance score, and of the Mini Mental State Examination score was not different between the treatment arms.

CONCLUSION:

BEV+IRI resulted in a superior PFS-6 rate and median PFS compared with TMZ. However, BEV+IRI did not improve OS, potentially because of the high crossover rate. BEV+IRI did not alter QOL compared with TMZ.

TRIAL REGISTRATION:

ClinicalTrials.gov NCT00967330.

PMID:
26976423
DOI:
10.1200/JCO.2015.63.4691
[Indexed for MEDLINE]

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