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Ann Oncol. 2018 Jun 1;29(6):1423-1430. doi: 10.1093/annonc/mdy120.

Bevacizumab plus hypofractionated radiotherapy versus radiotherapy alone in elderly patients with glioblastoma: the randomized, open-label, phase II ARTE trial.

Author information

1
Brain Tumor Center Zurich, University Hospital and University of Zurich, Zurich, Switzerland.
2
Department of Neurology, University Hospital and University of Zurich, Zurich, Switzerland.
3
Department of Neurology, Brain Tumor Center Aarau, Cantonal Hospital Aarau, Aarau, Switzerland.
4
Department of Clinical Neurosciences, University Hospital Lausanne, Lausanne, Switzerland.
5
Department of Medical Oncology, University Hospital Lausanne, Lausanne, Switzerland.
6
Department of Clinical Trials Center, University Hospital and University of Zurich, Zurich, Switzerland.
7
Department of Medical Oncology, University Hospital Bern, Bern, Switzerland.
8
Department of Radiation Oncology, Cantonal Hospital St. Gallen, St. Gallen, Switzerland.
9
Department of Neuropathology, Ruprecht-Karls-University Heidelberg, Heidelberg, Germany.
10
German Cancer Research Center (DKFZ), Heidelberg, Germany.
11
Genentech, Oncology Biomarker Development, Basel, Switzerland.
12
Department of Medical Oncology, University Hospital Basel, Basel, Switzerland.
13
Department of Neurology, Cantonal Hospital St. Gallen, St. Gallen, Switzerland.
14
Department of Radiation Oncology, University Hospital Geneva, Geneva, Switzerland.
15
Department of Medical Oncology, Cantonal Hospital Chur, Chur, Switzerland.
16
Department of Medical Oncology, Cantonal Hospital Lucerne, Lucerne Switzerland.
17
Department of Neuropathology, Heinrich Heine University Düsseldorf, Düsseldorf, Germany.
18
Department of Pediatric Hematology and Oncology, Ruprecht-Karls-University Heidelberg, Heidelberg, Germany.
19
Department of Neuropathology, University Hospital Zurich, Zurich, Switzerland.
20
F. Hoffmann-La Roche, Pharma Division, Product Development Oncology, Basel, Switzerland.
21
German Cancer Research Center, Essen/Düsseldorf, Germany.
22
Biostatistics Department, University of Zurich, Zurich, Switzerland.

Abstract

Background:

The addition of bevacizumab to temozolomide-based chemoradiotherapy (TMZ/RT → TMZ) did not prolong overall survival (OS) in patients with newly diagnosed glioblastoma in phase III trials. Elderly and frail patients are underrepresented in clinical trials, but early reports suggested preferential benefit in this population.

Patients and methods:

ARTE was a 2 : 1 randomized, multi-center, open-label, non-comparative phase II trial of hypofractionated RT (40 Gy in 15 fractions) with bevacizumab (10 mg/kg×14 days) (arm A, N = 50) or without bevacizumab (arm B, N = 25) in patients with newly diagnosed glioblastoma aged ≥65 years. The primary objective was to obtain evidence for prolongation of median OS by the addition of bevacizumab to RT. Response was assessed by RANO criteria. Quality of life (QoL) was monitored by the EORTC QLQ-C30/BN20 modules. Exploratory studies included molecular subtyping by 450k whole methylome and gene expression analyses.

Results:

Median PFS was longer in arm A than in arm B (7.6 and 4.8 months, P = 0.003), but OS was similar (12.1 and 12.2 months, P = 0.77). Clinical deterioration was delayed and more patients came off steroids in arm A. Prolonged PFS in arm A was confined to tumors with the receptor tyrosine kinase (RTK) I methylation subtype (HR 0.25, P = 0.014) and proneural gene expression (HR 0.29, P = 0.025). In a Cox model of OS controlling for established prognostic factors, associations with more favorable outcome were identified for age <70 years (HR 0.52, P = 0.018) and Karnofsky performance score 90%-100% (HR 0.51, P = 0.026). Including molecular subtypes into that model identified an association of the RTK II gene methylation subtype with inferior OS (HR 1.73, P = 0.076).

Conclusion:

Efficacy outcomes and exploratory analyses of ARTE do not support the hypothesis that the addition of bevacizumab to RT generally prolongs survival in elderly glioblastoma patients. Molecular biomarkers may identify patients with preferential benefit from bevacizumab.

Clinical trial registration number:

NCT01443676.

PMID:
29648580
DOI:
10.1093/annonc/mdy120

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