BEVACIZUMAB PLUS HYPOFRACTIONATED RADIOTHERAPY VERSUS RADIOTHERAPY ALONE IN ELDERLY PATIENTS WITH GLIOBLASTOMA: THE ARTE TRIAL

BACKGROUND: Two phase III trials of bevacizumab (BEV) in newly diagnosed glioblastoma demonstrated prolonged progression-free survival (PFS), but failed to prolong overall survival (OS). Retrospective reports and early phase trials of bevacizumab in glioblastoma patients emphasized that benefit was preferentially seen in frail or elderly patients, but such patients are underrepresented in most clinical trials. Here, we report the outcome of an elderly population with newly diagnosed glioblastoma randomized to receive hypofractionated radiotherapy alone or in combination with bevacizumab. METHODS: ARTE (NCT01443676) is a 2-arm, 2:1 randomized, parallel group, explorative, open-label trial of hypofractionated radiotherapy (RT) (15 x 2.66 Gy = 40 Gy) in combination with intravenous BEV every two weeks until progression (BEV+RT) versus RT alone. Major inclusion criteria included age 65 years or older, newly diagnosed glioblastoma, and Karnofsky performance score of 60 or more. An amendment (11/2013) requested demonstrating the absence of O6-methylguanine DNA methyltransferase (MGMT) promoter methylation when it became clear that MGMT promoter methylation predicted larger benefit from temozolomide alone than from radiotherapy alone in patients with glioblastoma aged 65 years or older. Cognitive functioning was monitored by Mini Mental Status Examination and quality of life by utilizing the EORTC QLQ-C30/BN20 modules. Cox proportional hazard models were applied to obtain prognostic factors. Results: Of 75 randomized patients, 50 received BEV+RT and 25 received RT alone. Isocitrate dehydrogenase (IDH)-1 mutation status was uniformly wildtype in all 41 patients with available documentation and MGMT was unmethylated in 55 (76%) of 72 patients with MGMT testing. Established prognostic factors were balanced between both treatment arms, including age, MGMT promoter methylation, Karnofsky performance score, or steroid intake at randomization. Common Terminology Criteria for Adverse Events grade 3 or 4 toxicity was infrequent in both treatment arms. Prior to progression, no differences in cognitive functioning or quality of life were noted between treatment arms. BEV+RT was superior to RT alone for median PFS (7.6 months [95% CI 6.2–9.0] vs. 4.8 months [95% CI 3.0–6.6], P=0.003), but not OS (12.1 months [95% CI 10.2–14.0] vs 12.2 months [95% CI 9.2–15.2], P=0.77). In a Cox model controlling for established prognostic factors to determine predictors of inferior PFS, an association with outcome was detected for BEV+RT versus RT (HR 0.36 [95% CI 0.20–0.65], p=0.001) and for KPS 90–100% versus 60–80% (HR 0.50 [95% CI 0.28–0.89], p=0.018). CONCLUSION: The results of the randomized ARTE trial fail to support the notion that the addition of BEV improves outcome specifically in elderly patients with glioblastomas without MGMT promoter methylation.