ARTE and craft of bevacizumab in elderly patients with glioblastoma
Authors: D. Schiff
Journal: Annals of Oncology (2018)

Glioblastoma is a disease strongly associated with aging; the median age at diagnosis is 64 years, with peak incidence between 75 and 84 years (CBTRUS 2013). Moreover, advancing age is a powerful adverse prognostic factor. While the ‘Stupp’ EORTC-NCIC study found that the addition of temozolomide to radiation improved overall survival (OS) [1.Stupp R. Mason W.P. van den Bent M.J. et al.Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma.N Engl J Med. 2005; 352: 987-996Crossref PubMed Scopus (12689) Google Scholar], particularly in patients whose tumors had MGMT promoter methylation [2.Hegi M.E. Diserens A.C. Gorlia T. et al.MGMT gene silencing and benefit from temozolomide in glioblastoma.N Engl J Med. 2005; 352: 997-1003Crossref PubMed Scopus (4665) Google Scholar], this study excluded patients older than 70 years. Moreover, subgroup analysis showed marginal benefit from temozolomide in patients older than 60 years and especially 65 years. Recent years have witnessed increased attention and a flurry of clinical trials seeking improved outcome in elderly glioblastoma patients. Roa et al. reported equivalent OS results with 40 Gy in 15 fractions over 3 weeks compared to 60 Gy in 30 fractions over 6 weeks in patients older than 60 years [3.Roa W. Brasher P.M. Bauman G. et al.Abbreviated course of radiation therapy in older patients with glioblastoma multiforme: a prospective randomized clinical trial.J Clin Oncol. 2004; 22: 1583-1588Crossref PubMed Scopus (571) Google Scholar]. The ‘Nordic trial’ later reported improved OS with 34 Gy in 10 fractions compared with 60 Gy in this age group [4.Malmstrom A. Gronberg B.H. Marosi C. et al.Temozolomide versus standard 6-week radiotherapy versus hypofractionated radiotherapy in patients older than 60 years with glioblastoma: the Nordic randomised, phase 3 trial.Lancet Oncol. 2012; 13: 916-926Abstract Full Text Full Text PDF PubMed Scopus (747) Google Scholar]. Together, these studies validated shorter, more convenient treatment schedules as an acceptable option in the elderly. The NOA-08 study asked whether dose-dense temozolomide was non-inferior to standard radiation in patients aged ≥65 years [5.Wick W. Platten M. Meisner C. et al.Temozolomide chemotherapy alone versus radiotherapy alone for malignant astrocytoma in the elderly: the NOA-08 randomised, phase 3 trial.Lancet Oncol. 2012; 13: 707-715Abstract Full Text Full Text PDF PubMed Scopus (716) Google Scholar]. While OS was similar in the two arms, tumor MGMT methylation status was a significant predictor of OS. Patients with methylated tumors did better with temozolomide, while those with unmethylated tumors did better with radiation. These findings suggested that patients with methylated tumors might be undertreated with radiation alone. During the same time frame, the anti-vascular endothelial growth factor monoclonal antibody bevacizumab underwent extensive evaluation in glioblastoma. Initial studies in recurrent glioblastoma showed high response rates and 6-month progression-free survival, leading to accelerated approval from the U.S. Food and Drug Administration [6.Friedman H.S. Prados M.D. Wen P.Y. et al.Bevacizumab alone and in combination with irinotecan in recurrent glioblastoma.J Clin Oncol. 2009; 27: 4733-4740Crossref PubMed Scopus (1810) Google Scholar]. Two large studies randomizing patients with glioblastoma to radiation/temozolomide and either bevacizumab or placebo were launched. Against this backdrop and some data that older glioblastoma patients seemed to derive the most benefit from bevacizumab [7.Lai A. Tran A. Nghiemphu P.L. et al.Phase II study of bevacizumab plus temozolomide during and after radiation therapy for patients with newly diagnosed glioblastoma multiforme.J Clin Oncol. 2011; 29: 142-148Crossref PubMed Scopus (351) Google Scholar], Swiss investigators launched the ARTE trial [8.Wirsching H.-G. Tabatabai G. Roelcke U. et al.Bevacizumab plus hypofractionated radiotherapy versus radiotherapy alone in elderly patients with glioblastoma: the randomized, open-label, phase II ARTE trial.Ann Oncol. 2018; 29: 1423-1430Abstract Full Text Full Text PDF PubMed Scopus (38) Google Scholar]. ARTE was a small open-label randomized phase II study exploring potential survival benefit from the addition of bevacizumab to hypofractionated radiotherapy in patients > 65 years with newly diagnosed glioblastoma. Temozolomide was not part of the regimen given the absence of data at that time suggesting benefit in the elderly. However, the trial was amended soon after opening to ensure sufficient numbers of subjects with MGMT-unmethylated tumors given the benefits from temozolomide in older patients with methylated tumors in the NOA-08 and Nordic trials. The primary end point was median OS, and planned secondary analyses included progression-free survival (PFS), quality of life and cognitive function before progression, and the prognostic value of tumoral methylation and gene expression profiling. With respect to survival, the results of ARTE closely mirrored those of the phase III studies adding bevacizumab to radiation and temozolomide, as well as the recently reported EORTC 26101 trial randomizing recurrent glioblastoma patients to lomustine plus/minus bevacizumab [9.Gilbert M.R. Dignam J.J. Armstrong T.S. et al.A randomized trial of bevacizumab for newly diagnosed glioblastoma.N Engl J Med. 2014; 370: 699-708Crossref PubMed Scopus (1542) Google Scholar, 10.Chinot O.L. Wick W. Mason W. et al.Bevacizumab plus radiotherapy-temozolomide for newly diagnosed glioblastoma.N Engl J Med. 2014; 370: 709-722Crossref PubMed Scopus (1449) Google Scholar, 11.Wick W. Gorlia T. Bendszus M. et al.Lomustine and bevacizumab in progressive glioblastoma.N Engl J Med. 2017; 377: 1954-1963Crossref PubMed Scopus (299) Google Scholar]. The addition of bevacizumab to hypofractionated radiotherapy improved PFS by almost 3 months (7.6 versus 4.8 months, P = 0.003); however, there was no improvement in OS (median OS 12.1 versus 12.2 months; P = 0.77). In light of the results of the three aforementioned randomized phase III trials glioblastoma trials of standard treatment with or without bevacizumab, the positive PFS but negative OS results in ARTE come as no surprise. Crossover to bevacizumab, which occurred in 31%–48% of control arm patients on the phase III trials [9.Gilbert M.R. Dignam J.J. Armstrong T.S. et al.A randomized trial of bevacizumab for newly diagnosed glioblastoma.N Engl J Med. 2014; 370: 699-708Crossref PubMed Scopus (1542) Google Scholar, 10.Chinot O.L. Wick W. Mason W. et al.Bevacizumab plus radiotherapy-temozolomide for newly diagnosed glioblastoma.N Engl J Med. 2014; 370: 709-722Crossref PubMed Scopus (1449) Google Scholar, 11.Wick W. Gorlia T. Bendszus M. et al.Lomustine and bevacizumab in progressive glioblastoma.N Engl J Med. 2017; 377: 1954-1963Crossref PubMed Scopus (299) Google Scholar] and 52% in ARTE, may have played a modest role in the negative OS results; in this regard, ARTE noted a trend towards OS benefit from bevacizumab in patients who did not receive second-line therapy, a finding also noted in AVAglio [12.Chinot O.L. Nishikawa R. Mason W. et al.Upfront bevacizumab may extend survival for glioblastoma patients who do not receive second-line therapy: an exploratory analysis of AVAglio.Neuro Oncol. 2016; 18: 1313-1318Crossref PubMed Scopus (33) Google Scholar]. Recently published registry data in the United Stated indicate that bevacizumab use in glioblastoma patients older than 65 years is associated with significantly improved OS and decreased risk of death (Hazard ratio = 0.80). Although the registry study tried to control for confounding factors, immortal time bias (wherein patients who survive longer due to better prognostic factors have a longer time period in which to receive the intervention) may account for these results [13.Davies J. Reyes-Rivera I. Pattipaka T. Skirboll S. et al.Survival in elderly glioblastoma patients treated with bevacizumab-based regimens in the United States.Neuro-Oncology Practice. 2018; (Feb 6 [Epub ahead of print])Crossref Scopus (7) Google Scholar]. An unexpected finding in ARTE was the relatively good outcome of the control arm, in whom the observed OS of 12.2 months substantially exceeded the predicted 10 months. The explanation is unclear, though this arm had a surprisingly high 32% response rate to initial radiation therapy and most patients (72%) received salvage therapy. In terms of secondary end points, quality of life (EORTC QLQ-C30 and QLQ-BN20) and neurocognitive function (assessed with Mini Mental Status Exam) were generally maintained in both arms until progression of disease. The well-known steroid-sparing effects of bevacizumab [14.Vredenburgh J.J. Cloughesy T. Samant M. et al.Corticosteroid use in patients with glioblastoma at first or second relapse treated with bevacizumab in the BRAIN study.Oncologist. 2010; 15: 1329-1334Crossref PubMed Scopus (77) Google Scholar] were recapitulated in ARTE, as 95% of treated patients came off steroids; nonetheless, so did 67% of patients in the control arm. What are the takeaway lessons from ARTE? Elderly glioblastoma patients seem to respond similarly to up-front use of bevacizumab to younger adult patients, with improved PFS and deterioration-free survival, an acceptable tolerability profile, steroid-sparing benefits, but no clear improvement in OS. Whether bevacizumab meaningfully improves quality of life remains uncertain. Biomarker studies, including the exploratory ones from ARTE, have not yielded consistent findings on which patients are likely to benefit [15.Schiff D. Wen P.Y. The siren song of bevacizumab: swan song or clarion call?.Neuro Oncol. 2018; 20: 147-148Crossref PubMed Scopus (3) Google Scholar]. The results of ARTE do not support routine early use of bevacizumab but support consideration of its incorporation into treatment in elderly patients who may tolerate radiation poorly because of poor performance status, large tumors and poorly controlled vasogenic edema and who may never be candidates for second-line chemotherapy. As such, ARTE adds to our gradually improving understanding of the role of chemotherapy for glioblastomas in the elderly. With the recent demonstration from the NCIC-EORTC CE.6 study that elderly patients with glioblastoma benefit from the addition of temozolomide to hypofractionated radiation therapy [16.Perry J.R. Laperriere N. O'Callaghan C.J. et al.Short-course radiation plus temozolomide in elderly patients with glioblastoma.N Engl J Med. 2017; 376: 1027-1037Crossref PubMed Scopus (405) Google Scholar], our management of this important patient population is improving. None declared.