ArticlesSingle-agent bevacizumab or lomustine versus a combination of bevacizumab plus lomustine in patients with recurrent glioblastoma (BELOB trial): a randomised controlled phase 2 trial
Introduction
Glioblastoma is the most common primary brain tumour in adults, and affects 600–800 people every year in the Netherlands. Standard care for newly diagnosed glioblastoma is surgical resection as extensively as is safely possible, followed by radiotherapy with concurrent temozolomide and six monthly cycles of adjuvant temozolomide.1 However, the prognosis remains poor, with a median survival of only 12–16 months and only 10% of patients surviving for 4–5 years.2 At tumour progression, treatment options are scarce and of poor effectiveness. On the basis of the results of recent phase 3 trials in which lomustine was used as the comparator, this drug is now one of the first-choice salvage treatment regimens3, 4 However, its use is limited by cumulative bone marrow suppression that might be clinically significant in patients pretreated with temozolomide. Moreover, less than 10% of patients respond and only roughly 20% of patients remain free from disease progression at 6 months. More effective treatments are urgently needed.
Glioblastomas are highly vascularised tumours in which the VEGF signalling pathway is upregulated. Bevacizumab is a humanised monoclonal antibody against circulating VEGF, and is registered by the European Medicines Agency for use in colorectal, lung, ovarian, renal, and breast cancer. Following a retrospective report showing an interesting high response rate in recurrent glioblastoma to treatment with a combination of bevacizumab and irinotecan,5 several phase 2 studies have reported high responses and 6-month progression-free survival (PFS) with bevacizumab.6, 7, 8 These findings led to the accelerated approval of bevacizumab for use in recurrent glioblastoma in the USA. However, the randomised phase 2 BRAIN trial8 that investigated bevacizumab alone and in combination with irinotecan did not show a convincing overall survival benefit of bevacizumab compared with historical series. Phase 3 trials in patients with newly diagnosed glioblastoma also did not show an overall survival benefit with the addition of bevacizumab to chemoradiotherapy with temozolomide, despite an impressive PFS benefit.9, 10 Such findings mean that the overall survival benefit of bevacizumab treatment in glioblastoma remains unclear. A drawback of the many phase 2 trials of bevacizumab in recurrent glioblastoma is that they do not include adequate control groups of patients who are not given the drug. Owing to this absence of properly controlled trials, the registration application for recurrent glioblastoma was rejected by the European Medicines Agency. However, bevacizumab is nonetheless used widely in several European countries.
Additional reports have suggested that bevacizumab and other anti-VEGF agents might induce an infiltrative non-enhancing growth pattern (gliomatosis cerebri) at disease progression.11, 12 Others have described a rapid normalisation of abnormally permeable tumour blood vessels with a reduction of enhancement of the tumour on contrast-enhanced MRI, even in the absence of a true tumour response (ie, a pseudo-response).13 The clinical significance of these findings is unclear, again because of the uncontrolled nature of the studies in which these results were recorded. Moreover, other investigators did not report this different pattern of progression in patients with recurrent glioblastoma treated with bevacizumab.14, 15, 16 Nonetheless, these early observations questioned the classical assessment of response and progression in neuro-oncology, and led to a revision of the response criteria used in trials for recurrent glioblastoma (the RANO criteria).17, 18 These criteria give more emphasis to changes on T2-weighted or fluid-attenuated inversion recovery (FLAIR) magnetic resonance (MR) images. These observations also clearly showed that the classical outcomes of 6-month PFS and the proportion of patients who achieve an objective response, which are used routinely in trials of recurrent glioblastoma, are not the best possible endpoints for trials of bevacizumab in recurrent glioblastoma.17, 19 We report the results of the BELOB study, the first randomised phase 2 trial of the role of bevacizumab in the treatment of recurrent glioblastoma that includes a bevacizumab-free control group.
Section snippets
Study design and participants
This multicentre trial was undertaken in 14 academic hospitals in the Netherlands (five university hospitals and nine community hospitals; see appendix for details). Patients were eligible for inclusion in the trial if they had histologically proven glioblastoma with a first progression after previous chemoradiotherapy with temozolomide, documented by MRI with at least one bi-dimensionally measurable target lesion with one diameter of at least 10 mm, visible on two or more axial slices 5 mm
Results
Between Dec 11, 2009, and Nov 10, 2011, 153 patients were enrolled (figure 1). Five patients were judged ineligible and were excluded from all analyses, three of whom had major violations of protocol entry criteria (increasing dose of steroids and less than a 4-week interval since previous chemotherapy in one patient; uncontrolled hypertension in one; and a subdural haemorrhage at baseline in one), one patient died before randomisation, and one patient withdrew consent before the start of
Discussion
To the best of our knowledge, this study is the first well-controlled randomised trial assessing the role of bevacizumab in the treatment of recurrent glioblastoma (panel). To avoid the uncertainties in the assessment of response and progression in patients given bevacizumab, we used overall survival at 9 months as the primary endpoint. The choice for this particular endpoint was based on the median overall survival reported in the BRAIN trial (9·2 months in the bevacizumab alone group and 8·7
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Contributed equally.