Elsevier

The Lancet Oncology

Volume 15, Issue 9, August 2014, Pages 943-953
The Lancet Oncology

Articles
Single-agent bevacizumab or lomustine versus a combination of bevacizumab plus lomustine in patients with recurrent glioblastoma (BELOB trial): a randomised controlled phase 2 trial

https://doi.org/10.1016/S1470-2045(14)70314-6Get rights and content

Summary

Background

Treatment options for recurrent glioblastoma are scarce, with second-line chemotherapy showing only modest activity against the tumour. Despite the absence of well controlled trials, bevacizumab is widely used in the treatment of recurrent glioblastoma. Nonetheless, whether the high response rates reported after treatment with this drug translate into an overall survival benefit remains unclear. We report the results of the first randomised controlled phase 2 trial of bevacizumab in recurrent glioblastoma.

Methods

The BELOB trial was an open-label, three-group, multicentre phase 2 study undertaken in 14 hospitals in the Netherlands. Adult patients (≥18 years of age) with a first recurrence of a glioblastoma after temozolomide chemoradiotherapy were randomly allocated by a web-based program to treatment with oral lomustine 110 mg/m2 once every 6 weeks, intravenous bevacizumab 10 mg/kg once every 2 weeks, or combination treatment with lomustine 110 mg/m2 every 6 weeks and bevacizumab 10 mg/kg every 2 weeks. Randomisation of patients was stratified with a minimisation procedure, in which the stratification factors were centre, Eastern Cooperative Oncology Group performance status, and age. The primary outcome was overall survival at 9 months, analysed by intention to treat. A safety analysis was planned after the first ten patients completed two cycles of 6 weeks in the combination treatment group. This trial is registered with the Nederlands Trial Register (www.trialregister.nl, number NTR1929).

Findings

Between Dec 11, 2009, and Nov 10, 2011, 153 patients were enrolled. The preplanned safety analysis was done after eight patients had been treated, because of haematological adverse events (three patients had grade 3 thrombocytopenia and two had grade 4 thrombocytopenia) which reduced bevacizumab dose intensity; the lomustine dose in the combination treatment group was thereafter reduced to 90 mg/m2. Thus, in addition to the eight patients who were randomly assigned to receive bevacizumab plus lomustine 110 mg/m2, 51 patients were assigned to receive bevacizumab alone, 47 to receive lomustine alone, and 47 to receive bevacizumab plus lomustine 90 mg/m2. Of these patients, 50 in the bevacizumab alone group, 46 in the lomustine alone group, and 44 in the bevacizumab and lomustine 90 mg/m2 group were eligible for analyses. 9-month overall survival was 43% (95% CI 29–57) in the lomustine group, 38% (25–51) in the bevacizumab group, 59% (43–72) in the bevacizumab and lomustine 90 mg/m2 group, 87% (39–98) in the bevacizumab and lomustine 110 mg/m2 group, and 63% (49–75) for the combined bevacizumab and lomustine groups. After the reduction in lomustine dose in the combination group, the combined treatment was well tolerated. The most frequent grade 3 or worse toxicities were hypertension (13 [26%] of 50 patients in the bevacizumab group, three [7%] of 46 in the lomustine group, and 11 [25%] of 44 in the bevacizumab and lomustine 90 mg/m2 group), fatigue (two [4%], four [9%], and eight [18%]), and infections (three [6%], two [4%], and five [11%]). At the time of this analysis, 144/148 (97%) of patients had died and three (2%) were still on treatment.

Interpretation

The combination of bevacizumab and lomustine met prespecified criteria for assessment of this treatment in further phase 3 studies. However, the results in the bevacizumab alone group do not justify further studies of this treatment.

Funding

Roche Nederland and KWF Kankerbestrijding.

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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