By Bindu Kanapuru, MD
Hematology/Oncology Division, IASIA-Falls Church, Falls Church, VA
Dr. Kanapuru reports no financial relationships relevant to this field of study.
SYNOPSIS: In a multicenter, randomized, double-blind, placebo-controlled clinical trial of bevacizumab added to standard temozolomide and radiation therapy for patients with glioblastoma multiforme, progression-free survival but not overall survival was enhanced. Notably, this prolongation of progression-free survival was associated with maintained quality of life and neurocognitive function. This latter important finding is in contrast to that observed in a similar trial, also published in the same New England Journal of Medicine issue, indicating bevacizumab-associated decline in quality of life and neurocognitive function. Thus, questions remain regarding when and how this drug should be used in the treatment of glioblastoma.
SOURCE: Chinot OL, Wick W, Mason W, et al. Bevacizumab plus radiotherapy — temozolomide for newly diagnosed glioblastoma. N Engl J Med 2014;370:709-722.
Glioblastoma remains the most common primary brain tumor in adults and is associated with significant morbidity and mortality.1,2 Currently, the standard of care for patients with newly diagnosed glioblastoma and good performance status includes concurrent radiotherapy and temozolomide, followed by adjuvant temozolomide.3,4 However, overall survival remains low, and, accordingly, there is great interest in developing and testing new agents. Glioblastomas are highly vascularized tumors that are characterized by the over-expression of vascular endothelial growth factor A (VEGF-A).5,6 Thus, there has been rationale for examining bevacizumab, an anti-VEGF-A agent, in patients with this tumor. Indeed, early studies have demonstrated a potential role for bevacizumab for patients with both newly diagnosed and recurrent glioblastoma.7-9
Chinot and colleagues report the results of the Avastin in Glioblastoma (AVAglio) study, which was conducted at 120 sites in 23 countries and sponsored by F. Hoffmann-La Roche. It was a randomized, placebo-controlled, phase III clinical trial to investigate the effect of the addition of bevacizumab to the standard treatment of radiotherapy and temozolomide in patients with newly diagnosed glioblastoma. Primary endpoints included progression-free survival and overall survival.
Eligible patients were ≥ 18 years of age with newly diagnosed, histologically confirmed supratentorial glioblastoma and a WHO performance status of 0-2. Additional inclusion criteria included adequate healing of craniotomy site, stable or decreasing glucocorticoid doses within the 5 days prior to randomization, and satisfactory renal, hepatic, and hematologic function. Exclusion criteria included recent intracranial hemorrhage, prior chemotherapy or immunotherapy for glioblastoma, prior radiotherapy to the brain, and recent intracranial abscess.
Patients were randomly assigned to receive either bevacizumab (10 mg/kg IV every two weeks) or placebo in addition to standard radiotherapy (2 Gy 5 days/week; maximum 60 Gy) and oral temozolomide (75 mg/m2/day for six weeks). All patients then received a 28-day treatment break, after which they received either maintenance bevacizumab (10 mg/kg IV every 2 weeks) or placebo plus temozolomide (150-200 mg/m2/day for 5 days) for six 4-week cycles. This was followed by bevacizumab monotherapy (15 mg/kg IV every three weeks) or placebo until disease progression or intolerable adverse effects occurred.
Between June 2009 and March 2011, 921 patients enrolled at 120 sites in 23 countries and were randomly assigned in a 1:1 ratio to bevacizumab (n = 458) or placebo (n = 463). The baseline characteristics were similar in the two groups.
The median progression-free survival was longer in the bevacizumab group than the placebo group (10.6 months vs. 6.2 months). The stratified hazard ratio for progression or death with bevacizumab was 0.64 (95% CI 0.5 to 0.74; p < 0.001). This benefit was observed across multiple subgroups, including patients with both methylated and unmethylated MGMT status. However, there were no significant differences in overall survival between the bevacizumab group and the placebo group (72.4% and 66.3% at one year, respectively; p = 0.049; 33.9% and 30.1% at 2 years; p = 0.24). The median overall survival was 16.8 months in the bevacizumab group and 16.7 months in the placebo group.
Secondary outcome measures included health-related quality of life and performance status, both of which were maintained longer in the bevacizumab group than in the placebo group.
The incidence of grade 3 or higher adverse events was greater in the bevacizumab group than the placebo group (66.8% vs. 51.3%), including those that are often associated with bevacizumab (bleeding, arterial thromboembolic events, hypertension, and proteinuria) (32.5% in the bevacizumab group, vs. 15.8% in the placebo group).
Thus, in this large-scale, multicenter, randomized, double-blind, placebo-controlled trial, data are presented supporting the addition of bevacizumab to standard radiotherapy and temozolomide for the treatment of newly diagnosed glioblastoma. Although overall survival was not improved, progression-free survival was extended by a median of 4.4 months, and this with maintained quality of life and performance status. Bevacizumab treatment was associated with reduced use of corticosteroids, but was associated with a greater frequency of the adverse events that have been experienced with this drug in other settings (hypertension, proteinuria, and arterial embolism). Of note, there was no demonstrable influence of MGMT status or other prognostic factors (age, performance status) with respect to progression-free survival.
In the same issue of the New England Journal of Medicine, Gilbert and colleagues reported the results of the Radiation Therapy Oncology Group (RTOG) 0825 trial, which also investigated bevacizumab for glioblastoma patients using a trial design almost identical to that of the AVAglia study.10 The RTOG results were also quite similar with respect to absence of observable enhancement of overall survival but enhancement of progression-free survival by 3.4 months. However, the RTOG findings were different in that quality of life and neurocognitive function were not maintained during treatment. This is an important difference because if the AVAglia findings of greater than four months of progression-free survival with maintained function and quality of life is what can be expected by the addition of bevacizumab, then inclusion of this drug in the initial treatment of patients with glioblastoma would be justified. However, looking at the RTOG findings, one might get the impression that the enhanced progression-free survival is countered by increased toxicity and worsening quality of life. Reconciliation of these important treatment outcomes is high priority. In the accompanying editorial,11 Fine suggests that the investigators from each trial examine the fine details of each study in a comprehensive way and look at issues such as patient characteristics, assessment tools, etc., that might account for the observed differences. That would seem like an excellent suggestion because it remains unclear when and how to use this drug for patients with glioblastoma, and from a consensus understanding, future trials may be designed that will take advantage of this targeted therapy, possibly combined with other agents currently under development.
- Ohgaki H. Epidemiology of brain tumors. Methods Mol Biol. 2009;472:323-342.
- Meyers CA, Hess KR. Multifaceted end points in brain tumor clinical trials: Cognitive deterioration precedes MRI progression. Neuro Oncol. 2003;5:89-95.
- Stupp R, MAson WP, van den Bent MJ, et al. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med. 2005;352:987-996.
- National Comprehensive Cancer Network. NCCN guidelines: Central nervous system cancers. Version 1. 2012 (http://www.nccn.org/professionals/physician_gls/pdf/cns.pdf).
- Chi AS, Sorensen AG, Jain RK, Betchelor TT. Angiogenesis as a therapeutic target in malignant gliomas. Oncologist 2009;14:621-636.
- Berkman RA, Merrill MJ, Reinhold WC, et al. Expression of the vascular permeability factor/vascular endothelial growth factor gene in central nervous system neoplasms. J Clin Invest. 1993;91:153-159.
- Narayana A, Gruber D, Kunnakkat S, et al. A clinical trial of bevacizumab, temozolomide, and radiation for newly diagnosed glioblastoma. J Neurosurg. 2012;116:341-345.
- Lai A, Tran A, Nghiemphu PL, 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;29:142-148.
- Kreisl TN, Kim L, Moore K, et al. Phase II trial of single-agent bevacizumab followed by bevacizumab plus irinotecan at tumor progression in recurrent glioblastoma. J Clin Oncol. 2009;27:740-745.
- Gilbert MR, Dignam JJ, Armstrong TS, et al. A randomized trial of bevacizumab for newly diagnosed glioblastoma. N Engl J Med 2014;370:699-708.
- Fine HA. Bevacizumab in glioblastoma. N Engl J Med 2014;370:764-765.