Bevacizumab Added to Radiotherapy/Temozolomide Improves Progression-Free Survival but Not Overall Survival in Newly Diagnosed Glioblastoma
In a double-blind phase III trial reported in The New England Journal of Medicine, Chinot et al assessed adding bevacizumab (Avastin) to radiotherapy and temozolomide in patients with newly diagnosed glioblastoma. This was the second of two similar studies published in the February 20 issue of NEJM, and in this report, unlike the study by Gilbert et al, the addition of bevacizumab was associated with prolongation of progression-free survival but not overall survival.
Study Details
In the trial, 921 adult patients were randomly assigned to receive bevacizumab at 10 mg/kg (n = 458) or placebo (n = 463) every 2 weeks plus radiotherapy (up to 60 Gy) and temozolomide at 75 mg/m2 for 6 weeks. After a 28-day break, patients received maintenance bevacizumab at 10 mg/kg or placebo every 2 weeks plus temozolomide at 150 to 200 mg/m2 per day for 5 days for six 4-week cycles, followed by bevacizumab monotherapy at 15 mg/kg or placebo every 3 weeks until disease progression or unacceptable toxic effects.
The coprimary endpoints were investigator-assessed progression-free survival and overall survival. The two groups were well balanced for baseline characteristics.
Overall, 62% of patients in the bevacizumab group and 69% in the placebo group received subsequent treatment after progression.
Survival Data
Median progression-free survival was 10.6 months in the bevacizumab group vs 6.2 months in the placebo group (stratified hazard ratio [HR] = 0.64, P < .001). Hazard ratios for progression-free survival consistently favored bevacizumab in subgroup analyses, including a significant benefit among patients with nonmethylated MGMT (O-6-methylguanine–DNA methyltransferase; 0.56, 95% confidence interval (CI) = 0.46–0.69), a nonsignificant benefit in those with methylated MGMT (0.76, 95% CI = 0.56–1.04), and significant benefits in recursive partitioning analysis (RPA) classes III, IV, and V.
Median overall survival was 16.8 vs 16.7 months (HR = 0.88, P = .10), with no significant differences observed in subgroup analyses. Overall survival was 72.4% vs 66.3% at 1 year (P = .049) and 33.9% vs 30.1% at 2 years (P = 0.24).
Quality of Life
Quality-of-life assessment on the European Organisation for Research and Treatment of Cancer quality-of-life questionnaire/brain-cancer module (QLQ-C30/BN20) showed deterioration-free survival was significantly longer for bevacizumab patients on all five prespecified scales, consisting of global health status, physical functioning, social functioning, motor dysfunction, and communication deficit (all P < .001) and on all 21 nonprespecified scales in an exploratory analyses (all P < .05).
There were no differences between groups in neurocognitive function assessed by the Mini–Mental State Examination. Karnofsky performance status was maintained at ≥ 70 for a median of 9.0 months in the bevacizumab group vs 6.0 months in the placebo group, and median survival without deterioration in performance status (9.0 vs 5.5 months, P < .001) and median time to deterioration (14.2 vs 11.8 months, P = 0.02) were longer in the bevacizumab group.
Among patients receiving glucocorticoids at baseline, use was discontinued for ≥ 5 consecutive days in 66% of bevacizumab patients vs 47% of placebo patients; among those not receiving glucocorticoids at baseline, median time to initiation was 12.3 vs 3.7 months (P = .002).
Adverse Events
Serious adverse events (39% vs 26%, P < .001) and grade ≥ 3 adverse events (67% vs 51%, P < .001) were more common with bevacizumab treatment. Grade ≥ 3 adverse events that were significantly more common (all P < .05) with bevacizumab included arterial thrombotic events (5.0% vs 1.3%), hypertension (11.3% vs 2.2%), proteinuria (5.4% vs 0%), and thrombocytopenia (15.0% vs 9.8%).
Other serious adverse events observed more frequently in the bevacizumab group included bleeding, complications of wound healing, gastrointestinal perforation, and congestive heart failure. Adverse events led to discontinuation of treatment in 26.5% vs 13.6% of patients, including discontinuation of bevacizumab or placebo in 24.7% vs 10.2% (both P < .001). Grade 5 adverse events occurred in 4.3% vs 2.7%.
The investigators concluded, “The addition of bevacizumab to radiotherapy-temozolomide did not improve survival in patients with glioblastoma. Improved progression-free survival and maintenance of baseline quality of life and performance status were observed with bevacizumab; however, the rate of adverse events was higher with bevacizumab than with placebo.”
Olivier L. Chinot, MD, of Aix-Marseille University, Assistance Publique–Hôpitaux de Marseille, is the corresponding author for The New England Journal of Medicine article.
The study was funded by F. Hoffmann–La Roche. For full disclosures of the study authors, visit www.nejm.org.
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