Phase II study of bevacizumab plus temozolomide during and after radiation therapy for patients with newly diagnosed glioblastoma multiforme

Abstract

Purpose: This open-label, prospective, multicenter single-arm phase II study combined bevacizumab (BV) with radiation therapy (RT) and temozolomide (TMZ) for the treatment of newly diagnosed glioblastoma (GBM). The objectives were to determine the efficacy of this treatment combination and the associated toxicity.

Patients and methods: Seventy patients with newly diagnosed GBM were enrolled between August 2006 and November 2008. Patients received standard RT starting within 3 to 6 weeks after surgery with concurrent administration of daily TMZ and biweekly BV. After completion of RT, patients resumed TMZ for 5 days every 4 weeks and continued biweekly BV. MGMT promoter methylation was assessed on patient tumor tissue. A University of California, Los Angeles/Kaiser Permanente Los Angeles (KPLA) control cohort of newly diagnosed patients treated with first-line RT and TMZ who had mostly received BV at recurrence was derived for comparison.

Results: The overall survival (OS) and progression-free survival (PFS) were 19.6 and 13.6 months, respectively, compared to 21.1 and 7.6 months in the University of California, Los Angeles/KPLA control cohort, and 14.6 and 6.9 months in the European Organisation for Research and Treatment of Cancer-National Cancer Institute of Canada cohort. Correlation of MGMT promoter methylation and improved OS and PFS was retained in the study group. Comparative subset analysis showed that poor prognosis patients (recursive partitioning analysis class V/VI) may derive an early benefit from the use of first-line BV. Toxicity attributable to RT/TMZ was similar, and additional toxicities were consistent with those reported in other BV trials.

Conclusion: Patients treated with BV and TMZ during and after RT showed improved PFS without improved OS compared to the University of California, Los Angeles/KPLA control group. Additional studies are warranted to determine if BV administered first-line improves survival compared to BV at recurrence.

Fig 1.

Treatment schema for (A) study group and (B) University of California, Los Angeles/Kaiser Permanente Los Angeles control group in which most patients received bevacizumab at recurrence. Wks, weeks.

Fig 2.

Kaplan-Meier analysis of (A) overall survival and (B) progression-free survival comparing current study group (gold; radiation therapy [RT] + temozolomide [TMZ] + bevacizumab [BV]) with University of California, Los Angeles/Kaiser Permanente Los Angeles control group (blue; RT + TMZ). Use of first-line BV shows early benefit in progression-free survival [Fleming(1,0) weighted log-rank test P < .005] and trended toward worse overall survival with later follow-up [Fleming(0,1) weighted log-rank test P < .06].

Fig 3.

Prespecified Kaplan-Meier analysis of overall survival comparing current study (gold) and University of California, Los Angeles/ Kaiser Permanente Los Angeles (KPLA) control (blue) groups for (A,B) MGMT methylation, (C,D) recursive partitioning analysis (RPA) class, and (E,F) age. (A) Unmethylated MGMT promoter subgroup appears to do less well with the addition of bevacizumab (BV) in first-line treatment [(Fleming(0,1); P < .005], while showing no difference within the (B) methylated subgroup [Fleming (1,0); P = .83). (D) RPA V/VI group shows early benefit from the treatment compared with University of California, Los Angeles/KPLA control [Fleming(2,0) P < .05), while showing no difference within the RPA III/IV group (C) [Fleming(0,1) P = .10]. (E) Patients with age younger than 50 years did significantly less well with BV compared to the University of California, Los Angeles/KPLA control group (log-rank P < .005), without any difference in the (F) older than 50 years group [Fleming(1,0); P = .42]. RT, radiation therapy; TMZ, temozolomide.

Fig A1.

Recursive partitioning analysis (RPA) classification of current study group and University of California, Los Angeles/KPLA control group. UCLA, University of California, Los Angeles; KPLA, Kaiser Permanente, Los Angeles; pts, patients; KPS, Karnofsky performance status; NFS, neurological functional status; MS, mental status.

Fig A2.

Progression-free survival and overall survival by Kaplan-Meier analysis of current study group stratified by MGMT promoter methylation status (gold, methylated; blue, unmethylated). Methylated MGMT promoter group responded significantly better than unmethylated group (progression-free survival and overall survival P < .005).