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.

Bevacizumab plus Radiotherapy–Temozolomide for Newly Diagnosed Glioblastoma

“…Other prognostic markers for glioblastoma (e.g., surgery status, Karnofsky performance status, age, and recursive partitioning analysis class) were also not predictive of survival, findings that were consistent with those in previous studies. 21 The addition of bevacizumab to standard radiotherapy-temozolomide therapy as first-line treatment for glioblastoma was also investigated in the phase 3, randomized, placebo-controlled Radiation Therapy Oncology Group (RTOG)-0825 study. That study showed a similar trend toward improvement in progression-free survival (hazard ratio, 0.79; 95% CI, 0.66 to 0.94; P = 0.007), with a 3.4-month extension of progression-free survival, although the difference was not significant according to the prespecified alpha level (P<0.004).…”

“…16 The results of phase 1/2 studies support a role for the anti-VEGF-A molecule bevacizumab in recurrent and newly diagnosed glioblastoma. [17][18][19][20][21][22] We report the results of a phase 3 trial of bevacizumab plus radiotherapy-temozolomide as compared with placebo plus radiotherapytemozolomide in patients with newly diagnosed glioblastoma.…”

A Metabolic Shift Favoring Sphingosine 1-Phosphate at the Expense of Ceramide Controls Glioblastoma Angiogenesis

“…Recently, the antiangiogenic drug bevacizumab (Avastin), a monoclonal antibody to VEGF, was approved in the United States for patients with recurrent GBM. Bevacizumab improves progression-free survival in GBM, associated with reduced steroid use, but confers little or no improvement in overall survival (4,5). Most targeted therapies to date are directed against druggable oncogenes identified through genomic profiling.…”

Standard of care therapy for malignant glioma and its effect on tumor and stromal cells

“…GBMs are highly vascularized tumors and bevacizumab therapy may extend survival in some recurrent patients (Zuniga et al, 2009). To date, clinical studies that have assessed the benefit of adding bevacizumab to standard therapy in primary GBM have been less impressive (Lai et al, 2011). However, one study found that combining therapies against endothelial cells and pericytes can result in a synergistic antitumor effect (Bergers et al, 2003) supporting the concept that the use of many drugs directed toward different molecular targets can achieve optimal treatment response.…”