Safety and efficacy of the addition of bevacizumab (BV) to temozolomide (TMZ) and radiation therapy (RT) followed by BV, TMZ, and irinotecan (CPT-11) for newly diagnosed glioblastoma multiforme (GBM).

2015 Background: Standard GBM treatment includes TMZ and RT, and results in a median progression-free survival and median survival of 6.9 and 15.8 months, respectively. GBM have high concentrations of vascular endothelial growth factor (VEGF), higher levels are associated with poorer prognosis. BV is a humanized antibody to VEGF with activity in recurrent GBMs. This study aims to improve the survival of newly diagnosed GBM patients by incorporating an anti-angiogenic agent with RT and TMZ, and adding a topoisomerase I inhibitor, and an anti-angiogenic agent to TMZ post-RT therapy. METHODS: Patients received standard RT and TMZ at 75 mg/m(2)/day, with BV at 10 mg/kg every 14 days beginning a minimum of 28 days post-operatively. Following the completion of RT, patients received 6 cycles of BV, TMZ and CPT-11. Each cycle was 28 days. BV was given at a dose of 10 mg/kg on days 1 and 15, TMZ at 200 mg/m(2) on days 1-5 and CPT-11 on days 1 and 15 at 125 mg/m(2) for patients not on an enzyme inducing anti-epileptic drug (EIAED) and 340 mg/m(2) for patients on an EIAED. The study was designed to differentiate between a 16-month survival rate of 45% and 60% with type I and II error rates of 0.05. RESULTS: 75 patients were enrolled between 8/07 and 9/08. All the patients have completed RT; 40 patients continue to receive BV, TMZ, and CPT-11. Twenty-two patients have completed 6 cycles of BV, TMZ, and CPT-11; 17 of them had a cold PET One patient developed a CNS hemorrhage (grade 2) necessitating stopping BV. Five patients developed thrombocytopenia for which TMZ was held (grade 3, n = 1; grade 4, n = 4). There were no other ≥ grade 3 toxicities, including no wound dehiscence during RT. Twelve patients had tumor progression, and 14 stopped because of toxicity, including: 6 with fatigue; 3 with PEs; 2 with grade 4 thrombocytopenia; the patient with CNS hemorrhage, and one each with a rectal abscess and sepsis. There have been 7 deaths: 5 from tumor progression; one each from sepsis and PEs. At a median follow-up of 9 months, 81% remain alive and progression-free. CONCLUSIONS: Adding BV to TMZ and RT followed by BV, TMZ with CPT-11 is tolerable and efficacious. No significant financial relationships to disclose.

Duke Scholars

Author James Emmett Herndon II Biostatistics & Bioinformatics, Division of Biostatistics

Author Henry Seth Friedman Neurosurgery, Neuro-Oncology