Bevacizumab continuation beyond initial bevacizumab progression among recurrent glioblastoma patients.

BACKGROUND: Bevacizumab improves outcome for most recurrent glioblastoma patients, but the duration of benefit is limited and survival after initial bevacizumab progression is poor. We evaluated bevacizumab continuation beyond initial progression among recurrent glioblastoma patients as it is a common, yet unsupported practice in some countries. METHODS: We analysed outcome among all patients (n=99) who received subsequent therapy after progression on one of five consecutive, single-arm, phase II clinical trials evaluating bevacizumab regimens for recurrent glioblastoma. Of note, the five trials contained similar eligibility, treatment and assessment criteria, and achieved comparable outcome. RESULTS: The median overall survival (OS) and OS at 6 months for patients who continued bevacizumab therapy (n=55) were 5.9 months (95% confidence interval (CI): 4.4, 7.6) and 49.2% (95% CI: 35.2, 61.8), compared with 4.0 months (95% CI: 2.1, 5.4) and 29.5% (95% CI: 17.0, 43.2) for patients treated with a non-bevacizumab regimen (n=44; P=0.014). Bevacizumab continuation was an independent predictor of improved OS (hazard ratio=0.64; P=0.04). CONCLUSION: The results of our retrospective pooled analysis suggest that bevacizumab continuation beyond initial progression modestly improves survival compared with available non-bevacizumab therapy for recurrent glioblastoma patients require evaluation in an appropriately randomised, prospective trial.

Dural venous sinus thrombosis in anaplastic astrocytoma following concurrent temozolomide and focal brain radiotherapy plus bevacizumab.

Malignant gliomas have long been a therapeutic dilemma in neuro-oncology, with a poor overall prognosis. Standard treatment, consisting of primary resection, followed by radiation therapy and temozolomide, has improved prognosis. Recently, studies have looked at the addition of bevacizumab (Avastin), a humanized murine IgG1 monoclonal antibody against vascular endothelial growth factor-A, to conventional regiments. Bevacizumab gained US FDA approval for single agent use in recurrent glioblastoma in 2009. Known side effects of bevacizumab include increased risk of arterial and venous thromboembolism, as well as hemorrhage. With emerging data for the use of bevacizumab in malignant gliomas, the extent of risks such as bleeding and thrombosis in patients with primary brain tumors treated with bevacizumab remains unknown. Here, we present only the second reported case of dural venous sinus thrombosis during treatment with bevacizumab and the first reported case for a primary glioma treated with temozolomide, radiation, and bevacizumab.

Inhibition of DNA replication by tirapazamine.

Tirapazamine (TPZ) is a hypoxia-selective cytotoxin that is currently being examined in Phase II and III clinical trials in combination with radiotherapy and cisplatin-based chemotherapy. Reductases convert TPZ to a cytotoxic radical that produces DNA damage under hypoxic conditions. Because one or more of the enzymes responsible for the bioactivation of TPZ is/are thought to be at or near the nuclear matrix, we hypothesized that TPZ may have a major affect on DNA replication, a process that is known to occur predominantly at the nuclear matrix. To assess the effect of TPZ on DNA replication, we measured the incorporation of radioactive thymidine into DNA of HCT116 human colon cancer cells and HeLa cells. We show that incorporation of radioactive thymidine is dramatically inhibited in cells that are pretreated with TPZ under hypoxic conditions. TPZ-induced inhibition of DNA synthesis was much greater than that produced by more toxic doses of ionizing radiation. We used the SV40-based in vitro DNA replication assay to study the mechanism of inhibition of DNA synthesis in cells treated with TPZ. Using this assay, we show that extracts prepared from cells treated with TPZ under hypoxic conditions had only 25-50% of the DNA replication activity measured in control cells. This reduction in DNA replication activity was associated with a reduction in levels of replication protein A (RPA) in cytoplasmic extracts used for the in vitro DNA replication assay and could be overcome by addition of recombinant human RPA. Furthermore, we show by indirect immunofluorescence that TPZ leads to a localization of the p34 subunit of RPA (RPA2) to small subnuclear foci. These results show that TPZ dramatically inhibits DNA replication and that the mechanism of inhibition, at least in part, involves changes in RPA that alter its cellular localization.