Given prior studies that suggest the use of angiotensin system inhibitors (ASIs) is associated with prolonged overall survival (OS) in glioblastoma (GBM) patients, we evaluated the effect of ASIs in glioma patients receiving chemotherapy and/or bevacizumab (BEV). Using retrospective IRB-approved electronic chart review of newly diagnosed WHO grade 2-4 glioma patients from the Kaiser Permanente Tumor Registry of Northern California, we evaluated the impact of ASIs on OS by Cox proportional hazard model analysis for subgroups who received cytotoxic therapy, cytotoxic therapy with BEV, or BEV alone, as well as those with recurrent GBM (rGBM). Of the 1186 glioma patients who received chemotherapy ASI exposure improved OS (HR 0.82; 95% CI 0.71, 0.93; p = 0.003). When stratified by BEV exposure, a sub-analysis revealed further OS advantage for the BEV group (HR 0.75, 95% CI 0.62, 0.90; p = 0.002). In a second cohort of 181 rGBM patients who received BEV in varying dosages, ASI exposure conferred an OS advantage (HR 0.649; 95% CI 0.46, 0.92; p = 0.016). Moreover, patients with ASI exposure who received low-dose BEV treatment (AUC < 3.6 mg wk/kg) had a significantly longer OS (median = 99 weeks; 95% CI 44.3, 205) than those without ASI (median OS = 55.6 weeks; 95% CI 37.7-73.7; p = 0.032). ASI use is associated with longer OS in glioma patients. Further survival advantage with ASI use was observed in rGBM patients receiving low-dose bevacizumab. These data warrant prospective evaluation of adding ASI to low-dose BEV treatment in GBM patients to improve the outcome of standard therapies.

Ziconotide is a therapeutic option for treatment of severe chronic pain in patients who have exhausted all other agents, including intrathecal morphine, and for whom the potential benefit outweighs the risks of serious neuropsychiatric adverse effects and of having an implanted device. Further studies are needed to determine the comparative efficacy of ziconotide and other pain therapies.

Bevacizumab (BEV, Avastin(®)) produces durable objective radiological responses of 20-26 %, median response durations of 16-18 weeks, and median overall survival (mOS) of 31-40 weeks. While the use of BEV is well-established, the lack of dose-response studies in glioblastoma (GBM) patients raises the question whether current dosing practice is optimal. As a result of differing approaches to BEV dosing that ranged from the FDA approved package insert dose of 10 mg/kg every 2 weeks to 7.5 mg/kg every 3-4 weeks, among physicians within Northern California Kaiser Permanente hospitals over 4+ years, we did an IRB-approved retrospective analysis of patients seen in Northern California Kaiser Permanente facilities and treated with BEV. Between September 1, 2008 and August 31, 2013, 181 patients received BEV for tumor progression/recurrence starting 2.6 weeks after completion of chemoradiation. The integrated BEV administered dose-week (AUCBEV) for all patients had a median AUCBEV of 3.6 mg·wk/kg). Maximum likelihood analysis found patients over 65 years did worse than younger patients (p = 0.004), women lived longer (p = 0.002), and patients treated below the AUCBEV did better than those treated above the median AUCBEV (p = 0.003). mOS for BEV starting 1 month after chemoradiation was 45 versus 68 weeks (p = 0.012) and BEV starting 3 months after chemoradiation was 40 versus 74 weeks (p = 0.0085). Dosing BEV at half the standard dose for progressive/recurrent GBM was at least equivalent to or, maybe better than standard dosing. Unexplained was the observation that females had longer OS with BEV than males.