Analysis Of Clinical Efficacy Of Low-dose Bevacizumab In Recurrent High-grade Glioma

BackgroundGliomas are the most common primary malignant brain tumors in adults.Highgrade glioma(grade Ⅲ and Ⅳ)exhibits poor prognosis with a high recurrence rate.Although bevacizumab has been widely used in the treatment of recurrent high-grade gliomas,the optimal dose of bevacizumab remains controversial.Retrospective clinical trials and preclinical studies have found that low-dose bevacizumab can achieve the same or even better clinical efficacy than conventional-dose bevacizumab,and may improve patient survival by delaying the progression of tumor hypoxia and increasing drug delivery.Therefore,we decided to systematically explore the efficacy of low-dose bevacizumab in recurrent high-grade glioma through meta-analysis,retrospective clinical studies and basic experiments.MethodChapter 1:A comprehensive search of relevant studies was performed in electronic literature databases such as PubMed,EMBASE and the Cochrane Library.Using meta-analysis methods to assess hazard ratios for overall survival and progression-free survival in the included population.Chapter 2:The electronic case system was searched for patients with recurrent glioblastoma who received bevacizumab treatment at our center.The included population was divided into a high-dose bevacizumab group and a low-dose bevacizumab group according to the average weekly dose of bevacizumab.Data collection and close follow-up were performed to evaluate the overall survival and progression-free survival between the two groups.Chapter 3:The orthotopic glioma-bearing mouse model was established and treated with different doses of bevacizumab.The survival of mice was counted and subsequent experiments such as immunohistochemistry were performed on the tumor tissue of the mice to explore the effect of different bevacizumab dose on mouse survival,tumor cell proliferation,hypoxia in tumor area and normalization of tumor blood vessels.ResultChapter 1:A total of 4 studies met the inclusion criteria and a total of 552 patients were included.Compared with the standard dose bevacizumab,reduced-dose bevacizumab provided a slight protective effect on the overall survival of patients with recurrent high-grade glioma,but the difference was not statistically significant(HR 0.77;95%confidence interval 0.53 to 1.10;P=0.151).Low-dose bevacizumab reduced the risk of disease progression by 34%,but there was no statistical difference in progression-free survival(HR 0.66;95%confidence interval 0.37 to 1.20;P=0.175).Chapter 2:A total of 26 patients with recurrent glioblastoma in our center met the inclusion criteria,and the median weekly dose of bevacizumab was 2.6 mg/kg/week.The patients were divided into a low-dose bevacizumab group and a high-dose bevacizumab group according to the median bevacizumab dose.Overall survival and progression-free survival were similar between low-dose and high-dose bevacizumab groups,with P values of 0.084 and 0.232,respectively.Chapter 3:Low-dose bevacizumab(intraperitoneally twice a week at 5 mg/kg)and high-dose bevacizumab(intraperitoneally twice a week at 10 mg/kg)significantly decreased both fluorescence intensity and tumor size compared with the vehicle control group of the mouse orthotopic glioma model(P<0.01).The survival of mice in the lowdose bevacizumab group showed a relatively prolonged trend,but the difference was not statistically significant.All bevacizumab treated groups can inhibit glioma cell proliferation,induce normalization of tumor blood vessels,and alleviate tumor hypoxia.ConclusionClinical data showed that low-dose and conventional-dose bevacizumab had similar clinical efficacy.Preclinical data suggested that lower dose BEV therapy was as effective as high dosages in tumor vascular normalization.Low-dose bevacizumab is a safe and feasible treatment in patients with recurrent high-grade glioma.Further prospective randomized controlled clinical trials are needed to verify the conclusions.