RECORD STATUS: None CITATION: Harper M L. Bevacizumab. University HealthSystem Consortium (UHC). Drug Monograph. 2002

OBJECTIVES: The purpose of this review is to discuss the side effect profile of bevacizumab, to discuss proposed mechanisms of these toxicities, and to provide suggestions for management of adverse events. METHODS: A search of MEDLINE and ASCO and SGO abstract databases of articles published between January 1970 and August 2009 addressing the toxicity of bevacizumab in solid tumors was conducted. Reporting was limited to best available evidence including any available phase III studies and ovarian cancer phase II studies. Original publications addressing underlying mechanisms of bevacizumab toxicities were included. RESULTS: Extensive experience with bevacizumab has proven the agent to be generally well tolerated, with an adverse event profile distinct from traditional cytotoxic chemotherapy and likely peculiar to its novel mechanism of action. The most common bevacizumab-attributable adverse event, hypertension, can be medically-managed, but more serious adverse events such as bowel perforation require drug discontinuation. CONCLUSIONS: Current best evidence supports the use of bevacizumab in selected patients, and safe administration of bevacizumab requires an understanding of the management of adverse events attributable to its use.

In comparing the safety of ranibizumab versus bevacizumab in age-related macular degeneration, the meta-analyses published thus far have given conflicting results, particularly about the risk of venous thrombotic events and ocular inflammation. From the comparison of the design and the findings of these meta-analysis, we tried to identify the potential explanations to account for these discrepancies. We separately evaluated the incidence of ocular inflammation with the two agents between randomized studies and non-randomized studies. While no increase in risk was found in randomized studies, non-randomized studies showed an increase in risk for bevacizumab versus ranibizumab. One interpretation of these findings is that bevacizumab itself does not represent any increase in risk of ocular inflammation and/or cardiovascular events under the rigorous conditions of a randomized study, but this agent can be at the origin of an increase in risk when administered in the nullreal worldnull; this setting could in fact leave space for less strictly controlled preparation of aliquots for intravitreal injection.

PURPOSE: The aim of this study was to assess the efficacy and safety of bevacizumab in the treatment of pterygium and to mainly explore its effects on recurrence rate and complications. METHODS: We searched MEDLINE, EMBASE, Web of Science, and Cochrane Central Register from the inception to July 2013 for relevant randomized controlled trials that examined bevacizumab therapy for pterygium. Data concerning study design, patient characteristics, treatment, and outcomes were extracted. The methodological quality of the studies included was assessed using the Jadad score. Relative risk (RR) was calculated for recurrence rate and complications. RESULTS: A total of 474 patients with 482 eyes in 9 randomized controlled trials were analyzed. The pooled estimate showed that bevacizumab had no statistically significant effect on preventing pterygium recurrence [RR 0.90, 95% confidence interval (CI) 0.77-1.07, P = 0.23]. None of the subgroup analyses yielded significant results in favor of bevacizumab (surgery group: RR 0.77, 95% CI 0.50-1.18, P = 0.23; nonsurgery group: RR 0.98, 95% CI 0.86-1.11, P = 0.76; primary pterygium group: RR 0.82, 95% CI 0.53-1.26, P = 0.36; recurrent pterygium group: RR 0.95, 95% CI 0.82-1.09, P = 0.44). There were no statistically significant differences in the complications between the 2 groups (RR 1.00, 95% CI 0.73-1.37, P = 1.00). However, the bevacizumab group was associated with a higher risk of developing subconjunctival hemorrhage (RR 3.34, 95% CI 1.07-10.43, P = 0.04). CONCLUSIONS: Topical or subconjunctival bevacizumab was relatively safe and well tolerated, but it had no statistically significant effect on preventing pterygium recurrence. A large-scale trial with a suitable dosage and a longer follow-up would be required to rule out the possibility of any treatment benefit.

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BACKGROUND: With the wide application of targeted drug therapies, the relevance of prognostic and predictive markers in patient selection has become increasingly important. Bevacizumab is commonly used in combination with chemotherapy in the treatment of metastatic colorectal cancer. However, there are currently no predictive or prognostic biomarkers for bevacizumab. Several clinical studies have evaluated bevacizumab-induced hypertension in patients with metastatic colorectal cancer. This meta-analysis was performed to better determine the association of bevacizumab-induced hypertension with outcome in patients with metastatic colorectal cancer, and to assess whether bevacizumab-induced hypertension can be used as a prognostic factor in these patients. METHODS: We performed a systematic review and meta-analysis on seven published studies to investigate the relationship between hypertension and outcome of patients with metastatic colorectal cancer treated with bevacizumab. Our primary endpoint was progression-free survival (PFS). Secondary endpoints were overall survival (OS) and overall response rate (ORR). Hazard ratios (HRs) for PFS and OS were extracted from each trial, and the log of the relative risk ratio (RR) was estimated for ORR. RESULTS: The occurrence of bevacizumab-induced hypertension in patients was highly associated with improvements in PFS (HR = 0.57, 95% CI: 0.46-0.72; P <0.001), OS (HR = 0.50; 95% CI: 0.37-0.68; P <0.001), and ORR (RR = 1.57, 95% CI: 1.07-2.30, P <0.05), as compared to patients without hypertension. CONCLUSIONS: Bevacizumab-induced hypertension may represent a prognostic factor in patients with metastatic colorectal cancer.

OBJECTIVES: Bevacizumab and erlotinib inhibit different tumour growth pathways, and both exhibit beneficial effects in the treatment of non-small-cell lung cancer (NSCLC). However, the efficacy of bevacizumab in combination with erlotinib remains controversial. Therefore, we conducted a meta-analysis to compare combination treatment with bevacizumab and erlotinib to bevacizumab or erlotinib monotherapy in the treatment of NSCLC. METHODS: Randomised controlled trials (RCTs) published in PubMed, Web of Science and EMBASE were systematically reviewed. The main outcome measures included overall survival (OS), progression-free survival (PFS), overall response rate (ORR) and adverse events. Results were expressed as HRs or risk ratios (RRs) with 95% CIs. RESULTS: 5 RCTs involving a total of 1736 patients were included in this meta-analysis. The combination of bevacizumab and erlotinib significantly improved PFS (HR=0.63, 95% CI 0.53 to 0.75; p=0.000) and the ORR (RR=1.91, 95% CI 1.19 to 3.06; p=0.007) in the second-line treatment of NSCLC compared with bevacizumab or erlotinib alone. However, no significant difference in OS was observed between the combination and monotherapy groups (HR=0.96, 95% CI 0.83 to 1.11; p=0.573). A subgroup analysis has shown that the greatest PFS benefit was associated with an age of <65 years(HR=0.74, 95% CI 0.57 to 0.96; p=0.026), Asian/Pacific Islander ethnicity (HR=0.23, 95% CI 0.10 to 0.54; p=0.001), Eastern Cooperative Oncology Group performance status (ECOG PS) 1 (HR=0.82, 95% CI 0.68 to 0.98; p=0.033), stage IIIB or IV disease (HR=0.68, 95% CI 0.57 to 0.82; p=0.000) and no history of smoking (HR=0.48, 95% CI 0.32 to 0.71; p=0.000). The incidence of grade 3/4 adverse events such as rash and diarrhoea was higher in the combination group than in the monotherapy group. CONCLUSIONS: The addition of bevacizumab to erlotinib can significantly improve PFS and the ORR in the second-line treatment of NSCLC with an acceptable and manageable risk of rash and diarrhoea. Further well-conducted, large-scale trials are needed to validate these findings.

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AIM: To assess the efficacy and safety of bevacizumab in the treatment of colorectal cancer. METHODS: All randomized controlled trials of bevacizumab for the treatment of colorectal cancer from January 2003 to June 2013 were collected by searching the Cochrane Library, PubMed, Chinese National Knowledge Infrastructure and Wanfang databases. The primary endpoint was overall survival (OS), and the secondary endpoints were progression-free survival, overall response rate and adverse events. Two reviewers extracted data independently. Statistical analyses were performed with Stata 12.0. The degree of bias was assessed using funnel plots for the effect size of OS at the primary endpoint. RESULTS: Following the inclusion criteria and exclusion criteria, ten studies comprising 6977 cases were finally included, of which nine were considered to be of high quality (4-7 points) and one of low quality (1-3 points). Our meta-analysis revealed the efficacy of bevacizumab in patients with colorectal cancer in terms of OS (HR = 0.848, 95%CI: 0.747-0.963), progression-free survival (HR = 0.617, 95%CI: 0.530-0.719), and overall response rate (OR = 1.627, 95%CI: 1.199-2.207). Regarding safety, higher rates of grade ≥ 3 hypertension, proteinuria, bleeding, thrombosis, and gastrointestinal perforation were observed in the bevacizumab treatment group (P < 0.05); however, the incidence of serious toxicity was very low. There was no publication bias in the 10 reports included in this meta-analysis. CONCLUSION: The clinical application of bevacizumab in colorectal cancer is effective with good safety.

CONTEXT AND OBJECTIVE: Many eye diseases involve increased local levels of vascular endothelial growth factor (VEGF), and there are several therapeutic strategies for them. Thus, the aim of this study was to evaluate the effectiveness and safety of bevacizumab for treating eye diseases involving increased local levels of VEGF, as the assumed pathophysiological mechanism. DATA SOURCES: The following databases were systematically searched for evidence: PubMed, CENTRAL (Cochrane Library), Literatura Latino-Americana e do Caribe em Ciências da Saúde (Lilacs) and reference lists, without language restrictions. Only randomized controlled trials were included. The primary outcome of interest was visual acuity, irrespective of the evaluation method. DATA SYNTHESIS: A total of 667 eyes in nine randomized trials were included. Meta-analysis showed that the proportion of patients with age-related macular degeneration who presented improvements from baseline regarding best-corrected visual acuity was higher among those treated with bevacizumab than among those in the photodynamic therapy group (risk ratio, RR, 0.49; 95% confidence interval, CI, 0.31 to 0.78; P = 0.01). CONCLUSIONS: The evidence available demonstrates that bevacizumab alone or combined with other treatments is more effective than other options, including photodynamic therapy, focal photocoagulation and triamcinolone. The use of bevacizumab instead of photodynamic therapy could reduce treatment costs by more than 99% and could significantly increase access to treatment. However, long-term studies are still needed in order to reduce uncertainty concerning the safety of this medication for all ocular neovascular diseases in which bevacizumab has the potential to improve visual acuity.