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Risk of bleeding associated with antiangiogenic monoclonal antibodies bevacizumab and ramucirumab: a meta-analysis of 85 randomized controlled trials
Authors Xiao B, Wang W, Zhang D
Received 21 February 2018
Accepted for publication 23 May 2018
Published 21 August 2018 Volume 2018:11 Pages 5059—5074
DOI https://doi.org/10.2147/OTT.S166151
Checked for plagiarism Yes
Review by Single anonymous peer review
Peer reviewer comments 2
Editor who approved publication: Prof. Dr. Geoffrey Pietersz
Bingkun Xiao,1 Weilan Wang,2 Dezhi Zhang3
1Department of Pharmaceutical Sciences, Beijing Institute of Radiation Medicine, Beijing, China; 2Department of Pharmacy, Chinese PLA General Hospital, Beijing, China; 3Department of Pharmacy, The 264th Hospital of PLA, Taiyuan, Shanxi, China
Aim: Bevacizumab and ramucirumab are antiangiogenic monoclonal antibodies, which target vascular endothelial growth factor-A and vascular endothelial growth factor receptor-2, respectively, used in various cancers. Bleeding events have been described with these two agents. We conducted an up-to-date meta-analysis to determine the relative risk (RR) associated with the use of antiangiogenic monoclonal antibodies, bevacizumab and ramucirumab.
Methods: This meta-analysis of randomized controlled trials was performed after searching PubMed, American Society for Clinical Oncology Abstracts, European Society for Medical Oncology Abstracts, and the proceedings of major conferences for relevant clinical trials. RR and 95% CIs were calculated by random-effects or fixed-effects models for all-grade and high-grade bleeding events related to the angiogenesis inhibitors.
Results: Eighty-five randomized controlled trials were selected for the meta-analysis, covering 46,630 patients. The results showed that antiangiogenic monoclonal antibodies significantly increased the risk of all-grade (RR: 2.38, 95% CI: 2.09–2.71, p<0.00001) and high-grade (RR: 1.71, 95% CI: 1.48–1.97, p<0.00001) bleeding compared with control arms. In the subgroup analysis, bevacizumab significantly increased the risk of all-grade (RR: 2.73, 95% CI: 2.24–3.33, p<0.00001) and high-grade bleeding (RR: 1.98, 95% CI: 1.68–2.34, p<0.00001), but ramucirumab only increased the risk of all-grade bleeding (RR: 1.94, 95% CI: 1.76–2.13, p<0.00001) and no difference was observed for the risk of high-grade bleeding (RR: 1.04, 95% CI: 0.78–1.39, p=0.79) compared with the control group. For lung cancer patients, bevacizumab significantly increased the risk of all-grade (RR: 4.72, 95% CI: 1.99–11.19, p=0.0004) and high-grade pulmonary hemorrhage (RR: 3.97, 95% CI: 1.70–9.29, p=0.001), but no significant differences in the risk of all-grade (RR: 1.09, 95% CI: 0.76–1.57, p=0.64) and high-grade (RR: 1.22, 95% CI: 0.35–4.21, p=0.75) pulmonary hemorrhage were observed for ramucirumab. The increased risk of all-grade and high-grade bleeding was also observed in colorectal cancer or non-colorectal tumors and low-dose or high-dose angiogenesis inhibitors.
Conclusion: Antiangiogenic monoclonal antibodies are associated with a significant increase in the risk of all-grade and high-grade bleeding. Ramucirumab may be different from bevacizumab in terms of the risk of high-grade bleeding and the risk of all-grade and high-grade pulmonary hemorrhage in lung cancer patients.
Keywords: bevacizumab, ramucirumab, antiangiogenic monoclonal antibodies, bleeding, meta-analysis
Introduction
Angiogenesis is a complex biological process that plays an important role in sustaining growth, invasion, and the metastatic potential of tumors, and this process is mainly driven by vascular endothelial growth factor (VEGF).1,2 One of the VEGF family members, VEGF-A (commonly referred to as VEGF), has been demonstrated to be important in angiogenesis. Among all receptors, vascular endothelial growth factor receptor (VEGFR)-2 is widely thought to be principally linked to the stimuli of angiogenesis in malignancies. Blocking the function of VEGF-A or its receptor VEGFR-2 has been the most important antiangiogenic strategy for cancer therapy.3
Bevacizumab and ramucirumab are the most important antiangiogenic monoclonal antibodies, which target VEGF-A and its receptor VEGFR-2, respectively, used in various cancers. Bevacizumab is approved by the Food and Drug Administration (FDA) for the treatment of patients with metastatic colorectal cancer, advanced non-squamous non-small cell lung cancer (NSCLC), metastatic renal cell carcinoma, recurrent glioblastoma, advanced cervical cancer, and platinum-resistant ovarian cancer, and ramucirumab is approved by the FDA for the treatment of advanced gastric or gastroesophageal junction adenocarcinoma, metastatic NSCLC, and advanced colorectal cancer.
Bleeding events are a kind of major adverse events reported in clinical trials of bevacizumab and ramucirumab, which may cause severe outcomes that could be even life threatening.4 The main mechanism of bleeding is that angiogenesis inhibitors disrupt tumor vasculature through inhibition of VEGF signaling and lead to thrombosis or bleeding.1,5
However, the relative risk (RR) of bleeding events in patients with cancer treated with these two antiangiogenic monoclonal antibodies has yet to be defined. Therefore, we conducted an up-to-date meta-analysis of available clinical trials to determine the RR of bleeding in cancer patients treated with antiangiogenic monoclonal antibodies, bevacizumab and ramucirumab.
Materials and methods
Search strategy
This study was conducted in accordance with the guidelines of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement6 (Supplementary material). We searched PubMed, American Society for Clinical Oncology Abstracts, and European Society for Medical Oncology Abstracts for relevant trials till September 2017. Moreover, we also searched the clinical trial registration website (https://www.ClinicalTrials.gov) to obtain information on registered randomized controlled trials (RCTs). Keywords used in the search were “bevacizumab,” “avastin,” “ramucirumab,” “IMC1121B,” “LY3009806,” and “randomized controlled trials.” The search was limited to RCTs published in English.
Selection of trials
Data abstraction and quality assessment were conducted independently by two reviewers. Disagreements were resolved by discussion with an independent expert. The RCTs were eligible for inclusion in our meta-analysis: 1) prospective Phase II and Phase III RCTs in patients with cancer, 2) random assignment of participants to these two antiangiogenic monoclonal antibodies treatment or control groups, 3) available data, including the event or incidence of bleeding and sample size for analysis. Phase I and single-arm phase II trials were excluded because of their lack of control groups.
Data extraction
We extracted details on study characteristics, treatment information, results, and safety profiles from the selected trials. Clinical endpoints were obtained from the safety profile of each clinical trial. All-grade, high-grade bleeding and all-grade, high-grade pulmonary hemorrhage in lung cancers were recorded according to the version of National Cancer Institute-Common Terminology Criteria for Adverse Events used in each trial.
Statistical analysis
Data were calculated by Review Manager version 5.2 (The Nordic Cochrane Centre, Copenhagen, Denmark). For the outcomes, the RR was calculated for dichotomous data. Statistical heterogeneity in the results of the trials was assessed by the chi-square test, and expressed by the I2 index.7 When there was no statistically significant heterogeneity, a pooled effect was calculated with a fixed-effect model. When considerable heterogeneity was found (p<0.1, or I2>50%), a random-effect model was employed. Subgroup analysis was conducted to examine whether the RRs of all-grade and high-grade bleeding varied by drug type, drug dosage, and cancer type.
Results
Search results
We reviewed 2,045 potentially relevant articles from our initial search strategies. A total of 1,906 articles were excluded on screening abstracts and titles for the following reasons: review articles, case reports, basic researches, Phase I or single-arm Phase II studies, irrelevant topics, and duplicate reports. The remaining 139 articles were retrieved for full evaluation, and 54 articles were excluded for unavailable data for assessment of bleeding or antiangiogenic monoclonal antibodies in both treatment and control arms. Finally, 85 RCTs were included in this meta-analysis.8–92 The study search process is shown in a flow chart (Figure 1).
 | Figure 1 Outline of the search flow diagram. |
Patients
A total of 85 studies and 46,630 patients were included for the analysis. Bevacizumab was investigated in 72 trials8–79 and ramucirumab was investigated in 13 trials.80–92 All of the studies included 21 colorectal cancer,8–26,85,86 15 breast cancer,27–39,87,88 16 lung cancer,40–52,80–82 three renal cell cancer,53,54 two pancreatic cancer,55,56 five ovarian cancer,57–61 six gastric or gastroesophageal junction adenocarcinoma,62–65,89–91 three glioblastoma,66–68 one lymphoma,69 one lymphocytic leukemia,70 two melanoma,71,72 two malignant mesothelioma,73,74 one prostate cancer,75 one cervical cancer,76 one leiomyosarcoma,77 two urothelial carcinoma,83,84 two hepatocellular carcinoma,78,92 and one soft tissue sarcoma.79 In addition, 35 trials9,10,12–20,22–26,46,49,52,55,58,62–65,72,78–84,87,88 were treated with low-dose drugs (28 trials for bevacizumab at 2.5 mg/kg/week, seven trials for ramucirumab at 3.3 mg/kg/week) and 46 trials11,21,27,28,30–39,41,42,44,45,47,48,50,51,53,54,56,57,59–61,66–71,73–77,85,86,89–92 were treated with high-dose drugs (40 trials for bevacizumab at 5 mg/kg/week, six trials for ramucirumab at 4 mg/kg/week). Other 4 three-arm trials8,29,40,43 were two arms of different dosage levels of bevacizumab and one arm of control. All of these RCTs were judged to be of adequate quality (Jadad score is 3–5). Baseline characteristics of the 85 RCTs are provided in Table 1.
 | Table 1 Characteristics of studies included in the meta-analysis |
RR of all-grade bleeding
Forty-three RCTs were available to calculate the RR of all-grade bleeding in patients assigned to angiogenesis inhibitors arms versus control arms. The results showed that antiangiogenic monoclonal antibodies significantly increased the risk of all-grade (RR: 2.38, 95% CI: 2.09–2.71, p<0.00001) bleeding compared with control arms. There was statistically significant heterogeneity (I2=74%) across the trials; we incorporated it into a random-effects model (Figure 2).
 | Figure 2 RR of all-grade bleeding. |
RR of high-grade bleeding
The RR of high-grade (≥grade 3) bleeding was determined in 82 RCTs. The results showed that antiangiogenic monoclonal antibodies significantly increased the risk of all-grade bleeding (RR: 1.71, 95% CI: 1.48–1.97, p<0.00001) with a fixed-effects models (I2=19%) (Figure 3).
 | Figure 3 RR of high-grade bleeding. |
RR according to drug type
As an exploratory analysis, patients were stratified according to drug type. We found that bevacizumab significantly increased the risk of all-grade (RR: 2.73, 95% CI: 2.24–3.33, p<0.00001) and high-grade bleeding (RR: 1.98, 95% CI: 1.68–2.34, p<0.00001), but ramucirumab only increased the risk of all-grade bleeding (RR: 1.94, 95% CI: 1.76–2.13, p<0.00001) and no difference was observed for the risk of high-grade bleeding (RR: 1.04, 95% CI: 0.78–1.39, p=0.79) compared with the control group. RR of all-grade and high-grade bleeding according to drug type is summarized in Tables 2 and 3, respectively.
 | Table 2 RR of all-grade bleeding associated with angiogenesis inhibitors in the subgroup analysis |
 | Table 3 RR of high-grade bleeding associated with angiogenesis inhibitors in the subgroup analysis |
In addition, we further assessed the risk of pulmonary hemorrhage of bevacizumab and ramucirumab in all lung cancer patients. The results showed that bevacizumab significantly increased the risk of all-grade (RR: 4.72, 95% CI: 1.99–11.19, p=0.0004) and high-grade pulmonary hemorrhage (RR: 3.97, 95% CI: 1.70–9.29, p=0.001), but no significant differences in the risk of all-grade (RR: 1.09, 95% CI: 0.76–1.57, p=0.64) and high-grade (RR: 1.22, 95% CI: 0.35–4.21, p=0.75) pulmonary hemorrhage were observed for ramucirumab. RR of all-grade and high-grade pulmonary hemorrhage is shown in Figures 4 and 5, respectively.
 | Figure 4 RR of all-grade pulmonary hemorrhage. |
 | Figure 5 RR of high-grade pulmonary hemorrhage. |
RR according to drug dosage
In the subgroup analysis by dosage, the increased risk of all-grade and high-grade bleeding was observed in both low-dose and high-dose angiogenesis inhibitors.
The risks of all-grade bleeding were comparable between patients with low-dose angiogenesis inhibitors (RR: 2.46, 95% CI: 1.95–3.11) and high-dose angiogenesis inhibitors (RR: 2.34, 95% CI: 2.00–2.73) (Table 2). The risk of high-grade bleeding was more frequently observed in patients with high-dose angiogenesis inhibitors (RR: 2.17, 95% CI: 1.79–2.64) than in those with low-dose angiogenesis inhibitors (RR: 1.31, 95% CI: 1.06–1.60) (Table 3).
RR according to tumor type
Studies were further stratified according to tumor type (colorectal cancer vs non-colorectal tumors). Increased risk of all-grade and high-grade bleeding was observed in both the colorectal cancer arm and non-colorectal tumors arm. The risks of all-grade (RRs for colorectal cancer and non-colorectal tumors were 2.24, 95% CI: 1.58–3.19 and 2.42, 95% CI: 2.09–2.80, respectively) (Table 2) and high-grade bleeding (RRs for colorectal cancer and non-colorectal tumors were 1.52, 95% CI: 1.13–2.03 and 1.77, 95% CI: 1.50–2.09, respectively) (Table 3) were comparable between patients with colorectal cancer and non-colorectal tumors.
Publication bias
To minimize publication bias, we selected papers strictly according to the inclusion criteria. Furthermore, a funnel plot was used to detect publication bias and no apparent bias was found according to it for all-grade and high-grade bleeding.
Discussion
To the best of our knowledge, this is the first and the largest meta-analysis to assess the risk of bleeding associated with antiangiogenic monoclonal antibodies bevacizumab and ramucirumab. The results of our meta-analysis showed a significant 2.38-fold increased all-grade bleeding risk and a 1.71-fold increased high-grade bleeding risk with these agents. A similar risk of bleeding is also associated with other VEGF receptor tyrosine kinase inhibitors.93
In order to identify potential risk factors, we performed subgroup analysis according to drug types. The results showed that ramucirumab differed from bevacizumab in terms of the risk of high-grade bleeding and the risk of all-grade and high-grade pulmonary hemorrhage in lung cancer patients. The mechanisms underlying these differences remained unclear. A possible explanation was that bevacizumab, as an anti-VEGF-A agent, specified both VEGFR-1 and VEGFR-2, whereas ramucirumab was only specified for VEGFR-2. VEGFR-2 was the major mediator of VEGF-driven responses in endothelial cells. The precise function of VEGFR-1 was not entirely established and some studies showed that VEGFR-1 could also regulate proliferation and survival of endothelial cells.94–97 Increased level of tumor VEGFR-1 expression has been shown to be associated with high tumor angiogenesis.96 VEGF/VEGFR-1 signaling-mediated tumor cell monocyte chemoattractant protein-1 expression could represent a mechanism responsible for the tumor angiogenic switch.97 Therefore, bevacizumab increased the risk of bleeding by inhibiting both VEGFR-1 and VEGFR-2. Squamous cell tumors are more frequently centrally located and have a greater tendency to cavitate as compared to adenocarcinoma, which is the main risk factor of pulmonary hemorrhage.98 The difference in the risk of pulmonary hemorrhage caused bevacizumab to be used only for non-squamous NSCLC and ramucirumab to be used for any tumor histology of NSCLC.
Our study also demonstrated that both low-dose and high-dose angiogenesis inhibitors increased the risk of bleeding. The risk of high-grade bleeding was more frequently observed in patients with high-dose angiogenesis inhibitors, suggesting that the risk may be dose-dependent and close supervision and careful management should be emphasized especially in patients with high dosage.
In a meta-analysis of bevacizumab, patients with colorectal cancer were found to have the highest risk of bleeding compared to other tumors.99 For colorectal cancer patients, high-grade bleeding such as perforation was commonly fatal and life threatening.100 Therefore, we performed a subgroup analysis according to colorectal cancer and non-colorectal tumors in order to identify the potential risk factors. Results showed that the risk of all-grade and high-grade bleeding was comparable between patients with colorectal cancer and non-colorectal tumors, suggesting that the increased risk of bleeding is associated with many tumor types.
Limitations
There are several limitations in this meta-analysis. First, we performed stratification analysis only for colorectal cancer and non-colorectal tumor types because too many tumor types were included in the analysis and assessment was difficult. Second, we did not evaluate the risk of pulmonary hemorrhage between bevacizumab and ramucirumab in lung squamous cell carcinoma patients due to the small sample size or absence of original data. Finally, our literature search was limited to articles published in English leading to some selection bias.
Conclusion
Despite the limitations of our meta-analysis, we conclude that antiangiogenic monoclonal antibodies are associated with a significant increase in the risk of all-grade and high-grade bleeding. Ramucirumab may be different from bevacizumab in terms of the risk of high-grade bleeding and the risk of all-grade and high-grade pulmonary hemorrhage in lung cancer patients. Clinicians should be aware of this adverse effect and ensure close monitoring, especially in patients at high risk.
Acknowledgment
This study was supported by the Beijing Natural Science Foundation (7142125).
Disclosure
The authors report no conflicts of interest in this work.
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