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Bevacizumab-related Mortality in Patients with Cancer

Bevacizumab is a humanized monoclonal antibody that targets vascular endothelial growth factor (VEGF). It was approved in the first-line setting for treatment of metastatic colorectal cancer (mCRC) in combination with intravenous 5-flurouracil in 2004. In 2006, it gained additional approval in mCRC as a second-line agent in those patients who did not receive it initially. It has also received approval in non-squamous non-small cell lung cancer, glioblastoma, metastatic breast cancer and metastatic renal cell carcinoma.1

The inhibition of angiogenesis and alteration of vascular function with bevacizumab has been associated with serious adverse events such as wound dehiscence, bleeding, thromboembolic events, bowel perforation and neutropenia. Some of these toxicities have resulted in a black box warning within the prescribing information for bevacizumab, which includes: gastrointestinal perforation, surgery and wound healing complications and hemorrhage.1 Fatal adverse events (FAEs) have also been reported in patients treated with bevacizumab; however its definitive role remains unclear.

In order to understand the overall risk of FAEs with bevacizumab, Ranpura and colleague conducted a systematic review and meta-analysis of 16 published randomized controlled trials (RCTs) across a variety of advanced solid tumors.2 All RCTs included were prospective phase II or III trials studying bevacizumab in combination with chemotherapy or biologic therapy compared with chemotherapy or biologic therapy alone. FAEs were defined as deaths which were related to adverse events reported according to the National Cancer Institute’s Common Terminology Criteria for Adverse Events (CTCAE) version 2 or 3.3 Of the 10,217 patients included, a total of 5589 patients were available for analysis. From this pool there were 148 FAEs reported.

The highest incidence of FAEs was in a phase II lung cancer trial4 (13.4%; 95% CI, 7.1%-23.8%) and the lowest incidence was in a phase III breast cancer trial where no FAEs occurred.5  The relative risk of FAEs in the 16 RCTs was 1.46 (95% CI, 1.09-1.94; P = .01; incidence 2.5% vs. 1.7%). These findings suggest significantly increased risk of FAEs when bevacizumab is added to chemotherapy or another biologic. Patients with squamous cell histology of lung cancer can not be treated with bevacizumab related to the risk of pulmonary hemorrhage. In trials with increased dose of bevacizumab to an equivalent of 5mg/kg weekly, patients were at a substantially higher risk of FAEs with a relative risk (RR) of 2.55 (95% CI, 1.44-4.53; P =.001; incidence, 2.7% vs. 1.1%). Those receiving lower dosing of bevacizumab at 2.5mg/kg per week were not associated with an increased risk of FAEs (RR, 1.36; 95% CI, 0.87-2.12; P =.17; incidence, 1.6% vs. 1.2%).  The highest RR for FAEs by tumor type was prostate and lung cancer. Tumor types with the lowest risk were renal cell carcinoma and breast cancer. The risk of FAEs according to chemotherapy regimen was higher in the platinum and taxane-based regimens versus other classes. This finding was statistically significant. Hemorrhage, pulmonary hemorrhage and gastrointestinal perforation were the top three FAEs associated with bevacizumab.

ManageCRC Commentary

While the data suggest benefit of bevacizumab in a variety of solid tumor indications, it is imperative for physicans, nurses and patients to recognize the potential associated adverse events. Appropriate selection of patients is critical to minimizing risk. Additionally, thorough assessment of patient reports prior to and between treatments is essential to optimal outcomes. Through these efforts it may be possible to identify potential FAEs and intervene prior to critical or fatal sequelae.


  1. Genentech. Avastin (bevacizumab) prescribing information. 2011. Link to prescribing information: http://www.gene.com/gene/products/information/pdf/avastin-prescribing.pdf
  2. Ranpura V, Sanjaykumar H, & Shenhong W. Treatment-related mortality with bevacizumab in cancer patients: A meta-analysis. JAMA. 2011; 305:487-494. doi:10.1001/jama.2011.5  Link to abstract http://jama.ama-assn.org/content/305/5/487.short
  3. National Cancer Institute. National Cancer Institute Common Toxicity Criteria. Available at: http://ctep.cancer.gov/protocoldevelopment/electronic_applications/docs/ctcv20_4-30-992.pdf (version 2.0, 1999) and http://ctep.cancer.gov/protocoldevelopment/electronic_applications/docs/ctcaev3.pdf(version 3.0, 2006)
  4. Johnson DH, Fehrenbacher L, Novotny WF, et al. Randomized phase II trial comparing bevacizumab plus carboplatin and paclitaxel with carboplatin and paclitaxel alone in previously untreated locally advanced or metastatic non-small-cell lung cancer. J Clin Oncol. 2004; 22:2184-2191. doi:10.1200/JCO.2004.11.022   Link to abstract http://jco.ascopubs.org/content/22/11/2184.abstract
  5. Miller KD, Chap LI, Holmes FA, et al. Randomized phase III trial of capecitabine compared with bevacizumab plus capecitabine in patients with previously treated metastatic breast cancer. J Clin Oncol. 2005; 23: 792-799. doi:10.1200/JCO.2005.05.098  Link to abstract http://jco.ascopubs.org/content/23/4/792

Article Created On : 3/10/2011 1:26:38 PM             Article Updated On : 3/10/2011 1:26:38 PM