Journal of the National Cancer Institute Advance Access published online on August 8, 2007
JNCI Journal of the National Cancer Institute, doi:10.1093/jnci/djm086
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Arterial Thromboembolic Events in Patients with Metastatic Carcinoma Treated with Chemotherapy and Bevacizumab
Affiliations of authors: Genentech, Inc, South San Francisco, CA (FAS, JRS, SNH, HPG, JN, EH, JW); Indiana Cancer Pavilion, Indianapolis, IN (KM); Department of Medicine, University of California at Los Angeles, Los Angeles, CA (FK); University of California at San Francisco Cancer Center, San Francisco, CA (EB); Duke University Medical Center, Durham, NC (HH)
Correspondence to: Frank A. Scappaticci, MD, PhD, Genentech, Inc, BioOncology, 455 East Grand Ave, South San Francisco, CA 94080 (e-mail: anthon{at}gene.com).
Background: Although combination treatment with bevacizumab (humanized monoclonal antibody against vascular endothelial growth factor) and chemotherapy improves survival of patients with various metastatic carcinomas, an increased risk of arterial thromboembolic events has been observed in some trials. We characterized this risk by performing post hoc analyses of randomized controlled trials that evaluated combination treatment with bevacizumab and chemotherapy versus chemotherapy alone. Low-dose aspirin was permitted in these trials, and its safety was also analyzed.
Methods: Data were pooled from five randomized controlled trials that included a total of 1745 patients with metastatic colorectal, breast, or non–small-cell lung carcinoma. The risk of an arterial or venous thromboembolic event was assessed by simple incidence rates, rates per 100 person-years, and/or hazard ratios (HRs). The association between patient characteristics and risk of an arterial thromboembolic event was investigated primarily by Cox proportional hazards regression. The relationship between low-dose aspirin and bleeding was explored by incidence rates and rates per 100 person-years.
Results: Combined treatment with bevacizumab and chemotherapy, compared with chemotherapy alone, was associated with increased risk for an arterial thromboembolic event (HR = 2.0, 95% confidence interval [CI] = 1.05 to 3.75; P = .031) but not for a venous thromboembolic event (HR = 0.89, 95% CI = 0.66 to 1.20; P = .44). The absolute rate of developing an arterial thromboembolism was 5.5 events per 100 person-years for those receiving combination therapy and 3.1 events per 100 person-years for those receiving chemotherapy alone (ratio = 1.8, 95% CI = 0.94 to 3.33; P = .076). Development of an arterial thromboembolic event was associated with a prior arterial thromboembolic event (P<.001) or age of 65 years or older (P = .01). Baseline or on-study aspirin use was associated with modest increases in grade 3 and 4 bleeding events in both treatment groups, from 3.6% to 4.7% for bevacizumab-treated patients and from 1.7% to 2.2% for control subjects.
Conclusions: Combination treatment with bevacizumab and chemotherapy, compared with chemotherapy alone, was associated with an increased risk of arterial thromboembolism but not venous thromboembolism.
| CONTEXT AND CAVEATS Prior knowledge An increased risk of arterial thromboembolic events had been observed in some clinical trials of combination treatment with bevacizumab (humanized monoclonal antibody against vascular endothelial growth factor) and chemotherapy in patients with various metastatic carcinomas. Study design Pooled analysis of five randomized controlled trials that included a total of 1745 patients with metastatic cancer Contribution Combination treatment with bevacizumab and chemotherapy, compared with chemotherapy alone, was associated with a modest increase in the risk of arterial thromboembolism but not venous thromboembolism. The absolute rate of developing an arterial thromboembolic event was 5.5 per 100 person-years for those in the bevacizumab group and 3.1 for those in the chemotherapy-alone group. Risk factors associated with an arterial thromboembolic event were history of an arterial thromboembolic event and age 65 years or older. Implications The risk factors for arterial thromboembolism should be considered when making treatment decisions for individual patients. Limitations Raw incidence rates may have overestimated the risk of an arterial thromboembolic event because of the delayed time to progression in the bevacizumab-treated group compared with the control group. Associations between risk of an arterial thromboembolic event and different tumor or histologic types, between risk and different chemotherapeutic agents combined with bevacizumab, and between risk and different disease settings (especially, metastatic versus adjuvant settings) could not be assessed.
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Manuscript received October 25, 2006; revised June 12, 2007; accepted July 3, 2007.
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J Natl Cancer Inst 2007 99: 1213.
J Natl Cancer Inst 2007 99: 1213.
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