Arterial thromboembolic events in patients with metastatic carcinoma treated with chemotherapy and bevacizumab.
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.
Scappaticci
Frank A
FA
Genentech, Inc., BioOncology, 455 East Grand Ave, South San Francisco, CA 94080, USA. anthon@gene.com
Skillings
Jamey R
JR
Holden
Scott N
SN
Gerber
Hans-Peter
HP
Miller
Kathy
K
Kabbinavar
Fairooz
F
Bergsland
Emily
E
Ngai
James
J
Holmgren
Eric
E
Wang
Jiuzhou
J
Hurwitz
Herbert
H
D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001157:Arterial Occlusive Diseases / Q000453:epidemiology*; D001241:Aspirin / Q000008:administration & dosage; D000068258:Bevacizumab; D002277:Carcinoma / Q000188:drug therapy* / Q000556:secondary*; D005260:Female; D006470:Hemorrhage / Q000453:epidemiology; D006801:Humans; D015994:Incidence; D008297:Male; D016032:Randomized Controlled Trials as Topic; D012307:Risk Factors; D013923:Thromboembolism / Q000453:epidemiology*; D020246:Venous Thrombosis / Q000453:epidemiology
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D000068258:Bevacizumab; D001241:Aspirin