Arterial Thromboembolic Events in Patients with Metastatic Carcinoma Treated with Chemotherapy and Bevacizumab

Genentech, Inc., BioOncology, 455 East Grand Ave, South San Francisco, CA 94080, USA.
Journal of the National Cancer Institute (Impact Factor: 12.58). 08/2007; 99(16):1232-9. DOI: 10.1093/jnci/djm086
Source: PubMed


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.
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.
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.
Combination treatment with bevacizumab and chemotherapy, compared with chemotherapy alone, was associated with an increased risk of arterial thromboembolism but not venous thromboembolism.

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    • "The evidence for the use of aspirin prophylaxis for ATE for patients using bevacizumab is conflicting. Scappatici et al (22) reported marginally more grade 3 and 4 bleeding events among aspirin users on bevacizumab than in the control subjects (3.7 vs. 1.8%). Conversely, a pooled analysis of low-dose aspirin for primary prophylaxis for ATEs in patients undergoing chemotherapy with bevacizumab did not identify any increased bleeding risk (23). "
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    ABSTRACT: Patients with cancer are at increased risk of thrombosis. Additionally, an increased mean platelet volume (MPV) has been demonstrated to be associated with thromboembolism. Tyrosine kinase inhibitors (TKIs) may modulate the activation of systemic coagulation in cancer patients, rendering them more susceptible to thromboembolism. The aim of the current study was to investigate the association between antiangiogenic TKIs and MPV. A total of 45 patients with metastatic renal cell carcinoma (RCC), who were treated with TKIs and were patients at the Akdeniz University Hospital and Afyon Kocatepe University Ahmet Necdet Sezer Research and Practice Hospital, were retrospectively reviewed. The results prior to treatment and after three months for the MPV values and platelet levels were evaluated. The MPV values increased following the treatment with TKIs; however, no statistically significant difference was observed between the baseline and three month values (P=0.286). Conversely, a significant decrease was observed in the platelet levels following treatment (P=0.005). Treatment with TKIs in patients with metastatic RCC caused a modest increase in MPV, which is an indicator of thrombocytic reactivity; however, further studies are required to validate these results.
    Oncology letters 11/2014; 8(5):2249-2252. DOI:10.3892/ol.2014.2495 · 1.55 Impact Factor
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    • "The safety and tolerability of anti-VEGF therapy is a concern of clinicians and patients, especially regarding arterial thromboembolic events.[37], [38] One meta-analysis showed that the intravitreal use of anti-VEGF antibodies was not associated with an increased risk of arterial thromboembolic events.[39] "
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    ABSTRACT: Background Bevacizumab is believed to be as effective and safe as ranibizumab for ophthalmic diseases; however, its magnitude of effectiveness and safety profile remain controversial. Thus, a meta-analysis and systematic review appears necessary. Methods PubMed and EMBASE were systematically searched with no restrictions. All relevant citations comparing ranibizumab and bevacizumab were considered for inclusion. Pooled effect estimates were obtained using a fixed- and random-effects meta-analysis. Results Nine independent randomised-controlled clinical trials (RCTs) involving 2,289 participants were identified. Compared with bevacizumab, the overall combined weighted mean difference (WMD) of the mean change in visual acuity for ranibizumab was 0.52 letters (95% CI −0.11–1.14). The odds ratios (ORs) of gaining ≥15, gaining 5–14, losing 5–14 and losing ≤15 letters were 1.10 (95% CI 0.90–1.33), 0.93 (95% CI 0.77–1.11), 0.89 (95% CI 0.65–1.22) and 0.95 (95% CI 0.73–1.25), respectively. The risk of serious systemic events increased by 17% (95% CI 6%–27%, p = 0.0042) for bevacizumab treatment in comparison with ranibizumab. No statistically significant differences between the two treatments were found for the nonfatal arterial thrombotic events, ocular serious adverse, death from vascular and all causes events. Conclusions Bevacizumab is not inferior to ranibizumab as a treatment for achieving visual acuity. The use of bevacizumab was associated with an increased risk of developing serious systemic events. Weighing the costs and health outcomes is necessary when selecting between bevacizumab and ranibizumab for ophthalmic diseases. Due to the limitations of the available data, further research is needed.
    PLoS ONE 07/2014; 9(7):e101253. DOI:10.1371/journal.pone.0101253 · 3.23 Impact Factor
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    • "Arterial thromboembolic events were uncommon in this study, which excluded patients with a history of these events. This was in contrast to other studies in which an increase in the incidence of thromboembolic events was observed in older patients (Scappaticci et al, 2007; Cassidy et al, 2010). Our study has some limitations. "
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    ABSTRACT: Background: Subgroup analyses of clinical studies suggest that bevacizumab plus XELOX is effective and tolerable in elderly patients with metastatic colorectal cancer (mCRC). The prospective BECOX study examined the efficacy and safety of bevacizumab plus XELOX, followed by bevacizumab plus capecitabine in elderly patients with mCRC. Methods: Patients aged ⩾70 years with Eastern Cooperative Oncology Group performance status 0 out of 1 and confirmed mCRC were included. Patients received bevacizumab 7.5 mg kg−1 and oxaliplatin 130 mg m−2 on day 1, plus capecitabine 1000 mg m−2 bid orally on days 1–14 every 21 days; oxaliplatin was discontinued after 6 cycles. The primary end point was time to progression (TTP). Results: The intent-to-treat population comprised 68 patients (65% male, median age 76 years). Median TTP was 11.1 months; median overall survival was 20.4 months; overall response rate was 46%. Grade 3 or 4 adverse events included diarrhoea (18%) and asthenia (16%). Grade 3 or 4 adverse events of special interest for bevacizumab included deep-vein thrombosis (6%) and pulmonary embolism (4%). Conclusions: Bevacizumab plus XELOX was effective and well tolerated in elderly patients in the BECOX study. The adverse-event profile was similar to previous reports; no new safety concerns were identified. Fit elderly patients with mCRC should be considered for treatment with bevacizumab plus XELOX.
    British Journal of Cancer 06/2014; 111(2). DOI:10.1038/bjc.2014.346 · 4.84 Impact Factor
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