Lani
08-07-2007, 08:42 PM
Bevacizumab Increases Risk for Arterial Thromboembolism
August 7, 2007 — Bevacizumab (Avastin, Genentech) was associated with a modest increase in the risk for arterial, but not venous, thromboembolism in a new analysis of clinical data from company-sponsored clinical trials. This adverse effect is already listed on the product's data sheet, but the new analysis provides more details and also "important information for clinicians who use bevacizumab to treat patients with metastatic cancer," according to the authors, led by company researcher Frank Scappaticci, MD, PhD.
The study was published online on August 7 in the Journal of the National Cancer Institute and is due to appear in the August 15 issue. Commenting on the paper, Genentech spokesperson Edward Lang told Medscape that the company had decided "to take another look at the data" and added that the results of this new analysis support and "are consistent with our experience."
Bevacizumab, a monoclonal antibody targeted against vascular endothelial growth factor (VEGF), acts as an angiogenesis inhibitor. In the setting of cancer, it blocks the formation of new blood vessels, and this inhibits tumor growth; the drug had significantly prolonged survival when used in combination with chemotherapy in several cancer types. However, the authors speculate that its action of interfering with VEGF may disrupt a negative feedback loop involving proinflammatory genes in the vascular endothelial cells and could lead to potential in situ thrombus formation.
In this latest analysis, the researchers pooled data from 5 randomized controlled trials involving a total of 1745 patients with metastatic colorectal, breast, or non–small-cell lung carcinoma. They compared patients treated with a combination of bevacizumab and chemotherapy with those treated with chemotherapy alone.
The absolute risk of developing an arterial thromboembolism was 5.5 events per 100 person-years for those receiving combination therapy, compared with 3.1 events per 100 person-years for those receiving chemotherapy alone (hazard ratio [HR] = 1.8; 95% CI, 0.94 – 3.33; P = .076). These rates are a little different from those in the product's data sheet (4.4% vs 1.9%), which are raw incidence rates. The authors argue that these raw incidence rates may have overestimated the risk for an arterial thromboembolic event because of the delayed time to progression in the bevacizumab-treated group and hence the correspondingly longer safety observation period in the combination-therapy group. Their calculation of the rate of events per 100 person-years partially corrects for this difference, they write.
It is also partially corrected for by using Kaplan-Meier hazard estimates, they add. Using this analysis, they found that the addition of bevacizumab increased the risk for an arterial thromboembolic event (HR = 2.0; 95% CI, 1.05 – 3.75, P = .031), but not the risk for a venous thromboembolic event (HR = 0.89; 95% CI, 0.66 – 1.20, P = .44).
Two patient groups appeared to be at a higher risk — those aged 65 years or more and those who already had a history of an arterial thromboembolic event, the authors note. However, the trials excluded any patient who had a stroke or myocardial infarction in the preceding year, and so the risk and benefit of using bevacizumab in such patients have not been established. Also, several important clinical questions cannot be answered by this analysis, they comment, including whether or not the increased risk for arterial thromboembolism varies by tumor type or different chemotherapy regimens.
A further question the authors addressed is whether there was any impact from the concomitant use of low-dose aspirin, which is now a standard of care in patients at high risk for arterial thromboembolic events. No definite conclusions can be drawn, as the number of aspirin users in these cancer trials was small, the authors comment, but they add that concomitant aspirin use did not appear to substantially alter the increased risk of bleeding attributable to bevacizumab. Aspirin was associated with a modest increase in the risk of serious bleeding in both treatment groups — in patients on bevacizumab and chemotherapy, the risk increased from 3.6% without aspirin to 4.7% with aspirin, while in patients on chemotherapy alone, the risk increased from 1.7% to 2.2%.
"Aspirin-based prophylaxis for an arterial thromboembolic event should be carefully considered for individual patients with metastatic adenocarcinoma who are at high risk for an arterial thromboembolic event and who have no contraindications for aspirin use," Dr. Scappaticci and colleagues conclude.
J Natl Cancer Inst. 2007;99:1232-1239.
August 7, 2007 — Bevacizumab (Avastin, Genentech) was associated with a modest increase in the risk for arterial, but not venous, thromboembolism in a new analysis of clinical data from company-sponsored clinical trials. This adverse effect is already listed on the product's data sheet, but the new analysis provides more details and also "important information for clinicians who use bevacizumab to treat patients with metastatic cancer," according to the authors, led by company researcher Frank Scappaticci, MD, PhD.
The study was published online on August 7 in the Journal of the National Cancer Institute and is due to appear in the August 15 issue. Commenting on the paper, Genentech spokesperson Edward Lang told Medscape that the company had decided "to take another look at the data" and added that the results of this new analysis support and "are consistent with our experience."
Bevacizumab, a monoclonal antibody targeted against vascular endothelial growth factor (VEGF), acts as an angiogenesis inhibitor. In the setting of cancer, it blocks the formation of new blood vessels, and this inhibits tumor growth; the drug had significantly prolonged survival when used in combination with chemotherapy in several cancer types. However, the authors speculate that its action of interfering with VEGF may disrupt a negative feedback loop involving proinflammatory genes in the vascular endothelial cells and could lead to potential in situ thrombus formation.
In this latest analysis, the researchers pooled data from 5 randomized controlled trials involving a total of 1745 patients with metastatic colorectal, breast, or non–small-cell lung carcinoma. They compared patients treated with a combination of bevacizumab and chemotherapy with those treated with chemotherapy alone.
The absolute risk of developing an arterial thromboembolism was 5.5 events per 100 person-years for those receiving combination therapy, compared with 3.1 events per 100 person-years for those receiving chemotherapy alone (hazard ratio [HR] = 1.8; 95% CI, 0.94 – 3.33; P = .076). These rates are a little different from those in the product's data sheet (4.4% vs 1.9%), which are raw incidence rates. The authors argue that these raw incidence rates may have overestimated the risk for an arterial thromboembolic event because of the delayed time to progression in the bevacizumab-treated group and hence the correspondingly longer safety observation period in the combination-therapy group. Their calculation of the rate of events per 100 person-years partially corrects for this difference, they write.
It is also partially corrected for by using Kaplan-Meier hazard estimates, they add. Using this analysis, they found that the addition of bevacizumab increased the risk for an arterial thromboembolic event (HR = 2.0; 95% CI, 1.05 – 3.75, P = .031), but not the risk for a venous thromboembolic event (HR = 0.89; 95% CI, 0.66 – 1.20, P = .44).
Two patient groups appeared to be at a higher risk — those aged 65 years or more and those who already had a history of an arterial thromboembolic event, the authors note. However, the trials excluded any patient who had a stroke or myocardial infarction in the preceding year, and so the risk and benefit of using bevacizumab in such patients have not been established. Also, several important clinical questions cannot be answered by this analysis, they comment, including whether or not the increased risk for arterial thromboembolism varies by tumor type or different chemotherapy regimens.
A further question the authors addressed is whether there was any impact from the concomitant use of low-dose aspirin, which is now a standard of care in patients at high risk for arterial thromboembolic events. No definite conclusions can be drawn, as the number of aspirin users in these cancer trials was small, the authors comment, but they add that concomitant aspirin use did not appear to substantially alter the increased risk of bleeding attributable to bevacizumab. Aspirin was associated with a modest increase in the risk of serious bleeding in both treatment groups — in patients on bevacizumab and chemotherapy, the risk increased from 3.6% without aspirin to 4.7% with aspirin, while in patients on chemotherapy alone, the risk increased from 1.7% to 2.2%.
"Aspirin-based prophylaxis for an arterial thromboembolic event should be carefully considered for individual patients with metastatic adenocarcinoma who are at high risk for an arterial thromboembolic event and who have no contraindications for aspirin use," Dr. Scappaticci and colleagues conclude.
J Natl Cancer Inst. 2007;99:1232-1239.