Bevacizumab Boosts Stroke and MI Risk in Metastatic Cancer

SOUTH SAN FRANCISCO, Aug. 7 -- When bevacizumab (Avastin) is added to chemotherapy for metastatic cancer it raises the risks of heart attacks, strokes, and other arterial thromboembolic events, found researchers here.
In a pooled retrospective analysis of suggestive safety data from five Genentech-sponsored individual trials, combination therapy with bevacizumab doubled the risk of thromboembolic events compared with chemotherapy alone (P=0.031), found Frank A. Scappaticci, M.D., Ph.D., of Genentech here, and colleagues.
Despite these risks, bevacizumab is still beneficial for overall and progression-free survival in metastatic cancer, Dr. Scappaticci and colleagues said in the Aug. 15 issue of the Journal of the National Cancer Institute. Physicians should consider the risk for individual patients, they wrote.
The analysis included trials that randomized a total of 1,745 patients with metastatic colorectal cancer, breast cancer, or non-small-cell lung cancer to treatment with bevacizumab plus chemotherapy or with chemotherapy alone.
Nearly all patients (94%) were given 5-FU- (Adrucil) or capecitabine- (Xeloda) based chemotherapy.
The researchers identified 13 events in the control group and 37 in the combination therapy group by searching study databases for angina, arterial thrombosis, cerebral infarct or ischemia, MI, cerebrovascular accident, and myocardial ischemia. Most events were MI (or angina) or stroke (or transient ischemic attack).
The addition of bevacizumab increased the arterial thromboembolic event rate from 1.7% for chemotherapy alone to 3.8% (difference 2.1%, 95% confidence interval 0.7% to 3.7%) for a doubling in risk (hazard ratio 2.0, P=0.031).
The absolute rate similarly increased 1.8-fold with bevacizumab, though this was not a statistically significant difference (5.5 events per 100 person-years of exposure versus 3.1 for chemotherapy alone, P=0.076).
Thirty-day mortality from arterial thromboembolic events was likewise elevated among bevacizumab-treated patients (0.62% versus 0.26% among controls).
Venous thromboembolism--although substantially more common at almost 10% of patients -- did not show the same pattern of elevated risk. The occurrence rate of grade 3 or 4 venous thromboembolic events was comparable between groups (9.97% with bevacizumab versus 9.85% without it, HR 0.89, P=0.44).
They calculated point estimates of benefit accounting for thromboembolic risk in one of the colorectal cancer trials and found "clinically and statistically significant improvements" for the bevacizumab combination compared with chemotherapy alone.
Tumor progression events were less common with bevacizumab plus chemotherapy than with chemotherapy alone (HR 0.54, 95% CI 0.45 to 0.66) as were events impacting overall survival (HR 0.66, 95% CI 0.54 to 0.81).
Adjusting for arterial thromboembolic events eliminated the overall benefit for the subgroup of patients ages 65 or older with a prior arterial thromboembolic event (HR 0.55 for progression-free survival, 95% CI 0.22 to 1.37, and 0.59 for overall survival events, 95% CI 0.27 to 1.28).
"Nevertheless, the point estimates of benefit in this group were consistent with the overall population," the researchers said, leading them to conclude, "the risks and benefits for bevacizumab treatment were consistent across all subgroups examined."
In multivariate analysis, these patient groups were also at significantly elevated risk of arterial thromboembolic events (P<0.001 for prior arterial thromboembolic event and P=0.01 for age 65 or older).
Subgroup analyses showed the same trend, though not significant, in rates for older patients (4.7 per 100 person-years for controls versus 10.0 with bevacizumab, P=0.082), those with a history of arterial thromboembolic (5.9 versus 24.4, P=0.060), and those with both risk factors (3.6 versus 27, P=0.052).
The concomitant use of bevacizumab, chemotherapy, and aspirin did not appear to substantially increase the risk of serious bleeding compared with the use of aspirin and chemotherapy alone. In addition, the small number of arterial thromboembolic events and also of aspirin users in our study did not allow definitive conclusions about the prophylactic benefit of aspirin.
However, they pointed out that "the use of low-dose aspirin for the prophylaxis of arterial thromboembolic events in high-risk patients is supported by an extensive body of literature and is a recommended standard of care."
"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," the researchers concluded.
They cautioned that the raw incidence rates in their analyses may overestimate risks with bevacizumab "because of the delayed time to progression and correspondingly longer safety observation period" for combination therapy patients.
But, they also noted that the study did not consider functional disabilities caused by these events and did not include patients with stroke or MI in the year prior to trial enrollment.
Other important clinical questions remain as well, the investigators wrote. These include whether arterial thromboembolic risk varies by tumor type, different chemotherapy agents when combined with bevacizumab, or other disease settings (such as adjuvant treatment).
Nevertheless, the findings will be useful for clinicians who treat patients with metastatic cancer, they concluded.
"The risk factors for arterial thromboembolism should be considered when making treatment decisions for individual patients," they wrote.
The study was funded and written with assistance from Genentech and Roche. Genentech also designed, oversaw, and participated in the study. Dr. Scappaticci and three other researchers reported owning stock in Genentech. Researchers also reported conflicts of interest for Genentech, Pfizer, Roche, GlaxoSmithKline, Bristol-Myers Squibb, Amgen, and Entremed. Genentech supported all clinical trials in the pooled analyses. Primary source: Journal of the National Cancer InstituteSource reference: Scappaticci FA, et al "Arterial Thromboembolic Events in Patients with Metastatic Carcinoma Treated with Chemotherapy and Bevacizumab" J Natl Cancer Inst 2007;99:1232-1239.