The study reviewed here found that people who got Avastin (chemical name: bevacizumab) as part of a cancer treatment plan were about 30% more likely to develop a serious blood clot in a vein compared to people being treated for the same type of cancer who didn't get Avastin. Doctors call a blood clot in a vein a venous thromboembolism.
Avastin is a targeted therapy approved by the U.S. Food and Drug Administration to be used in combination with Taxol (chemical name: paclitaxel) to treat people with advanced (metastatic) HER2-negative breast cancer who haven't yet received chemotherapy. Avastin also is used to treat other advanced cancers, including lung, colon, and kidney cancer. Avastin is given intravenously.
Avastin works by blocking the growth of new blood vessels in a cancer tumor. (Growing new blood vessels is called angiogenesis). With no new blood vessels, the cancer doesn't get the nutrients it needs to grow. Cancer cells can make a protein, called vascular endothelial growth factor (VEGF), to make angiogenesis happen. Avastin blocks the VEGF protein. Researchers think that blocking the VEGF protein may make blood clots in veins more likely to form, which is why the risk of venous thromboembolism is higher in people treated with Avastin.
Common side effects of Avastin include high blood pressure, nosebleeds, and extra protein in the urine. People treated with Avastin also may have weakness, pain, and diarrhea. Other possible side effects are more serious, including a higher risk of stroke or heart problems, kidney malfunction, and reduced white blood cell count.
Doctors thought Avastin might increase the risk of developing a serious blood clot in a vein, but the research results were mixed. The results from the study reviewed here strongly suggest that Avastin DOES increase the risk of a blood clot in a vein.
The researchers looked at information from 15 studies involving almost 8,000 people being treated with Avastin for cancer (including breast cancer). Overall, the risk of getting a blood clot in a vein was about 30% higher in people treated with Avastin compared to people who didn't get Avastin. But the increase in blood clot risk was different depending on the type of cancer being treated. The highest risk of a blood clot was seen when Avastin was used to treat colon cancer and certain lung cancers. The risk of a blood clot wasn't as high when Avastin was used to treat breast cancer.
Symptoms of blood clots in the leg or the arm include:
A blood clot that breaks free and travels to the lungs can be serious and even life threatening. A blood clot in the lungs can cause chest pain, shortness of breath, and a decrease in blood oxygen levels. These symptoms can develop suddenly or gradually over time.
People being treated for breast and other cancers have a higher than average risk of developing venous thromboembolism. Many factors add to this higher risk:
The best way to deal with a blood clot in a vein is to stop it from happening. Talk to your doctor about your venous thromboembolism risk and ask how you can manage that risk.
Visit the blood clots page in the Breastcancer.org Side Effects section to read some general tips on how to prevent blood clots.
STONY BROOK, N.Y., Nov. 18 (MedPage Today) -- Bevacizumab (Avastin) raised the risk of venous thromboembolism by more than 30% regardless of dose in a meta-analysis, researchers here said.
Cancer patients treated with the drug had a relative risk for venous thromboembolism of 1.33 (95% CI 1.13 to 1.56) compared with control patients when data from 15 published trials involving nearly 8,000 patients were combined, Shenhong Wu, M.D., Ph.D., of the State University of New York at Stony Brook, and colleagues found.
The risk was virtually identical at a bevacizumab dose of 2.5 and 5 mg/kg per week, the latter the highest approved dose for the drug, the researchers reported in the Nov. 19 issue of the Journal of the American Medical Association.
However, the researchers noted, the agent's benefits may still outweigh these and other risks.
Still, they said, "it is imperative for physicians and patients to recognize the risk."
Dr. Wu and colleagues also called for research on prevention and management of venous thromboembolism associated with bevacizumab.
An earlier meta-analysis by researchers at Genentech, which markets the drug, found an association with heart attacks and strokes, but not venous thromboembolism, in five randomized trials.
That study also found that overall survival was still improved with the drug. (See: Bevacizumab Boosts Stroke and MI Risk in Metastatic Cancer)
Dr. Wu and colleagues undertook their own meta-analysis to resolve the apparent conflict between the Genentech study and other reports of venous thromboembolism rates of up to 19% in patients treated with bevacizumab.
The Genentech analysis, they said, "has propagated a view that venous thromboembolism is not one of the more serious adverse effects attributed to bevacizumab."
In their review, they pooled data from 15 trials involving cancers of the kidney, lung, bowel, breast, and pancreas, as well as mesothelioma.
Six of the trials reported venous thromboembolism events of all severity grades. The overall, pooled event rate in these trials was 11.9% (95% CI 6.8% to 19.9%).
In these studies, the overall relative risk of all-grade venous thromboembolism associated with bevacizumab was 1.29 (95% CI 1.03 to 1.63).
In 13 trials, rates of high-grade venous thromboembolism -- combining events of grade three to five -- were reported. The overall rate was 6.3% (95% CI 4.8% to 8.3%).
The overall relative risk for high-grade events was 1.38 (95% CI 1.12 to 1.70), the researchers found.
Bevacizumab appeared most likely to increase the risk of high-grade events in patients with mesothelioma and renal cell carcinoma. But the increased risk in these individual trials was not significant because of small event numbers.
On the other hand, raw event rates did differ significantly by cancer type.
Patients with renal cell carcinoma had the lowest rates -- 3.0% (95% CI 1.6% to 5.5%) for all-grade events and 2.0% (95% CI 0.9% to 4.2%).
The highest rates were seen in patients with colorectal cancer and non-small-cell lung cancer.
Venous thromboembolism rates in the colorectal cancer trials were 19.1% (95% CI 16.1% to 22.6%) for all-grade events and 7.3% (95% CI 5.0% to 10.5%) for high-grade events.
In non-small-cell lung cancer, rates were 14.9% (95% CI 8.2% to 25.5%) for all-grade events and 6.5% (95% CI 5.3% to 8.1%) for high-grade events.
Mesothelioma patients showed an even greater rate of high-grade events, at 17.0% (95% CI 9.1% to 29.5%), although that was in a single trial in 108 patients in which lower-grade events were not reported.
Dr. Wu and colleagues said the mechanism likely involves bevacizumab's biological target, vascular endothelial growth factor.
Inhibition of VEGF may expose sub-endothelial, pro-coagulant molecules that would otherwise remain hidden, the researchers said.
Other potential effects include reduction in release of nitric oxide, increases in hematocrit and blood viscosity, or release of pro-coagulant molecules from dying tumor cells, they said.
Dr. Wu and colleagues added that increased venous thromboembolism risk might be a class effect of angiogenesis inhibitors. Increased venous thrombosis rates have also been seen with thalidomide and lenalidomide, which also inhibit angiogenesis, they said.
As a result, the researchers suggested that combining such agents, which is now being studied in ongoing trials, "may have an increased risk of venous thromboembolism."
The researchers noted that their meta-analysis was limited by methodological differences between studies, although tests of heterogeneity lent credence to their conclusions.
Dr. Wu and colleagues also pointed out that the studies were all conducted at major clinics and academic institutions, where the patients may not be fully representative of those in the community.
In addition, detection and grading of venous thromboembolism may have varied among studies.
No external funding for the analysis was reported.
Dr. Wu reported relationships with Pfizer and Onyx Pharmaceuticals. No other potential conflicts were reported.
Primary source: Journal of the American Medical Association Source reference: Nalluri S, et al "Risk of venous thromboembolism with the angiogenesis inhibitor bevacizumab in cancer patients a meta-analysis" JAMA 2008; 300: 2277-85.
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