By Ingfei Chen

Blood Clotting Controversy

By Ingfei Chen

Is it possible that angiogenesis inhibitors may also increase cancer patients’ risk of developing blood clots in the veins?

Medical oncologist Shenhong Wu at Stony Brook University in New York and his colleagues culled and then evaluated data from 15 well-designed studies of nearly 8,000 people with late-stage solid tumors. All the patients had been treated with chemotherapy or a biological agent like interferon, plus Avastin or a placebo.

Their analysis, published in November 2008, showed that the Avastin takers had a 33 percent greater relative risk of developing life-threatening blood clots in the veins, or venous thromboembolism, than the patients who had been given placebos. So Wu’s team suggested that physicians consider heading off blood clotting in high-risk individuals by prescribing blood-thinning therapy when a patient starts taking Avastin. The researchers also proposed that the U.S. Food and Drug Administration (FDA) add a black box warning for venous thromboembolism to the drug’s label. (Wu receives speaking fees from Bayer and Pfizer, which make Nexavar and Sutent, respectively.)

But not everyone agrees. As Gary Lyman, a medical oncologist at Duke University in Durham, N.C., and a member of the FDA’s oncology drugs advisory panel, points out, the increase in the overall number of venous thromboembolism cases due to Avastin in Wu’s analysis was actually small—about two to three more cases for every 100 patients on the drug.

It’s also possible that the study overestimated the risk because the individuals on Avastin lived longer than those on the placebo, which meant they had more time to develop these blood clots. To investigate that possibility, scientists at Genentech, which makes Avastin, examined their in-house clinical trial data from more than 6,000 patients, taking into account which patients lived longer. They saw no heightened risk of venous blood clots from the drug, says Philippe Bishop, a Genentech vice president. The company has shared its results—which it has submitted for publication—with the FDA.

The American Society of Clinical Oncology panel that drew up guidelines in 2007 for handling venous thromboembolism took a hard look at the Avastin trials. The committee deemed it premature to recommend that all Avastin users take blood thinners to prevent clots, because those drugs themselves can cause bleeding problems (and the angiogenesis inhibitor might too), says Lyman, the panel’s chairman. But it did generally recommend that blood thinners be considered for cancer patients at high risk of developing venous blood clots either from being very ill and hospitalized or because they have received outpatient treatments of thalidomide plus chemotherapy.