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When Combined with Chemotherapy, Bevacizumab Is Associated with Increased Risk of Death

Cancer patients who receive the targeted therapy bevacizumab (Avastin) in combination with chemotherapy are at increased risk of serious side effects that may lead to death, according to a meta-analysis of 16 clinical trials that was conducted by researchers at Stony Brook University School of Medicine in New York. The results were published February 2, 2011, in JAMA.

The risk of fatal adverse events varied by the type of chemotherapy agents used with bevacizumab, lead author Vishal Ranpura, M.D., and his colleagues reported. There were also suggestions that the risk might vary by tumor type and bevacizumab dose, but the study did not have the statistical power to provide a definitive answer in either case. 

More than 10,200 patients were enrolled in the randomized trials included in the analysis. Overall, fatal events were relatively rare, occurring in 2.5 percent of trial participants who received bevacizumab, compared with 1.7 percent of patients who did not—an approximately 50 percent increase in risk. However, the increased risk was more than threefold higher in patients who received bevacizumab in combination with platinum or taxane chemotherapy agents, such as carboplatin and paclitaxel, respectively.

The most common fatal event, accounting for nearly one-quarter of the total, was hemorrhage. Neutropenia, a decrease in a specific type of white blood cell that can put patients at increased risk of infections, was next, followed by perforations of the gastrointestinal tract, blockages of the pulmonary arteries, and cerebrovascular events such as stroke.

The benefits of bevacizumab can outweigh the risks of its use in a proportion of patients, explained Shenhong Wu, M.D., Ph.D., the study's senior author, but the finding should prompt closer scrutiny of how bevacizumab is used. Oncologists, he said, "should have a healthy respect for the toxicity of this drug and the possibility that it can cause fatal events."

The finding of an increased risk of serious events in patients treated with bevacizumab "is generally consistent with what's known about the drug," said Helen Chen, M.D., of NCI's Division of Cancer Treatment and Diagnosis. "What is clear [about bevacizumab] at this point is that the patients' susceptibility to serious adverse side effects from bevacizumab can have a lot to do with the tumor setting and comorbidity." Certain tumor types can predispose patients to an increased risk of certain events, she continued, such as bleeding in patients with advanced lung cancer.

Cary Presant, M.D., of the Wilshire Oncology Medical Group, who is also a clinical professor of medicine at the USC Keck School of Medicine, believes that the study's finding will likely affect clinical practice. "I do believe…that [bevacizumab] usage will go down," he said. "This obligates every physician who wants to use [bevacizumab] to have a conversation with their patients about fatal events, and it will lead to less use of this drug in cases where the beneficial effects are more marginal."

The strongest evidence of benefit with bevacizumab still seems to be in treating patients with metastatic colorectal cancer, Dr. Presant continued. "But some patients with lung [or] breast cancer might be inclined to choose not to receive it because the benefits are not as great."

An antiangiogenic agent that binds to vascular endothelial growth factor (VEGF), bevacizumab was the first FDA-approved drug designed to target the blood supply that feeds tumors. In addition to being approved for the treatment of colorectal cancer, the monoclonal antibody is approved to treat lung cancer, kidney cancer, and glioblastoma. (See the table below on specific indications.)

Bevacizumab is also approved to treat metastatic, HER2-negative breast cancer. In December 2010, however, the FDA announced it was beginning the process of withdrawing that approval for breast cancer based on results from several post-market clinical trials that failed to show an improvement in overall survival and which, the agency stated, did not "provide a sufficient benefit in slowing disease progression to outweigh the significant risk to patients." Genentech, which manufactures bevacizumab, has asked for a public hearing on the FDA's withdrawal decision.

In an accompanying JAMA editorial, Daniel Hayes, M.D., of the University of Michigan Comprehensive Cancer Center noted that treatment with bevacizumab can run as high as $100,000 a year, yet there is still substantial uncertainty around appropriate use of the drug in cancer care.

"Why, despite the impressively solid preclinical data and the promising early clinical results, has bevacizumab not been more successful in improving overall survival?" he wrote. Improvements in median overall survival were seen in only three of the pivotal trials on which the FDA based its approvals. In two of the trials, survival increased by less than 3 months.

"Careful review of response rates to bevacizumab suggest that bevacizumab works well, but only in selected patients," Dr. Hayes wrote further. Despite being broadly tested in numerous clinical trials, he continued, "few insights are available about specific subgroups of patients who may benefit."

In a statement responding to the JAMA study, Genentech noted that "the majority of our clinical studies include collection of blood, tumor tissue, and DNA for biomarker analysis as part of a comprehensive biomarker program." To date, although some studies have reported a correlation between certain markers and outcomes of bevacizumab-based therapy, no markers have undergone the rigorous validation studies needed for use in the clinic, Dr. Chen stressed.

Genentech has proposed a phase III clinical trial of bevacizumab in HER2-negative breast cancer that would have a biomarker component. Based on a retrospective analysis of a previous trial, the company explained in a document filed with the FDA, the new trial would assess whether plasma levels of the protein VEGF-A are indicative "of a more substantial benefit" with bevacizumab.


Bevacizumab and Its Indications

Indication Treatment Trial results on which the FDA based its approval
Metastatic colorectal cancer, first-line In combination with IFL (irinotecan, fluorouracil, leucovorin) Improved median overall survival (OS) by 4.7 months; also improved progression-free survival (PFS)
Metastatic colorectal cancer, second-line In combination with FOLFOX4 (folinic acid [leucovorin], fluorouracil, oxaliplatin) Improved OS by 2.2 months; also improved PFS
Unresectable locally advanced, recurrent, or metastatic non-small cell lung cancer (non-squamous histology), first-line In combination with carboplatin and paclitaxel Improved OS by 2.0 months
Metastatic kidney cancer, post-nephrectomy In combination with interferon-alfa Improved PFS
Progressive glioblastoma, second-line Single agent Objective response rate
Metastatic breast cancer, no prior chemotherapy* In combination with paclitaxel Improved PFS
* The FDA is in the process of removing the indication for breast cancer
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