Avastin and chemo could be a fatal combo

by Aimee Keenan-Greene 

Fatal adverse events (FAEs) have been reported in cancer patients treated with the widely used angiogenesis inhibitor bevacizumab (Avastin) in combination with chemotherapy. Is bevacizumab to blame?

Researchers now say when bevacizumab (be va siz' yoo mab) is used in combination with chemotherapy or biological therapy, treatment-related mortality increases, compared to chemotherapy alone. That's the finding of a new study just published in the Journal of the American Medical Association.

Mike Mitka, writing for the JAMA Author Insights, says:

The researchers found that the overall incidence of fatal adverse events with bevacizumab was 2.5%; when compared with chemotherapy alone (1.7%), adding bevacizumab was associated with a 1.5 times increased risk of fatal adverse events. This association was greatest when bevacizumab was used in combination with taxanes or platinum agents (3.5 times greater risk), but combining bevacizumab with other chemotherapeutic agents was not associated with increased risk. 

Researchers at Stony Brook University Medical Center in Stony Brook, NY, conducted a systematic review and meta-analysis of 16 randomized controlled trials involving over 10,000 patients. 

“In previous studies, we noticed that Avastin was associated with serious adverse events. We wanted to see if those serious adverse events were associated with fatal toxicity—and they are. Physicians should discuss this fatal toxicity with their patients to explain the risks and benefits of using this drug. 

Physicians should also be aware that when using Avastin, they should pay closer attention to spotting serious side effects, and to manage and treat them in order to avoid fatal toxicity.", said Shenhong Wu, MD, PhD, the study’s principal investigator and assistant professor of medicine in the division of hematology and oncology at Stony Brook.

The FDA first approved Avastin in February 2004 for use in combination with intravenous 5-FU-based chemotherapy as a treatment for first-line metastatic colorectal cancer (MCRC), according to the manufacturer Genentech. 

Conventional chemo kills growing cells to destroy more malignant ones than benign. Avastin blocks a specific protein that allows cancers to develop the blood vessels they need to spread and grow, according to USA Today.

The most common causes of FAEs were hemorrhage 23.5 percent, neutropenia 12.2 percent, and gastrointestinal tract perforation 7.1 percent. 

The National Institutes of Health says bevacizumab comes with a warning - it may cause patients to develop a hole in the wall of your stomach or intestine. Bevacizumab may slow the healing of wounds, such as cuts made by a doctor during surgery. In some cases, bevacizumab may cause a wound that has closed to split open. Bevacizumab may cause severe, life-threatening bleeding in the lungs of people who are using bevacizumab along with chemotherapy to treat lung cancer.  

In December, The U.S. Food and Drug Administration said Avastin (bevacizumab) will no longer be approved to treat breast cancer because the drug has not been shown to be safe and the risks outweigh the benefits.

The move comes after the FDA reviewed the results of four clinical studies involving breast cancer and Avastin last July. They determined the drug does not prolong overall survival in breast cancer patients or provide a sufficient benefit in slowing disease progression. 

Other risks from taking Avastin include severe high blood pressure; bleeding and hemorrhage; the development of perforations (or “holes”) in the body, including in the nose, stomach, and intestines; and heart attack or heart failure.  Avastin has also been associated with several other serious and potentially life-threatening side effects including the risk of stroke, wound healing complications, organ damage or failure; and the development of a neurological condition called reversible posterior leukoencephalopathy syndrome (RPLS), characterized by high blood pressure, headaches, confusion, seizures, and vision loss from swelling of the brain.

Avastin itself is not being removed from the market and will not affect its approval for treating colon, brain, and lung cancers.

“After careful review of the clinical data, we are recommending that the breast cancer indication for Avastin be removed based on evidence from four independent studies,” said Janet Woodcock, M.D., director of the FDA’s Center for Drug Evaluation and Research. 

“Subsequent studies failed to confirm the benefit observed in the original trial. None of the studies demonstrated that patients receiving Avastin lived longer and patients receiving Avastin experienced a significant increase in serious side effects. The limited effects of Avastin combined with the significant risks led us to this difficult decision. The results of these studies are disappointing. We encourage the company to conduct additional research to identify if there may be select groups of patients who might benefit from this drug.”, Woodcock added.

Removing the breast cancer indication from the Avastin label will be a process, until then, Oncologists currently treating patients with Avastin for metastatic breast cancer should use their medical judgment when deciding whether a patient should continue treatment with the drug or consider other therapeutic options.

Avastin, in combination with chemotherapy (paclitaxel), was approved in February 2008 under the FDA’s accelerated approval program, based on the results of a clinical trial known as “E2100,” which evaluated the drug in patients who had not received chemotherapy for their metastatic HER2-negative breast cancer. 

The FDA said they are willing to working with Genentech on any proposals to conduct additional studies of Avastin in patients with metastatic breast cancer designed to identify a population of patients in which the drug’s benefits exceed the risks.

Breast cancer forms in tissues of the breast, usually the ducts- the tubes that carry milk to the nipple,  and lobules - the glands that make milk.  

The National Cancer Insititute estimates there will be more than 207, 000 new cases of breast cancer diagnosed in the US this year. Almost 40,000 women will die from the disease.

Avastin, used with interferon alfa, is also approved to treat metastatic kidney cancer.