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Cancer Drug Avastin Linked to Death Risk

Study Shows Risk of Dying Higher With Avastin Than Chemo Alone; Drugmaker Criticizes Study's Methods

By Brenda Goodman
WebMD Health News

Reviewed By Laura J. Martin, MD

Feb. 1, 2011 -- Patients treated with Avastin, a top-selling cancer medication, appear to have a 50% increased risk of dying from treatment-related adverse events compared to the use of chemotherapy alone, a new research review finds.

What's more, the risk of fatal problems like bleeding, blood clots, and bowel perforations may more than triple when the biologic therapy Avastin is used with certain kinds of chemotherapy drugs, particularly taxanes or platinum medications.

But Avastin's manufacturer found fault with the study. Genentech, the maker of Avastin, says the study includes data in which Avastin was a treatment for types of cancer that are not on the FDA-approved list of uses for Avastin.

The review, which will be published in the Feb. 2 issue of the Journal of the American Medical Association, pools the results of 16 studies of 5,589 patients who were taking Avastin for solid tumors of the colon, lung, breast, prostate, kidney, or pancreas.

Overall, patients who took Avastin, which is an antibody that is given by intravenous infusion, had about 50% more fatal adverse events compared to those on chemotherapy alone.

About 2.5% of people who took Avastin died from drug-related adverse events compared to 1.7% on standard chemotherapy.

Those differences got larger, however, when Avastin was combined with certain kinds of chemotherapy medications, including taxanes and platinum agents. About 3.3% of people on these combined treatments experienced fatal events.

“It has an impact on how much people may use this drug, I think,” says study researcher Shenhong Wu, MD, PhD, an oncologist and assistant professor at the Stony Brook University School of Medicine in New York. “We used to think this drug was not very toxic, but I think now we understand more.”

Other experts disagree. "I'm not sure the risks with this drug are any different than any of the other cancer drugs," says Scott Kopetz, MD, who treats gastrointestinal cancers at the University of Texas M.D. Anderson Cancer Center in Houston.

In the case of stage IV colon cancer, "These are patients that have an average life expectancy due to their cancer of two years. These patients are living longer, by several months on [Avastin]," says Kopetz, who was not involved in the study.

"For patients with metastatic disease, we can shrink tumors and, in some cases, delay the growth of the cancer,” he says. “We can't cure it, but we can delay the progression of the disease."

Genentech Responds

Genentech takes issue with some of the study's methods.

Particularly, the fact that the analysis includes results from trials of the drug in three advanced cancer types, including prostate, pancreatic, and squamous cell lung cancer, for which it is not FDA approved and “should not be used,” according to a statement.

“Overall, the authors note that ‘the absolute risk of treatment-related mortality is low' and the data should be considered in the context of potential benefit with Avastin,” according to the statement.

“Like other cancer medicines, Avastin has serious risks that are clearly described in its label and need to be considered by doctors and patients, in the context of its potential benefits.

As we continue to study Avastin, our goal is to identify the people who will derive a more substantial benefit from the medicine. This is why 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, we have studied a large number of different biomarkers (more than 10,000 in animal models, and more than 100 in clinical studies) across many different types of cancer and we are dedicated to continuing this work.”

Questions About Avastin

Avastin is a monoclonal antibody that works by blocking the formation of new blood vessels, which helps to choke off a tumor's supply of oxygen and other nutrients.

It was first approved in 2004 in the U.S. for treatment of colorectal cancers.

Avastin has subsequently been approved to treat non-small-cell lung cancer, glioblastoma, renal cell carcinoma, and metastatic breast cancer.

Just months after it went on the market, however, the FDA warned doctors that the use of the drug appeared to be associated with a twofold increased risk of thromboembolic events, including heart attacks and strokes.

Other warnings were issued by the agency in 2006 and 2007 about increased risks for a rare brain capillary leak syndrome and non-gastrointestinal fistulas in patients on Avastin.

And in December 2010, the agency moved to rescind the drug's breast cancer indication, saying Avastin had not been proven to be safe or effective for that use.

If the indication is removed, doctors could still use the drug in an off-label way to treat breast cancer, though it is far less likely that it would be covered by insurance. “Off-label” refers to the legal practice of prescribing medication for a purpose not approved by the FDA.

According to an editorial that accompanies the study, the drug costs more than $50,000 a year.

Genentech is appealing the agency's decision, saying that patients deserve to have the treatment option.

“Avastin has helped people with five different incurable cancers; many have lived a longer time without their disease worsening, and in certain cases, Avastin has extended their lives,” says Charlotte Arnold, senior manager of corporate relations for Genentech.

According to IMS health, a company that tracks pharmaceutical sales trends, from October 2009 through September 2010, global sales of Avastin were around $5.5 billion, making it the world's top-selling cancer medication.

Advice to Patients

Patients diagnosed with the cancers Avastin is approved to treat are often told they have a limited amount of time to live, and in that context, a medication that can extend their life for a short time or even simply maintain their quality of life can be a precious glimmer of hope.

Wu says he tries to carefully select the patients he puts on Avastin and he tries to help them understand that taking it is a gamble.

“Normally, I explain to them the risk of this treatment, including the very bad risks that people may die from this treatment,” Wu says. “I also explain to them the potential benefits of treatment.”

“If we watch them very carefully, it is a reasonably safe drug,” he says.

When the cost is considered, however, the picture gets more complicated.

“Available data suggest that [Avastin] is biologically active in most but not all solid tumors,” writes Daniel Hayes, MD, an oncologist who treats breast cancer at the University of Michigan Comprehensive Cancer Center, in his editorial on the study.

“However, the benefits of extended adjuvant [Avastin] in unselected populations may not be justified by the modest disease-free survival and questionable overall survival benefits reported thus far.”

SOURCES:

Ranpura, V. Journal of the American Medical Association, Feb. 2, 2011.

Hayes, D. Journal of the American Medical Association, Feb. 2, 2011.

Shenhong Wu, MD, PhD, assistant professor of medicine, Stony Brook University School of Medicine.

Charlotte Arnold, senior manager of corporate relations, Genentech.

Genentech.

National Cancer Institute: “FDA Approval for Bevacizumab.”

IMS Health.

© 2011 WebMD, LLC. All rights reserved.



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