In November, following an emotional public hearing some months earlier, the Food and Drug Administration withdrew approval for the cancer drug Avastin for patients with metastatic breast cancer — the late-stage, incurable form of the disease. The reason: emerging evidence that the drug does not prolong life and also that it's been linked to serious side effects.
Now, confusingly, Avastin is back in the news again — this time, with positive results in two early trials of women with early-stage breast cancer whose tumors have not traveled beyond the breast or nearby lymph nodes.
The results are suggestive, but not conclusive, says Dr. Len Lichtenfeld, deputy chief medical officer of the American Cancer Society. "This is not the kind of study that will have doctors changing their practice tomorrow. It's going to take some time to sort out."
Here's a closer look at Avastin, its track record and its potential.
The drug is an antibody that binds and inactivates a naturally occurring substance — vascular endothelial growth factor — that helps the body form new blood vessels. Tumors need a blood supply to deliver nutrients and oxygen, and they coax new vessels to grow to them. Avastin blocks this process and essentially starves the tumor.
The drug was a potentially game-changing treatment when it was first approved by the FDA in 2004, for colorectal cancer. It introduced a totally new therapeutic strategy to prevent tumors from growing. Today, the drug is approved for that cancer as well as ones of the kidney, brain and lung.
It was approved via an accelerated process in 2008 for metastatic breast cancer after early positive results in such patients indicated it seemed to halt tumor growth. But as patients were tracked for longer periods of time, it became clear that they weren't living any longer. Additional studies confirmed the lack of any survival edge and revealed far more about the side effects. The drug seems to worsen some side effects of chemotherapeutic drugs given with it and also increased risk of severe high blood pressure, bleeding complications, heart attack and heart failure.
In July 2010, after reviewing all the evidence, an FDA advisory committee voted, 12-1, to withdraw the drug for breast cancer treatment, concluding that the benefits did not outweigh the risks. The agency gave the public and the drug's maker, Genentech, a chance to weigh in during the June hearing but decided to withdraw approval, announcing its decision Nov. 18.
And now, the new studies. How do they fit in?
Published last week in the New England Journal of Medicine, both tested whether Avastin, in combination with chemotherapeutic drugs, would help shrink tumors before surgery. This strategy is called neoadjuvant therapy, and in many cases it has allowed doctors to reduce the extent of surgery, says Dr. Helena Chang, a surgical oncologist who directs the Revlon/UCLA Breast Center. "We've learned that neoadjuvant therapy before surgery might convert a mastectomy into a lumpectomy." It can also make removing lymph nodes unnecessary, she adds.
The first study, done in Germany, studied 1,948 patients with a type of breast cancer called HER2-receptor-negative who were just starting treatment. Patients were randomly assigned to receive neoadjuvant therapy — a combination of the chemotherapy drugs epiruvicin, cyclophosphamide and docetaxel — with or without Avastin.
Patients then had surgery to remove tissue from the breast site where tumors had been detected as well as the lymph nodes that had cancer in them. Their tissue was assessed microscopically to search for cancer cells.
Researchers reported that 18.4% of patients receiving Avastin responded completely to neoadjuvant therapy — they had "not a single tumor cell left," says study coauthor Dr. Gunter von Minckwitz, a researcher with the German Breast Group in Neu-Isenburg. In the group that did not get Avastin, 14.9% of patients had a complete response.
The second study, done in the U.S., studied 1,206 patients, again with HER2-receptor-negative breast cancer. Various combinations of chemotherapy drugs were tested with or without Avastin. Results showed 34.5% of patients with Avastin responded completely to the neoadjuvant therapy compared with 28.2% who did not receive it.
The results in both studies were statistically significant but quite small — the percent of patients helped by Avastin increased by 4 percentage points in Germany and 6 in the U.S.
Still, these results, along with others yet to come, "may show us that there's a place for this drug" in treating early breast cancer cases, says U.S. study coauthor Dr. Harry Bear, a surgical oncologist at Virginia Commonwealth University Medical Center in Richmond. "It's a setting where we're more likely to increase cure rate or prolong survival, much more than with metastatic disease," he says.
But it's too soon to tell: These studies only focus on pathology results. They haven't followed patients long enough to see how diseases progress and whether the drug offers any survival edge. To that end, both research groups plan to follow their subjects for at least five years.
There are some confusing things about the two studies in identifying which patients might best respond to the Avastin.
In the U.S. study, the positive effects of Avastin were detected only in a subgroup of patients with so-called hormone-sensitive tumors, which grow when exposed to estrogen or progesterone. But in the German study, the opposite was true — statistically positive effects were seen only when looking at the hormone-insensitive subgroup. That might mean that hormone-sensitivity is irrelevant to the response to Avastin and the results just fell out that way by chance.
Researchers hope that preserved tissue samples from both studies may reveal other characteristics of cancers that can help predict which patients are most likely to benefit from Avastin.
Researchers took steps to manage the known cardiovascular side effects, screening study subjects for cardiac function before enrolling them and monitoring blood pressure throughout the study.
Both studies, however, reported increased rates of neutropenia with fever (a low white blood cell count that diminishes the body's response to infection), mucositis (sores and sensitivity of the mucous membranes lining the mouth, stomach and intestines), hand-foot syndrome (red, tender palms and soles) and high blood pressure. Both also reported cardiac dysfunction — a reduction in how much blood the heart pumps out with each beat — in 1% to 3% of patients on Avastin.
For now, doctors will see no change in their practice.
Chang says she is encouraged by the results but is not ready to recommend Avastin to her patients. "I want more evidence," she says.
"What we really need is a test that tells us which women are most likely to benefit, because there's significant cost, in dollars and in side effects and risks," Lichtenfeld says.