In late June, the Food and Drug Administration (FDA) held an unusual, open-door and emotionally-packed meeting of its Oncologic Drugs Advisory Committee (ODAC). The topic was Avastin, a costly cancer treatment. The panel listened to testimony from women, including my cousin, about their ongoing cancer treatments. It heard, also, from representatives of some breast cancer advocacy groups, from Genentech -- the drug's manufacturer, and from the agency's Center for Drug Evaluation and Research.
The committee rendered a clear-cut recommendation. It voted 6-0 against Avastin. Soon FDA Commissioner Dr. Margaret Hamburg will give final word on the matter, in what's likely to be one of the most difficult decisions in her career and may define her tenure at the agency. Most observers expect she'll follow the panel's recommendation and set a seemingly essential precedent: to follow the bulk of evidence, collected imperfectly from several clinical trials, and say no. I wonder if she'll have the guts, instead, to let the indication hold.
The reason I believe Avastin should be available for breast cancer treatment is that it helps a fraction of women, albeit a small one, to live active, enjoyable lives. Critics say, rightly, that there's no biomarker or genetic abnormality to test for susceptibility to this costly, sometimes toxic treatment. Because there's no way to tell in advance who will respond, most women who receive the drug don't benefit, while all are exposed to its potential risks.
I'd counter that the judicious use Avastin -- or any cancer therapy, for that matter -- rests on two points: that patients be relatively young and sufficiently well to enter a doctor's office, communicate about its risks and provide informed consent; and that oncologists, who might recommend the drug to their patients, have no potential to profit by its prescription.
A bit of background is due. Avastin, or bevacizumab, is a monoclonal antibody derived from the once-promising, now reality-checked work of the late Dr. Judah Folkman. Over two decades ago, he put forth the notion, along with some data in mice, that tumors could be stopped by blocking their blood supply. Genentech latched onto his ideas before they became popular. In 1989 the nascent biotech company isolated the human form of Vascular Endothelial Growth Factor, a molecule that stimulates blood vessel formation. The company developed bevacizumab to bind and block the growth factor's effects. Fifteen years later, anti-angiogenesis therapy became all the rage. In 2004 the FDA issued its first approval of Avastin, in combination with chemotherapy, for metastatic colon cancer. Other indications followed for lung, brain and kidney tumors. Now, Avastin brings in over $3 billion annually for Genentech from the U.S. and over $5 billion world-wide.
For breast cancer, approval in 2008 came with immediate controversy upon an accelerated review of data that Avastin, together with a chemotherapy "backbone" agent, staves off tumor progression by a few months. Now, the marginal benefit - of delayed "progression free survival" -- appears slimmer than before. And there's never been evidence from a randomized trial that Avastin prolongs life, on average, among women who take it for breast cancer.
The problem with statistics for Avastin is that they don't take into account the "super-responders," the 4 or 5 or maybe 6 percent of real women who stand in the outlying tail of the survival curve. Some dismiss these cases as anectdotes; others insinuate that breast cancer patients who've spoken out about their response to Avastin don't really understand their illness and should be silent. Is it so discomfiting to see that some real women don't fall into the convenient middle of a Bell curve?
But the medical literature is far from perfect, as are most clinical trials, and even good studies contain real exceptions -- on either end of the spectrum. The resolution, I'd suggest, lies in the realm of good-quality clinical medicine, a topic that's been unfortunately absent in this controversy.
Say an oncologist prescribes Avastin to a 50-year-old woman with recurrent breast cancer and enlarged lymph nodes, or metastases evident in her lungs and liver. The doctor could give one, two or three cycles, together with an appropriate chemotherapy, and assess how the patient responds. If the patient tolerates the treatment well and her tumor shrinks or clearly stabilizes, the patient and doctor might decide to continue with the regimen. If the patient has significant side effects, or her tumor progresses, they'd stop.
This sort of clinical decision-making, based on an individual doctor's evaluation of a patient over time, flies in the face of an emerging emphasis on algorithms and evidence-based medicine. But any seasoned physician might tell you, and I know from my experiences treating people with rare blood disorders, that finding the right drug for a patient can take some trial and error. After years in practice, including care of patients with breast cancer, the more I appreciated the differences among individual patients' tumors. It could be, for example, that some women's metastases are more vascular than others, and so they're more responsive to this drug. Still, many people don't trust doctors' decisions, or their capacity to fairly evaluate a treatment's value.
The key to making the decision to give Avastin -- or any other cancer drug -- rational, and ethical, is in disconnecting the oncologist's prescription from potential gain in his or her income. As things stand, doctors make money by administering medications by infusion. Even in academic medical centers, physicians' salaries are often determined by the amount of "billable" procedures they order and do. If doctors had no financial incentive to prescribe drugs like Avastin, the public would have more confidence in their advice. And if a physician caring for a woman with progressive, triple-negative breast cancer gave her Avastin and she did well compared to how she'd been feeling on other drugs, she might want to, appropriately, stick with it.
In the past two months, the European Commission has elected to extend coverage of Avastin for women with advanced breast cancer. Here in the U.S., the National Comprehensive Cancer Network has reaffirmed its commitment to providing the drug. It's noteworthy that not a single member of the FDA's panel who voted on this issue is a breast cancer specialist.
By contrast, just two weeks after the Avastin hearings, the same FDA panel gave the nod to Adcetris. The panel advised in a 10-0 vote that this new drug, also an antibody, receive accelerated FDA approval as a salvage treatment for patients with a relatively rare form of lymphoma who've relapsed after bone marrow transplant. Several ODAC members are lymphoma experts; perhaps the panel was more able to appreciate the nuances of treating lymphoma patients and see the potential for Adcetris to help a small subset of cancer patients.
To be sure, Avastin is far from ideal and costs nearly $100,000 per year. Like most oncology treatments, it carries significant risks. Toxicity includes allergic reactions and high blood pressure, which are usually manageable, and, occasionally, intestinal perforation and other serious effects. I'd add also that very few cancer meds have a good response rate when given singularly. Most successes in oncology involve combination regimens.
As for costs, doctors and patients do need to come to grips with the issue, but not only for Avastin. As I've considered and was outlined by others in the New England Journal of Medicine, patients' age and, broadly, their functionality should be factored into the risk/potential benefits analysis of almost any medical intervention. Until better drugs come along, it doesn't seem reasonable to withhold Avastin from women, particularly those who are relatively young and otherwise healthy, with metastatic breast cancer who choose to try it with informed consent.
Some say the Avastin breast cancer decision will be a landmark for the application of evidence-based medicine in health care, and that it tests the FDA's capacity to say no. I'd suggest, rather, that this dilemma might generate a deeper discussion, on how the FDA and providers ought to weigh in on evidence derived from groups of participants in clinical trials, and how aggregated data can be applied to individual persons with disease.
In the end, I don't see this issue as about Avastin, about health care economics, or about breast cancer or even patient advocacy. Ultimately, it's a question of the limits of evidence-based medicine. The answer requires a re-thinking of how oncologists choose treatments and are compensated and, perhaps, how our disjointed and over-reaching health care system might assess the value of patients' lives.