Feb. 26, 2008 -- Cancer patients die 10% more often -- and have a 57% higher risk of dangerous blood clots -- if they take the anemia drugs Procrit, Epogen, or Aranesp to fight the side effects of chemotherapy.
The findings come from a careful analysis of data from 13,611 cancer patients enrolled in 51 different placebo-controlled clinical trials of the anemia drugs. These drugs -- Procrit, Epogen, and the newer Aranesp -- are known as erythropoiesis-stimulating agents or ESAs because they stimulate the growth of red blood cells.
"In our report we show these drugs increase the risk of thromboembolism [blood clots] by 57%, a number that's been reported before," Northwestern University professor Charles Bennett, MD, tells WebMD. "What is new is the mortality findings. We don't know the risk for an individual cancer patient -- but the more concerning thing is there is a safety problem here."
Bennett and colleagues aren't the first researchers to suspect that cancer patients taking Procrit, Epogen, and Aranesp do worse than those not taking the drugs. But their paper shows that the risk is real.
Only last November, the FDA insisted that the makers of the drugs put stronger warnings on their labels. Since then, the manufacturers notified the FDA that breast and cervical cancers got worse in patients taking the drugs during clinical studies. The studies also found that patients taking the drugs had more life-threatening blood clots than those not taking anemia drugs.
The FDA's oncology-drug advisory panel will meet on March 12-13 to discuss these reports -- and the Bennett study. The panel will decide whether the FDA should put further restrictions on the use of the anemia drugs.
Anemia Drug Benefits Overrated, Risks Underrated?
Both cancer itself and cancer chemotherapy can cause anemia, a condition in which the blood has too few oxygen-carrying red blood cells. Cancer patients often require blood transfusions. But with the introduction of the first ESA in 1989, doctors were able to avoid blood transfusions by using what seemed to be a safe medication.
This could not have been a more timely development. In the early 1990s, there were grave concerns about the safety of the blood supply. And as far as anybody knew, the drugs were extremely safe. That's because Procrit, Epogen, and Aranesp are designed to stimulate a growth receptor found on blood stem cells, says study researcher Stephen Lai, MD, PhD, a head and neck surgeon at the University of Pittsburgh Cancer Institute.
"We thought that receptor was found only on blood stem cells, so the drugs' effects would be very precise," Lai tells WebMD. "But then we saw that brain cells also had the receptor, and that the drugs help some blood vessels to develop. And then someone got the idea to see if cancer cells have it. Sure enough, all these different solid tumors express the receptor."
The effect on tumor cells, Lai says, is to help them invade deeper into the body.
Meanwhile, U.S. doctors began using more and more of the drugs. Instead of using the drugs to bring patients' red blood cell counts up to minimum levels, they began using it to bring blood cell counts as close to normal as possible. Fueling the process was a rebate scheme in which the companies making the drugs paid doctors millions of dollars to give the drugs to their patients.
"We had a class of drug approved for a very specific indication. But through a variety of professional concerns and legitimate patient interests -- combined with heavy advertising and doctor-reimbursement policies -- we expanded use of these drugs beyond their original intent," Len Lichtenfeld, MD, deputy chief medical officer at the American Cancer Society, tells WebMD.
The unchecked use of Procrit, Epogen, and Aranesp began to unravel in May 2006, when a research review by the U.S. Agency for Healthcare Research and Quality showed that the drugs increased patients' risk of deadly blood clots.
But Lichtenfeld says what really shocked cancer doctors was the FDA's January 2007 release of a "Dear Health Care Professional" letter from Aranesp maker Amgen. The letter informed doctors that cancer patients no longer on chemotherapy but still taking Aranesp appeared to die more often than patients not taking it.
Now the Bennett study confirms this suspicion -- and strongly suggests that it applies to the entire class of ESA drugs.
Whither Procrit, Epogen, Aranesp?
Procrit, Epogen, and Aranesp are top-selling drugs. Until the mid-March FDA panel meeting, it won't be clear exactly how doctors should use the medications.
"This is like the HRT [hormone replacement therapy] story," Lichtenfeld says. "Several years ago, research suggested HRT had significant side effects and not as much benefit as thought. The pendulum swung from very many women using HRT to very few women using HRT. But now a balance has been achieved, where there is not so much HRT use as in the past, but still a major if limited role for the treatment. With ESAs, we will come to a similar conclusion. But for now, use will be very conservative."
Lai says Procrit, Epogen, and Aranesp have complex effects on tumors -- effects that are not yet fully known. The drugs seem to have different effects on different tumors.
"I don't think these drugs have a huge overall effect on tumor progression, but they definitely do make a contribution to the disease," he says. "The size of that contribution still needs to be completely understood."
Lai worries that while researchers figure this out, oncologists -- and their patients -- will be denied a useful class of drugs.
"I think the fear among oncologists is that the ESAs may just be removed from all cancer indications, and I don't know that is the best decision," he says. "You begin with patients with severe cancers who have severe treatment-related side effects. You have to balance the benefits of ESAs against the risks of what could happen to a patient's tumors if you use the drugs."
Bennett, Lai, and colleagues report their findings in the Feb. 27 issue of The Journal of the American Medical Association.