http://www.nytimes.com/2007/02/27/health/27drug.html
Studies Show Anemia Drugs May Harm Cancer Patients
By ANDREW POLLACK
Published: February 27, 2007
New studies are raising questions about whether drugs that have been used
by millions of cancer patients might actually be harming them.
The drugs, sold by Amgen, Roche and Johnson & Johnson, are used to treat
anemia caused by chemotherapy and meant to reduce the need for blood
transfusions and give patients more energy. But the new results suggest
that the drugs may make the cancer itself worse.
In the studies, the drugs have generally been used in ways not approved on
the labels. And the companies say that, when used according to
instructions, the drugs have a long history of safety.
In a statement yesterday, Amgen said it strongly believed its drugs were
“safe and effective medicines when used in approved populations consistent
with label dosing recommendations.”
Nevertheless, some cancer specialists and securities analysts say the new
information may make doctors more cautious in using the drugs, which have
combined sales for the three companies exceeding $11 billion and have been
heavily promoted through efforts that include television commercials.
“These are drugs that were presumed to be entirely safe, given for
supportive care and to improve quality of life,” not to actually treat
cancer, said Dr. Eric Winer, director of breast oncology center at the
Dana-Farber Cancer Institute in Boston. “So any concern that they could
shorten someone’s life are taken quite seriously.”
The Food and Drug Administration is planning to convene an advisory
committee meeting to review the products, Dr. Richard Pazdur, the agency’s
director for cancer drugs, said in an e-mail message last week alerting
cancer doctors to the new findings.
All the drugs are versions of erythropoietin, or Epo, a substance made by
the human kidney that increases levels of hemoglobin, the oxygen-carrying
component of red blood cells.
Amgen makes
Aranesp, with sales of $4.1 billion last year, as well as
Epogen, which had sales of $2.5 billion, although Epogen is supposed to be
used only to treat anemia in kidney dialysis patients.
Under license from Amgen, Johnson & Johnson sells
Procrit in the United
States and Eprex abroad, with combined sales last year of $3.2 billion.
Roche’s drugs NeoRecormon and Epogin, now sold only outside the United
States, had sales last year of $1.8 billion. But Roche is hoping to enter
the American market with a new drug called Cera.
Amgen has the most to lose from any setback because it relies more heavily
on the Epo drugs, which account for nearly half its revenue. Amgen’s stock
touched above $75 briefly in late January, before word of the negative
studies began emerging. The shares closed yesterday at $66.20, down 3
cents.
The new doubts about cancer safety add to those raised recently regarding
the drugs’ other major use — to treat anemia caused by kidney disease. A
study published in The New England Journal of Medicine in November found
that patients treated aggressively with Procrit had a higher risk of heart
problems or death than those treated less aggressively.
The run of bad news for cancer treatment started in late January when
Amgen announced that in one of its clinical trials, patients getting
Aranesp were more likely to die than those getting placebo. The trial was
testing the drug in patients whose anemia was caused by the cancer itself,
not by chemotherapy.
On Feb. 16, the Cancer Letter, an influential Washington newsletter,
reported that a Danish study in patients with head and neck cancer had
been stopped early because the cancer seemed to recur more in patients
being treated with Aranesp.
Last week, The Journal of Clinical Oncology published a paper online
describing a small Canadian trial in lung cancer patients that had been
stopped early because those getting Eprex were dying sooner.
And on Friday, Roche said it was suspending patient enrollment in a lung
cancer trial comparing its Cera against Amgen’s Aranesp because of
apparently greater than expected number of deaths in at least some of the
arms of the trial.
It is not known why the drugs cause problems, if they do. It is known that
raising hemoglobin levels too high increases the risk of blood clots. And
most of these new trials did aim to increase hemoglobin above the levels
recommended in the drugs’ labels, though that was not the case with
Amgen’s own trial.
But there is some evidence that clots were not the problem in these
trials. Rather, some experts say, Epo may spur tumor growth. Some studies
suggest that certain tumor cells, such as those in head and neck cancer,
have proteins on their surface that bind to Epo. When that happens it sets
off a cascade of reactions spurring growth.
“I think there’s enough biologic plausibility to the argument that they
can serve as a growth factor for the cancer cell,” said Dr. Jennifer R.
Grandis, a professor at the University of Pittsburgh who has done studies
of the matter. She said the head and neck cancer practice at her
institution does not routinely use Epo and that she would not want it
herself.
But Dr. David P. Steensma at the Mayo Clinic, who has reviewed studies of
Epo safety, said the existence of Epo receptors on tumors had not been
proved because the studies have been flawed. He said that there have been
previous studies of the drugs that suggested they actually had a positive
effect on survival.
A combined analysis of 57 trials concluded the impact of the drugs on
survival was uncertain.
Dr. Steensma said he was still comfortable using the drugs to correct
severe anemia, but added, “I think we need to be real careful about going
beyond that.”
Concerns about the safety of the drugs for cancer were first raised in
2003 by two studies that showed patients getting Epo had worse outcomes.
But some experts said those studies were flawed and not convincing.
Studies Show Anemia Drugs May Harm Cancer Patients 
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