The New York
July 14, 2007
Market Forces Cited in Lymphoma Drugs' Disuse
By ALEX BERENSON
The patients' stories sound nearly impossible.
After an hourlong infusion, Linda Stephens, 58, has been cancer-free
for seven years. Dan Wheeler, three years. Betsy de Parry, five years.
Before treatment, all three had late-stage non-Hodgkin's lymphoma, a
cancer of the immune system, and a grim prognosis.
All three recovered after a single dose of Bexxar or Zevalin, both
federally approved drugs for lymphoma. And all three can count
themselves as lucky.
Not just because their cancers responded so well. But because they got
the treatment at all.
Non-Hodgkin's lymphoma is the fifth most common cancer in the United
States, with 60,000 new cases and almost 20,000 deaths a
fewer than 2,000 patients received Bexxar or Zevalin last year, only
about 10 percent of those who are suitable candidates for the drugs.
"Both Zevalin and Bexxar are very good products," said Dr. Oliver W.
Press, a professor at the University of Washington and chairman of the
scientific advisory board of the Lymphoma Research Foundation. "It is
astounding and disappointing" that they are used so little. The
reasons that more patients don't get these drugs reflect the
market-driven forces that can distort medical decisions, Dr. Press and
other experts on lymphoma treatment say. A result can be high costs
but not necessarily the best care.
The drugs have not been clinically proven to prolong survival,
compared with other therapies. But patients are more likely to respond
to them than standard treatments, and trials to test whether the drugs
do have a survival benefit are nearly complete.
Other, more thoroughly tested lymphoma drugs are preferred as
first-line treatments. But doctors often repeatedly prescribe such
drugs even after they have lost their effectiveness — and when Bexxar
and Zevalin might work better.
One reason is that cancer doctors, or oncologists, have financial
incentives to use drugs other than Bexxar and Zevalin, which they are
not paid to administer. In addition, using either drug usually
requires oncologists to coordinate treatment with academic hospitals,
whom the doctors may view as competitors.
As a result, many doctors prescribe Bexxar and Zevalin only as a last
resort, when they are unlikely to succeed because the cancer has
advanced. "Oncologists use everything in their cupboard before they
refer," Dr. Press said. "At least half the patients who get referred
to me have had at least 10 courses of treatment."
While Bexxar and Zevalin help many patients, only a minority become
cancer-free for many years. But clinical trials indicate that they are
as good as or better than other treatments. When the drugs were
approved, analysts expected they would be used widely.
But the drugs have run into an obstacle that so far has been
impassable. Because they are radioactive, they are almost always
administered in hospitals, not doctors' offices. As a result, doctors
are not paid by Medicare and private insurers for prescribing them, as
they are when they give patients a more common treatment,
In addition, most oncologists outside academic hospitals treat many
different cancers and may be only vaguely familiar with the drugs,
said Dr. Andrew D. Zelenetz, chief of the lymphoma service at Memorial
Sloan-Kettering Cancer Center. "There are a number of barriers," Dr.
Dr. Press and Dr. Zelenetz acknowledge that they have their own
financial incentives to support the drugs. Dr. Press has been paid to
speak at medical education seminars sponsored by the makers of the
drugs. Dr. Zelenetz has been paid when the companies sponsor clinical
trials at Memorial Sloan-Kettering. But both said the money was a
small part of their total income and had not colored their views.
Some patients say they would not have received Bexxar and Zevalin if
they had not demanded them. Mr. Wheeler of Kalamazoo, Mich., said he
received Bexxar in April 2004 only after insisting on it when his
lymphoma recurred. "I told my local oncologist, I want Bexxar, you
give me a referral," Mr. Wheeler said. "I've been a real pain."
Mr. Wheeler, whose lymphoma was diagnosed in 2000 and recurred in
2003, has been cancer-free since receiving Bexxar. His cancer was
growing when he received the infusion. He thinks he would be dead by
now if he had not received the drug.
Ms. Stephens feels similarly. She was diagnosed with lymphoma in
December 1998, and chemotherapy proved both difficult and ineffective.
By August 1999, her disease was spreading. "Every lymph node in my
body was involved," she said. She received Bexxar as part of a
clinical trial in January 2000 and quickly began gaining strength. She
has remained in remission since, she said.
Zevalin and Bexxar are the first in a new class of drugs
radioimmunotherapies. Essentially, they deliver radioactive particles
directly to cancerous cells to kill them. Idec, now part of Biogen
Idec, invented Zevalin. Corixa, a Seattle company bought by
GlaxoSmithKline, developed Bexxar. Both drugs are very expensive,
costing about $25,000 per treatment. But one dose is usually enough.
The cost of the drugs is similar to a full four-month regimen of
chemotherapy and Rituxan, another lymphoma treatment.
For decades, lymphoma has been treated with chemotherapy, drugs that
attack cancer cells but that can have severe side effects. Alongside
chemotherapy, most patients now get Rituxan. It was discovered by
Idec, the same company that found Zevalin, and is marketed in the
United States by Genentech.
The Food and Drug Administration approved Rituxan in 1997. Since then,
the drug has become standard treatment for newly diagnosed lymphoma
patients, based on clinical trials showing that it makes chemotherapy
Because lymphoma is relatively common, and Rituxan costs $20,000 for a
typical course of treatment, it is the top-selling cancer drug
worldwide, with sales in 2006 of $4 billion.
Doctors agree that Rituxan is an excellent drug with only minor side
effects for most patients.
Still, the few head-to-head clinical trials that have been conducted
show that Bexxar and Zevalin are as effective as Rituxan, if not
In a study published in The Journal of Clinical Oncology in 2002, the
tumors in 80 percent of patients who received chemotherapy and Zevalin
shrank, compared with 56 percent who received chemotherapy and
Rituxan. Of patients who received Zevalin, 30 percent went into
complete remission, compared with 16 percent who got Rituxan.
Dr. Antonio J. Grillo-López, who oversaw the development of Rituxan
and Zevalin as the chief medical officer at Idec, thinks Zevalin is
the more potent of the two. "The early- stage studies showed that in
fact Zevalin was superior," he said. Dr. Grillo-López retired from
Idec in 2001 and said he no longer had any financial interest in
When it reviewed the clinical trials for Zevalin in 2001, the F.D.A.
found that "as compared to the Rituxan therapy, Zevalin was associated
with a superior overall response rate." The F.D.A. noted that another
study found that 58 percent of people who had failed Rituxan treatment
showed some response to Zevalin. Bexxar has shown similar results.
The F.D.A. approved Zevalin in 2002 and Bexxar in 2003, in both cases
for the treatment of slow-growing lymphoma that had failed previous
When regulators approved Zevalin, Wall Street analysts projected it
would reach $100 million in sales in 2003. Merrill Lynch predicted it
could eventually hit $500 million in sales — about 20,000 doses a
But Zevalin hit roadblocks immediately. Its five-figure price caused
insurers to balk. Further, its radioactivity made some oncologists
worry that it might prevent them from giving other treatments later.
Prescribing Zevalin also requires oncologists to coordinate care with
the hospitals that administer it. To get either Zevalin or Bexxar,
patients first receive a low-radiation diagnostic dose, then imaging
scans, then a high-radiation therapeutic dose, which comes a week
after the first dose. Over the next weeks the patient's red and white
blood cell counts must be monitored.
The back-and-forth makes the treatment complicated to oversee, said
Dr. Joseph M. Connors, a lymphoma specialist in Vancouver, British
Columbia. "The doctors looking after people tend to turn to tools that
they themselves know how to use and are familiar with," he said.
For most oncologists, infusions of chemotherapy, Rituxan and other
drugs are still their primary source of income. Even so, oncologists
might have felt bound to use Bexxar and Zevalin if the drugs had been
proven to extend survival over older treatments, Dr. Connors said.
While preapproval trials showed that the drugs shrank tumors more
frequently than Rituxan and suggested patients would survive longer,
the test groups were too small to prove it.
Dr. Connors said that Idec and Corixa should have designed their
clinical trials to prove — not just suggest — that the drugs increased
Two clinical trials meant to answer that question are under way, but
their results have not been reported. Until they are, doctors will be
reluctant to use Bexxar and Zevalin, Dr. Connors said. For now, the
drugs remain niche products. Biogen Idec reported worldwide sales of
$18 million for Zevalin last year. That was about 1,000 doses of
Zevalin used commercially. Dr. Press reported that GlaxoSmithKline had
sold about 600 doses of Bexxar last year.
Advocates for the drugs worry the companies may stop making them.
Biogen Idec said in October that it might shed Zevalin. Although the
company continues to manufacture the drug, it no longer actively
promotes it. A spokeswoman for Biogen Idec said the company planned to
keep making Zevalin and continued to offer technical support to
doctors using it. GlaxoSmithKline said it expected to keep making
Patients who have benefited from Bexxar and Zevalin say they cannot
understand why the drugs are not more widely used.
Ms. de Parry received Zevalin in 2002, when she was 52. She had
already failed chemotherapy and Rituxan. But she responded quickly to
the injection and has remained cancer-free. "It's not that I believe
that radioimmunotherapy is right for everybody," she said. "I just
think that patients, all patients, should know their options."