Wednesday, October 22, 2003

The Letrozole Study
By Carol Tavris, Ph.D. and Avrum Bluming, M.D.

Most people get their news from the headlines-reading through the
paper, logging on to an Internet home page, or getting a quick TV flash.
News-by-headline is fine if you want to find out the latest sports scores,
traffic conditions, and jury verdicts. When it comes to medical news,
however, consumers and physicians had better read on.

More than 20 years ago, Allen L. Hammond of the American Association
for the Advancement of Science cautioned the public that "In today's
news-conscious world, there is an enormous emphasis on breakthroughs. But
with rare exceptions, science is a process, not an isolated event.
Conveying the way science really works, the interplay of persistence and
luck, the painstaking accumulation of evidence, the clash of proponent and
critic, the gradual dawning of conviction demands a look behind the

His observation is even more crucial in medicine, where scientific
discoveries can have grave consequences for life and death. But how often,
how many times, have the headlines blared news of some new miracle
drug--followed, as the night the day, by later news of the drug's side
effects, ineffectiveness, or risks? Many consumers do not realize that
because of the enormous pressure on pharmaceutical companies to get new
drugs to market fast--because drug testing takes time and vast sums of
money--the temptation to cut a drug trial short, if the results merely
seem promising, is often overwhelming.

The latest version of this now-familiar story appeared on October 9,
when the New England Journal of Medicine posted on the Web an article due
to be published four weeks later in its weekly print journal. Major
news organizations trumpeted the story of the apparently beneficial result
of a new medication for breast cancer, Letrozole. What was so important
about this research that the NEJM couldn't wait a month, and that made
the researchers halt their study after only two and a half years of the
five planned?

The study evaluated more than 5,000 post-menopausal breast cancer
patients to determine whether adding five years of treatment with Letrozole
improved the disease-free survival of those who had already received
five years of treatment with Tamoxifen. The Letrozole group did not
differ in survival rates compared to a control group that was given a
placebo. However, the Letrozole group was said to have a statistically
significant 46 percent decrease in the risk of a recurrent or new breast

Sounds impressive? It's not. For one thing, the two groups were not
matched by the extent of cancer at the time of their first surgery nor by
the type of chemotherapy they had had. These differences might have
affected the recurrence of breast cancer, quite independent of their
receiving Letrozole.

Second, the researchers were reporting *projected* results, not actual
ones! Because the study was stopped prematurely, none of the women had
actually received the full five years of Letrozole.

Third, although 46 percent sounds like an impressive decrease in risk,
it's a statistical manipulation. The absolute decrease in risk was only
6 percent. The New England Journal's own editorial acknowledged that
even if the beneficial effect reported in this study were valid, the use
of Letrozole would reduce one breast cancer occurrence for every 100
women treated.

Already we are reading letters to newspapers from people saying, "Thank
God the researchers halted this study early so that we may benefit! If
only my beloved sister (mother) (wife) had had this amazing drug!"
That is the reaction the hoopla is designed to generate, and that is what
troubles us. We are distressed by the decision of the investigators to
terminate the Letrozole study prematurely, before they could get more
definitive answers about the recurrence of the disease and about the
women's overall survival. And we are even more distressed by the New
England Journal of Medicine's decision to create an atmosphere of drama and
urgency by its early release of the article.

All of us, consumers and physicians, would do well to look behind the
headlines of medical "breatkthroughs," and to remember that headlines
sell news--and news sells drugs.

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