Ralph W. Moss, Ph.D. Weekly CancerDecisions.com
Newsletter #106 11/05/03
NOTE TO READER: This week we present a special
investigative report on a recently announced clinical
trial of Femara (letrozole). Although this is rather
lengthy, we felt it was important to put all of this
information in your hands at one time, rather than
breaking it up into weekly installments. Consequently,
there will be no newsletter next week, but we intend to
return to our regular schedule after that. -R.W.M.
FEMARA TAKES THE CANCER WORLD BY STORM
It is being hailed as the biggest breakthrough in the
treatment of breast cancer in years. An anti-estrogen
drug called Femara (letrozole) has been found to
decrease the risk of recurrences in post-menopausal
women who have been treated for early-stage
hormone-sensitive breast cancer.
Leaders of an
international clinical trial called off the trial when
analysts found a big difference in responses between
the two 'arms' of the study. The women who were already
on Femara were advised to continue taking the drug,
while those who had been given an inert placebo were
offered the chance to start on Femara.
In the wake of this finding, most leaders of the cancer
field have agreed that all post-menopausal women with a
history of treated early-stage hormone-sensitive breast
cancer should take this new drug after completing five
years of treatment with the standard anti-hormonal
drug, tamoxifen. "If you fit the profile it's very,
very clear," said James Doroshow, MD, chairman of the
division of medical oncology and therapeutics at City
of Hope Cancer Center in Duarte, Calif (Gardner 2003).
The decision could affect 100,000 women per year in the
US alone, and hundreds of thousands more around the
world. The study was greeted with a barrage of
enthusiasm the likes of which has not been seen in a
quite some time.
"This is up with the biggies, it is up with the major
majors," enthused Larry Norton, MD, chief of medical
oncology at Memorial Sloan-Kettering Cancer Center in
New York and one of the study authors (Kolata 2003).
"I think it's exciting," said Dr. C. Kent Osborne,
director of the Breast Center at Baylor College of
Medicine and the Methodist Hospital in Houston (ibid.).
Dr. Harold J. Burstein of the Dana-Farber Cancer
Institute, Boston, described the findings as an
"unexpected and robust difference in the rate of
"Everyone thought letrozole would have a modest
effect," said Dr. James N. Ingle, the principal
investigator for the United States in the study.
"Everyone was surprised" (ibid.).
The US government was quick to embrace the study. It is
a "very important advance in breast cancer treatment,"
which will "improve the outlook for many thousands of
women," according to Andrew von Eschenbach, MD,
director of the National Cancer Institute, which led
the study in the United States. The study was featured
prominently at the government's website, www.cancer.gov
In the often bleak landscape of cancer therapeutics,
new treatments are always welcome. But amidst the
outpouring of celebratory news stories, I wish to
interject a few words of caution. Let us see if we can
figure out what exactly Femara did--and did not do--for
the women who were enrolled in this important clinical
trial over a four-year period.
As stated, the 5,187 women who took part in this
Canadian-led trial were all post-menopausal, and had
been treated for early-stage breast cancer. All had
already taken the standard drug tamoxifen for a period
of 4.5 to 6 years following their initial treatment.
It has been found that the protective effect of taking
tamoxifen wanes over time, levelling off after about
five years. Thus, the essential purpose of the present
study was to find out if Femara could be given as a
long-term therapy in place of tamoxifen after the latter
had begun to lose its effectiveness.
And, make no mistake, the study DID indeed show that
there was a significant reduction in the risk of breast
cancer recurrences in women who received Femara
compared to those who received only an inert placebo In
total, during the four-year period of the study, 132
women taking the placebo experienced recurrences
compared to just 75 who were taking Femara.
Understandably, press reports have focused on the fact
that Femara significantly reduced the occurrence of new
tumors, which is true. However, we need to be quite
clear on our terms of reference here. Femara reduces
the risk of recurrence by 43 percent, but this is not
the same thing as reducing deaths by 43 percent.
Put another way, Femara was shown to increase the
period of "disease-free survival," or the length of
time before the disease recurs, during which period the
patient shows no evidence of disease (NED). In real
terms the study demonstrated that after an average of
four years 13 percent of women on the placebo, but only
7 percent of those on Femara, had suffered a
Impact on Deaths
"Our study ushers in a new era of hope by cutting these
ongoing recurrences and deaths from breast cancer after
tamoxifen by almost one half," said the lead author,
Paul E. Goss, MD. The reader can see that this
statement is technically true, but its significance is
In this study, there were 2,594 women in the control
group and 2,593 women in the Femara group. Over the
four-year period in question, 17 women taking the
placebo pills died of breast cancer compared to 9
taking Femara, for a total of 26. Thus, there was an
overall reduction of 8 deaths from breast cancer.
Statistical abstractions such as relative risk and
absolute risk can be extremely confusing. Studies have
found that many doctors do not clearly understand the
difference between relative risk and absolute risk, and
frequently confuse the two, basing treatment decisions
on mistaken interpretations of the term 'risk'.
on or go to the address listed below for an excellent
discussion of the ways in which these statistical concepts
are used in clinical medicine:
I read these figures differently from most
commentators. What the figures say to me is that, for
post-menopausal women, the risk of dying from
early-stage breast cancer after undergoing conventional
therapy is very small to start with. Even in the
placebo group the death rate was under one percent over
the duration of the study. Stated this way the results
seem somewhat less spectacular than suggested by Dr.
Goss's dramatic claim that the death rate had been cut
That the overall death rate should be so low may
initially seem surprising: we are accustomed, after
all, to thinking of breast cancer as a relentlessly
deadly disease. However, early-stage, post-menopausal,
estrogen-receptor-positive breast cancer is generally
not as aggressive a disease as many people fear.
Naturally, after a first bout one needs to remain
vigilant for any sign of a recurrence. But if a tumor
does recur, either in the same or in the opposite
breast, it can usually be adequately treated with
conventional methods, such as further excisional
surgery (as apparently happened to most of the women
who experienced recurrences during this study).
According to surgeon Richard Evans, MD, in his
thought-provoking book "The Cancer Breakthrough You've
Never Heard Of," this watch-and-wait strategy, followed
whenever necessary by conservative surgery, is
generally effective at removing the tumor before it
spreads to internal organs (provided that the recurrent
tumor is found before it becomes bigger than the
Review the website of Texas Cancer Center for a fuller
explanation of Dr. Evans' views by clicking or going to:
In the Femara study, there was an excess of 29 cases of
distant metastases in the placebo group compared to
the group receiving the drug over the four years of the
study. Unfortunately the authors do not state whether
this figure reached statistical significance, a crucial
A true picture of the impact of treatment on the
incidence of distant metastases is one of several
important things that were lost through early
termination of the study.
Most importantly, we should be absolutely clear on the
fact that in this study Femara was NOT shown to
increase overall survival in a statistically
significant way. A total of 42 women in the placebo
group died of all causes while taking part in the trial
compared to 31 in the Femara group.
While the trend was
in Femara's favor, this difference did not reach
statistical significance (technically, it had a "p"
value of =0.25). In other words, even the relatively
small survival advantage conferred by Femara in this
regard may simply have been due to chance.
Some oncologists see the drug's positive impact on
"disease-free survival" as a sure-fire indicator that
the drug will eventually be shown to increase actual
For instance, Dr. Larry Norton, MD said he
was confident Femara would save lives. "Disease-free
survival predicts survival," he asserted. "It always
has. And there is a very big decrease in cancer
incidence so there will be a survival difference."
However, not everyone sees it that way. For instance,
in a leading cancer textbook, Principles and Practice
of Radiation Oncology (3rd edition), Dr. Thomas Pajak,
past Director of Statistics of the American College of
Radiology, argued that "there is no general agreement
about what constitutes a treatment failure or how NED
[no evidence of disease, ed.] survival is to be
In his view, there is no substitute for
proof of effectiveness based upon the actual survival
of everyone in the trial.
"Absolute survival," he wrote, "is usually the most
objective measure of treatment because a patient is
either alive or dead. It calls for no interpretation"
(p. 233). This is the view I ascribe to. Disease-free
survival is a somewhat arbitrary measure, referring to
a decrease in deaths due specifically to a particular
kind of cancer over a limited period of time.
only to deaths that are directly attributable to the
extension and progression of the disease. But deciding
on a cause of death is somewhat subjective. It also
does not take into account the possibility that the
treatment itself may shorten the survival of some
patients through its own adverse effects on the body.
As we shall see, Femara is not without risks and side
effects, the impact of which may only become apparent
after patients have been followed for a considerably
longer time than they were in the present truncated
It has become a common practice to call a halt to a
clinical trial if one arm of the treatment appears in
an interim analysis to be yielding significantly better
results than a competing arm.
In this case, the trial
was terminated about half way through its projected
duration, after independent analysts noted that the
Femara patients were having fewer recurrences of their
breast cancer. Although I understand and respect the
ethical concerns that prompted this decision, I think
it was wrong to halt the study at this time.
this decision, the long-term effects of the treatment
remain uncertain. The public may never discover through
a rigorous trial whether Femara treatment actually
increases overall survival, or what its possible
long-term side effects may be.
Meanwhile, hundreds of
thousands of women will receive a treatment whose full
effects remain obscure. Those women will, in effect,
become unwitting participants in an open-ended
experiment. To me, that in its own way is just as
unethical as withholding a promising treatment.
A similar point of view was expressed by John Bryant,
PhD, and Norman Wolmark, MD, in an accompanying
editorial in the New England Journal of Medicine.
"[T]he primary aim of the study was not fully achieved
- namely, "to determine the disease-free survival and
overall survival for women who have previously received
~5 years of adjuvant tamoxifen randomized to receive
either letrozole 2.5 mg daily or placebo daily for five
years," they wrote.
"Thus, although the results
demonstrate a meaningful biologic effect of letrozole
therapy after tamoxifen therapy, they do not
demonstrate a significant survival benefit, nor do they
convey information about the optimal duration of
treatment beyond two to three years" (Bryant 2003).
Early closure of a clinical trial can also "freeze" a
desirable result in time, before it has a chance to
trend downward. In other words, trials may be abruptly
halted at the point that the treatment in question is
still showing superiority (in this case over the
A crude way of putting this is "quitting
while you're ahead." A full-term trial might have
yielded less dramatic results or even negative results
concerning overall survival.
What About the Cost?
I now wish to turn my attention to the economic impact
of using this drug. Nowadays, a new treatment cannot be
launched into the world without considering its overall
Many thousands of post-menopausal women will
undoubtedly be convinced by this study to take Femara
in order to ward off the possibility of a breast cancer
recurrence. They are understandably eager to have any
edge at all in the fight against this frightening
But the rush to prescribe Femara as a
long-term treatment comes at a time when the US and
other countries are struggling with the problem of
runaway drug costs. Many Americans are already
desperately trying to cope with the inflated price of
prescription drugs, and are looking to decrease those
costs by shopping on the Internet or by buying from
Canadian or Mexican pharmacies.
Thus, the imperative to
take Femara could be a serious economic blow to many
older women and their families, who are trying to
survive in perilous economic times.
What will be the cost of taking this medication, both
to the individual and to society?
I have seen a quoted figure of $200 per month for this
new treatment. Perhaps one can find it for such a
price. But when I called the local branch of a national
pharmacy chain, I was told that the cost of 60 Femara
pills was $487.99, in other words, $8.13 per day (since
the dosage is normally one 2.5 milligram pill per day).
At this rate, the cost per patient will be closer to
$250 per month or about $3,000 per year at the retail
Some women have insurance that will cover some or all
of this cost. Others do not. Those who are on Medicare
will only get limited reimbursement. Femara has until
now only been approved by the FDA for use in treating
post-menopausal women with advanced breast cancer; it
has not yet been approved for long-term secondary
prevention in women with early breast cancer.
company says it will be filing for this new indication
with both the European authorities the US Food and Drug
Administration probably in the second half of next year
(Gardner 2003). Despite reassuring words from the
manufacturer, Novartis, some insurance companies may
balk at paying.
Furthermore, because of the early termination of the
study it is unclear how long women are supposed to take
this drug in order to receive benefit. The women on the
study were given Femara for a period averaging 2.4
years (after they had already spent five years taking
Many women will probably wind up taking
Femara for five years, and quite possibly longer. So,
at retail, we're talking about a cost of around $15,000
per woman. And what happens after five years? The
problem is that there is no cut-off point at which the
recurrence of breast cancer stops being a threat, so
they may be advised to take the drug indefinitely.
How much will this new use of Femara add to the US
national health bill? This is more difficult to
calculate. Of the 211,000 US women who get invasive
breast cancer each year, at least 100,000 are
post-menopausal women with early stage
estrogen-receptor positive tumors and therefore
potential candidates for the drug.
Simple math tells us
that the retail cost of this will be around
However, that only accounts for this year's "class" of
US breast cancer patients. There is already a huge
backlog of individuals who have completed tamoxifen
treatment but eagerly want to do something now to
prevent a possible recurrence of their disease.
are being told that Femara fills that void. These
patients can be expected to create an enormous demand
for this new "miracle drug" in the months ahead.
At a press conference on Oct. 9, Dr. Goss advocated
Femara for many of these women:
"There isn't any plausible biological reason to think
that the drug would not work if there had been a
greater gap from tamoxifen [than three years, ed]," Dr.
"It is my belief that any woman who had
receptor-positive tumors could be accepted but . . .
trying to individualize that patient's risk will be
important" (Gardner 2003).
This attitude, if accepted, will open a floodgate of
demand for Femara in the US. And this is in addition to
the huge international market for the drug.
simply a gold mine for Novartis, Femara's Swiss
manufacturer. I would not be surprised if, with all
this favorable publicity, Femara becomes a
billion-dollar-a-year seller forNovartis… medicine's
equivalent of "going platinum."
Adverse Effects…and Their Cost
The financial consequences of long-term Femara
prescription are not the only alarming aspect of the
current rush to medicate. There is, in addition, a
distinct possibility that women taking Femara may
experience serious adverse effects from the drug
itself. Because Femara works by directly inhibiting the
body's production of estrogen, taking it is often
associated with an upsurge in menopausal symptoms.
According to the manufacturer's website, "approximately
one-third of the patients treated with Femara can be
expected to experience adverse reactions. The most
frequently reported adverse reactions in the clinical
trials were hot flushes, nausea and hair thinning. Many
adverse reactions can be attributed to the normal
pharmacological consequences of estrogen deprivation."
According to the American Cancer Society website, other
reported side effects are pain in bones and muscles,
headache and fatigue. These symptoms can be extremely
debilitating, as women going through menopause know
only too well. For women who thought they had finally
finished with the unpleasant process of menopause the
return of these symptoms will undoubtedly cause
considerable psychological as well as physical distress
and will lead to a significant loss in well-being and
More Threatening Consequences
Femara may also contribute to more threatening
conditions associated with low estrogen, such as
coronary artery disease and osteoporosis.
Osteoporosis is a condition in which the bones become
extremely porous, are subject to fracture, and heal
slowly. Estrogen deficiency has been clearly linked to
menopausal osteoporosis (Riggs 1998). Femara and
similar drugs have been shown to increase bone
resorption, i.e., the loss of the bone's substance
through pathologic or physiologic means (Harper-Wynne
2001). In the present study, more women in the Femara
group than in the placebo group reported a diagnosis of
new-onset osteoporosis, and fractures occurred in more
women in the Femara group than in the placebo group
(3.6 percent and 2.9 percent, respectively).
authors themselves state: "Because of the early
discontinuation of our study, however, these data may
underestimate the long-term effects of letrozole
[Femara] on bone metabolism." This is an extremely
important point - and another example of why stopping a
study prematurely may yield an unrealistically
favorable view of the treatment.
Separate studies are under way to evaluate whether
women given long-term Femara should at the same time be
given drugs called bisphosphonates (such as the
FDA-approved agent Fosamax) in order to counteract the
bone-thinning effects of the estrogen-lowering drug. If
this is found to be warranted, then the cost to the
individual and to society will increase proportionately.
(My local pharmacy sells 35 milligram Fosamax pills for
There is also a concern that, again because of its
anti-estrogenic action, Femara may contribute to an
increased incidence in cardiovascular disease, a
condition that has been clearly associated with lowered
Indeed, the authors of the present
study did find an increase in the number of
"cardiovascular events" (such as heart attacks and
strokes) between the Femara group (88 events, or 4.1
percent) over the placebo group (77 events or 3.6
percent). This difference did not reach statistical
However, as the authors themselves state,
"longer follow-up is needed to rule out the possibility
that letrozole [Femara] has adverse cardiovascular
effects." If Femara does indeed cause even a small
increase in heart attacks and strokes, this alone could
outweigh its positive impact on breast cancer
Is Femara A Conceptual Breakthrough?
Femara is an aromatase inhibitor, a type of drug that
limits the ability of an enzyme called aromatase to
create estrogen, which is a major growth factor in
hormone-receptor positive breast cancers. Aromatase
inhibitors have been shown to effectively suppress
estrogen levels in post-menopausal women.
Dr. Andrew Eschenbach, MD, director of the US National
Cancer Institute, has hailed this class of drugs as a
conceptual breakthrough. "This is one more example of
the ability to interrupt the progression of a cancer
using a drug that blocks a crucial metabolic pathway in
the tumor cell."
However, the idea of arresting breast
cancer progression by curtailing the amount of estrogen
in the body is nothing new. It has been known for
decades that estrogen fuels the growth of many breast
For that reason doctors have long practiced
"ovarian ablation," the surgical removal of the ovaries
from pre-menopausal women with breast cancer. The use
of drugs such as tamoxifen and Femara is simply a
pharmacological way of accomplishing the same thing. It
does not represent a breakthrough in thinking, although
a breakthrough is indeed desperately needed in the
fight against cancer.
Finally, I wish to comment on the general way in which
Femara has been promoted in the media worldwide. There
was a time when scientists maintained a discreet
distance from the treatments that they researched. They
were careful to avoid any semblance of being
promotional. A scientist's role was to question
everything, especially his or her own pet theories and
Now, the news surrounding each new cancer
"breakthrough" seems to become more and more frenetic
in tone. Doctors and scientists, once noted for their
sobriety, are now often enthusiastic ringleaders in
this media circus.
Richard P. Feynman, PhD, the Nobel laureate who gained
universal fame for exposing the defective "O-ring" in
the Challenger shuttle disaster, memorably expressed
his thoughts on scientific objectivity and integrity
"[S]cientific integrity [is]...a kind of utter
honesty-a kind of leaning over backwards. For example,
if you're doing an experiment, you should report
everything that you think might make it invalid - not
only what you think is right about it: other causes
that could possibly explain your results....[T]he idea
is to give all of the information to help others to
judge the value of your contribution; not just the
information that leads to judgment in one particular
direction or another" (Feynman 1985).
A generation or two ago, scientists would often refuse
to profit individually from their involvement in
medical research. Prof. Wilhelm C. Roentgen renounced
the patent on X-rays in order to make his discovery
available to all mankind.
In the 1930s, one of my
mentors, Albert Szent-Györgyi, MD, PhD, refused to take
a patent on his discovery of ascorbic acid (vitamin C)
but instead donated his meager supply of the compound
to prevent scurvy in Scandinavian children (Moss 1987).
This sort of altruism has become exceedingly rare.
Nowadays, it is sometimes difficult to tell the
difference between statements coming from researchers
and those originating in the public relations
departments of Big Pharma. More and more scientists are
making their initial presentations of data not at
medical meetings but at company press conferences.
you read the fine print at the end of this Femara paper
(Goss, et al., 2003) you learn that Drs. Goss, Norton
and several others received consulting and lecture
fees, and/or research support from Novartis. They have
also been among the most outspoken advocates of the
wider use of Femara.
It is hard to escape the conclusion that the public is
being stampeded into accepting this new treatment
before all the salient facts have been sifted and
When scientists themselves become financially
entangled with huge pharmaceutical companies, who is
left to look out for society's interests? Who can make
sure that data is interpreted in a cool and
dispassionate way, and that wide scale illusions are
not fostered in a public that is desperate for cures?
--Ralph W. Moss, PhD
Eastell R, Adams J. Results of the 'Arimidex' (anastrozole,
A), tamoxifen (T), alone or in combination (C) (ATAC) trial:
effects on bone mineral density (BMD) and bone turnover
(ATAC Trialists' Group). Ann Oncol 2002;13:Suppl 5:32.
John Bryant, Ph.D., and Norman Wolmark, M.D. Letrozole after
Tamoxifen for Breast Cancer--What Is the Price of Success? N
Engl J Med 2003;349;19, at: http://www.nejm.org
Feynman Richard P. Surely You Must Be Joking, Mr. Feynman.
New York: Bantam, 1985.
Gardner, Amanda. New Breast Cancer Drug Leaves Questions.
HealthDay, Fri Oct 17, 2003.
Goss PE, Ingle JN, Martino S, et al. A Randomized Trial of
Letrozole in post-menopausal Women after Five Years of
Tamoxifen Therapy for Early-Stage Breast Cancer. N Engl J
Med. 2003 Oct 9.
Harper-Wynne C, Ross G, Sacks N, et al. A pilot prevention
study of the aromatase inhibitor letrozole: effects on
breast cell proliferation and bone/lipid indices in healthy
post-menopausal women. Breast Cancer Res Treat 2001;69:225.
Kolata, Gina. New Drug Regimen Greatly Cuts Risk of
Recurring Breast Cancer
Published: Oct. 10, 2003.
Moss, Ralph W. Free Radical. New York: Paragon House, 1987
Riggs BL, Khosla S, Melton LJ III. A unitary model for
involutional osteoporosis: estrogen deficiency causes both
type I and type II osteoporosis in post-menopausal women and
contributes to bone loss in aging men. J Bone Miner Res
More information on aromatase inhibitors can be found at:
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