Breast
Cancer Study On Letrozole Stirs Concerns
The announcement recently
that a clinical trial on a breast cancer medication was
being halted early because the results were so promising leaves
women with much hope but also many questions.
The study, which appears
in the New England Journal of Medicine, found
that women taking letrozole, one of a new class of drugs called
aromatase inhibitors, had about half the rate of cancer recurrences
as women taking a placebo.
"We've had an enormous
number of phone calls coming in and have decided as a group
that it really is exciting data, but that it shouldn't result
in knee-jerk action," says Dr. Amy Tiersten, an associate professor
of medicine at New York University School of Medicine in New
York City. "It requires a visit with the doctor to go over the
pros and cons."
Study
Results Summarized
The women enrolled
in the study were all postmenopausal, had had breast cancer
but were free of malignancies when they enrolled in the study,
and had stopped taking tamoxifen within the past three months.
Tamoxifen has been
successful in preventing recurrences in women who have estrogen-receptor-positive
breast cancer (when the cancer is fueled by the hormone estrogen).
The drug reduces the risk of recurrence by 47 percent and the
risk of death by 26 percent for five years after surgery.
Unfortunately, tamoxifen
stops working after that time and may even reverse its action.
While tamoxifen works
by occupying the estrogen receptor and preventing the hormone
from binding, letrozole goes further and actually blocks production
of the hormone.
The women in this
study had good results when they started taking letrozole within
three months of stopping tamoxifen.
About the only thing
experts know right now is that women who match the profile of
the study participants should strongly consider taking letrozole.
That is, these women have to be postmenopausal, have had receptor-positive
cancer (but are currently cancer-free), and have finished tamoxifen
within the last three months.
"If you fit the profile
it's very, very clear," says Dr. James Doroshow, chairman of
the division of medical oncology and therapeutics at City of
Hope Cancer Center. "[The study] involved many, many patients
and I would think that even if you are within the first six
months to a year after tamoxifen, extrapolating those results
is probably not an enormous stretch."
Questions
About Timing
The questions begin
when physicians consider women who have been off tamoxifen
for two, three, or more years, although the study authors believe
these women could also benefit.
"There isn't any plausible
biological reason to think that the drug would not work if there
had been a greater gap from tamoxifen for three months," study
author Dr. Paul Goff said at a recent press conference. "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."
There is also an issue
of how long a woman should take letrozole. The study was halted
after a median follow-up of 2.4 years.
"So it really only
tells us about women who receive letrozole for two to three
years," Dr. Tiersten says. "The design of the study was meant
to randomize patients to five years, so that's a big question
as to how long women should be taking aromatase inhibitors -
and it raises a lot of big questions in terms of what the best
adjuvant hormonal therapy is for women."
The issue is complicated
not just by timing, but by sequencing as well. In what order
should women be taking tamoxifen and letrozole or another aromatase
inhibitor, or should they skip tamoxifen altogether?
There are currently
three aromatase inhibitors available and, Dr. Goff said, "at
this point for the research that's been done in humans, there
isn't an easy way to distinguish between them. They all look
as if they act in a similar way." Trials are underway to try
to find subtle differences.
One study did find
that anastrozole, another aromatase inhibitor, was superior
to tamoxifen and to a combination of tamoxifen and anastrozole,
Dr. Doroshow says. It was, however, just one study and should
probably be duplicated before current practice is changed.
Letrozole also has
some side effects. Because it eliminates production of estrogen,
it can exacerbate menopausal symptoms. It may also have an effect
on bone density.
Finally, there is
the question of cost. Letrozole, which comes in pill form and
costs about $200 a month, is already approved for metastatic
breast cancer.
According to Novartis,
which makes the medication, the company will be filing for a
new indication with European authorities and with the US
Food and Drug Administration (FDA), probably in the
second half of next year. It does not foresee any insurance
problems in the meantime.
"There's probably
some variety with insurance but, in general, we don't anticipate
significant problems for reimbursement if the doctor thought
it was appropriate," says Gloria Stone, a Novartis spokesperson.
But, as Dr. Tiersten
points out, a good proportion of the women who would qualify
for letrozole under the new indication are over 65 and have
Medicare, which has limited prescription coverage.
That particular quagmire
will have to be worked out at the policy level. For women who
can afford the drug, Dr. Doroshow says, "the only reasonable
strategy is to discuss all the risks and benefits, the limits
of the data as they exist, and the fact that it will be a considerable
amount of time before one knows more about how to deal with
these questions."
Always consult your
physician for more information.
Online
Resources
(Our Organization
is not responsible for the content of Internet sites.)
American
Cancer Society
American
Society for Clinical Oncology
Centers
for Disease Control and Prevention (CDC)
National
Cancer Institute (NCI) Letrozole Q and A
National
Institutes of Health (NIH)
National
Women's Health Information Center
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December 2003
Breast
Cancer Study On Letrozole Stirs Concerns
Study
Results Summarized
Questions
About Timing
National
Cancer Institute (NCI) Addresses Questions
Komen
Foundation Expert Suggests Caution
Online
Resources
National
Cancer Institute (NCI) Addresses Questions
What were
the results of the study?
According to the NCI,
the study found that cancer returned much less often in the
women taking letrozole compared to those on placebo.
The participants in
the study - post-menopausal women who had been treated for early-stage
breast cancer and who were given letrozole or a placebo (an
inactive substance) after completing five years of tamoxifen
therapy - were followed for an average of 2.4 years and for
as long as five years.
In total, 132 women
taking the placebo had their disease recur compared to 75 on
letrozole.
Overall, after an
average of four years, only 7 percent of those on letrozole
had a recurrence, yet 13 percent of the women on the placebo
had a recurrence.
These reductions included
fewer recurrences in the breast where the original cancer occurred,
in the opposite breast and in internal organs.
The results of this
study appeared recently in an advance, on-line edition of the
New England Journal of Medicine.
This study was the
first to use an aromatase inhibitor during years five through
10 after a breast cancer diagnosis in patients who had completed
five years of treatment with tamoxifen.
Why was the
study stopped early?
According to the NCI,
It was stopped early because there was a significant decrease
in recurrence among the group taking letrozole compared to the
group taking a placebo.
The study was monitored
by an expert, independent data safety monitoring committee.
This committee reviewed
the side effect data every six months and in late August 2003,
saw the first data analyzed about patient outcome.
The committee concluded
that the results indicated taking letrozole was so beneficial
that women should have the opportunity to take the drug.
They recommended that
the trial be stopped and that the women participating in the
trial be informed if they had been receiving letrozole or the
placebo.
Women who have been
receiving the placebo are now being given the option of taking
letrozole.
Always consult your
physician for more information.
Komen
Foundation Expert Suggests Caution
The researchers who
conducted the new study say about 80,000 to 100,000 women in
the United States alone are potential candidates for letrozole
treatment.
A statement issued
by the Susan G. Komen Breast Cancer Foundation,
says, even though "the encouraging news about letrozole could
alter current practices in cancer treatment, not all patients
are candidates to take the drug, and many questions about the
drug’s long-term side effects and efficacy remain unanswered."
Dr. Cheryl Perkins,
senior clinical advisor for the Komen Foundation, says, “While
letrozole may represent an extension of the time to disease
recurrence, additional study is needed to determine the long-term
side effects such as osteoporosis that are a result of estrogen
depletion caused by the drug.
“In addition,
more follow-up time is needed to determine whether there may
be increased risk of cardiovascular events," she says. "Other
important questions, such as the benefit to women who have been
without tamoxifen treatment for more than three months, remain
unanswered.”
Dr. Perkins added,
“Many factors should be evaluated with a physician when
making treatment decisions, and patients who opt not to take
letrozole should feel just as empowered as those who do. It’s
about helping women make the choice that’s right for them
based on knowledge and understanding of the latest information
available.”
Always consult your
physician for more information.
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