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New
Drugs Offer Hope in Breast Cancer Fight
By
Thomas H. Maugh II, the
Los Angeles
Times
October
10, 2003
A new class of drugs will
change the way breast cancer is treated, significantly reducing the
disease's recurrence in post-menopausal women who have completed the
normal regimen of surgery and chemotherapy, an international team reported
Thursday.
The new drugs, called aromatase inhibitors, could improve the survival
chances of as many as half of the 213,000 American women who contract
breast cancer each year.
One of the new drugs, called letrozole, proved so effective in a study of
women who had already finished a five-year regimen of the drug tamoxifen
that the study was halted prematurely and the results released on the
Internet before their publication next month in the New England Journal of
Medicine.
Among breast cancer survivors who have completed five years of
prophylactic therapy with tamoxifen, the risk of recurrence is normally
about 1% to 2% per year. Letrozole, sold under the brand name Femara by
Novartis Inc., reduced recurrence by 43%.
"This is going to change the way we treat breast cancer," said
Dr. James Doroshow of City of
Hope
in
Duarte
. "There are hundreds of thousands of women
who could potentially benefit."
About two-thirds of all breast cancers are sensitive to circulating levels
of estrogen, which stimulates the tumor's growth. Tamoxifen interferes
with this process by blocking estrogen receptors throughout the body.
Several clinical studies have shown that five years of treatment with
tamoxifen after the conclusion of surgery and chemotherapy can sharply
reduce recurrence of tumors.
But continued administration of tamoxifen after five years produces no
additional benefit and may, in fact, harm women, the studies have shown.
A recurrence of the disease while women are taking tamoxifen or afterward
requires a new course of chemotherapy, surgery or radiation.
The aromatase inhibitors were designed to block the body's production of
estrogen, thereby preventing the hormone from stimulating tumor growth. In
the new study, for example, circulating levels of estrogen were reduced by
95%.
The aromatase inhibitors cannot be used in pre-menopausal women, however,
because they do not block estrogen production in the ovaries, which is the
predominant source in young women.
Femara and the closely related drugs anastrazole (sold as Arimidex by
AstraZeneca) and exemestane (sold as Aromasin by Pharmacia) are already
used to treat metastatic breast cancer and locally aggressive breast
cancer. Because they worked by a different mechanism than tamoxifen,
clinicians hoped they could be effective when tamoxifen's benefits wore
off.
To test this idea, a team headed by Dr. Paul Goss of
Princess
Margaret
Hospital
in
Toronto
enrolled 5,187 Canadian, American and European
post-menopausal women who had been taking tamoxifen for four to six years.
After they completed their tamoxifen regimen, half the women received
daily doses of letrozole and half received a placebo.
The study was intended to monitor the women for five years, but when the
preliminary results were evaluated by a safety committee after 2.4 years,
the drug's effects were so impressive that the study could not ethically
be continued. Women receiving the placebo were informed of the results and
encouraged to take letrozole.
The team found that 75 of the women taking letrozole had their cancers
recur, compared with 132 of those taking a placebo. Overall, 13% of those
taking a placebo had a recurrence, compared with 7% of those taking
letrozole. Seventeen women taking the placebo died of breast cancer,
compared with nine of those taking letrozole, but there were not enough
deaths for the difference to be clinically significant, Goss told a news
conference Thursday.
The benefit of the drug "was substantially greater than
expected," Dr. Norman Wolmark of
Allegheny General
Hospital
in
Pittsburgh
noted in an editorial accompanying the study.
The findings were so dramatic, Goss said, that "I would argue 'take
letrozole' to any woman who has previously been exposed to tamoxifen."
The side effects of letrozole — as with those of tamoxifen — are
essentially the symptoms of menopause: a higher risk of osteoporosis, hot
flashes, sweating, edema, sore muscles and fatigue. About 4.5% of those
taking letrozole stopped taking the drug because of side effects, compared
with 3.6% of those taking a placebo.
Although stopping the study early was "absolutely necessary
ethically," Doroshow said, it left many questions unanswered.
Clinicians have no idea, for example, how long letrozole treatment will
remain effective and whether there are unforeseen long-term risks.
Doroshow noted that some physicians are already beginning to prescribe
letrozole instead of tamoxifen for women who have just completed
chemotherapy, because its side effects are milder. That also opened
further questions, such as whether letrozole should be followed by
tamoxifen, which sequence of the two drugs would be most effective and
could they be used together?
"It will be another 10 years before we know the answers to those
questions," Doroshow said.
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