[MOL] Tamoxifen [00447] Medicine On Line


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[MOL] Tamoxifen



Tamoxifen has a beneficial effect in approximately 50% of women with
metastatic breast cancer. It reduces cancer recurrence and mortality rates
in stage I and II disease and reduces the risk of new primary cancer in the
other breast. The possibility that the drug may prevent or delay the
development of breast cancer in healthy women with a family history of the
disease has prompted the initiation of large-scale, double-blind controlled
trials of tamoxifen (20 mg/kg/day) in the United States, the United
Kingdom, Italy, and Australia. The US clinical trial, begun in 1992, is the
most ambitious and controversial trial ever undertaken by the National
Cancer Institute (NCI). This $68 million trial is being conducted by the
National Surgical Adjuvant Breast and Bowel Project (NSABP), a group headed
for years by Bernard Fisher at the University of Pittsburgh.

NSABP had signed up some 11,000 healthy women aged 35 to 78 and was
attempting to recruit another 5000 -- half of whom were to receive
tamoxifen for 5 years, and half to receive placebo, with follow-up for 7
years -- when NCI suspended the trial. Government audits had turned up
irregularities in NSABP data (in particular, data concerning the merits of
lumpectomy versus mastectomy). As a result, NCI suspended all NSABP
clinical trials, including the tamoxifen study, and forced the resignation
of Fisher and his deputy, Carol Redmond. Currently NSABP is installing a
new data auditing system, forming a new management team, and electing new
leaders. [Anderson C. Science. 1994; 263:1679. Marshall E. Science. 1994;
264:1524-1527.]

Some of the best tamoxifen data are from a large trial coordinated by NSABP
(the B-14 trial) involving a dozen centers and nearly 3000 patients with
hormone-sensitive, nonmetastatic breast cancer. Tamoxifen was shown to
reduce the incidence of new breast cancer by about 40% and to reduce
cholesterol levels and prevent bone loss. It was also shown to increase the
risk of endometrial cancer (Oncolink-NCI-PDQ), deep-vein thrombosis, and
possibly ocular degeneration. Most cases of endometrial cancer were
detected early enough to treat, but there were some deaths. However, the
increase in mortality was more than offset by the decrease in mortality
from breast cancer. [Fisher B et al. J Natl Cancer Inst. 1994; 86:527-537.]

A number of other clinical trials also found that tamoxifen increased the
risk of endometrial cancer. In a Swedish study involving 1372 subjects
randomized to tamoxifen or placebo, endometrial cancer developed in 23
women in the tamoxifen group compared with 4 in the placebo group during
9-year follow-up. A British study of 111 subjects enrolled in the UK Pilot
Breast Cancer Prevention trial found that tamoxifen- treated women had more
uterine abnormalities than patients in the placebo group (39% had a
thickened endometrium, compared with 10% of placebo subjects, and 16% had
atypical hyperplasia, compared with none in the placebo group). [Kedar RP
et al. Lancet. 1994;1318-1324.] There is also evi-dence that tamoxifen may
increase the risk of gastrointestinal cancer and damage the fetus when
taken during pregnancy.

An NCI panel has imposed two conditions on the current NSABP trial:
stronger warnings about uterine cancer and annual endometrial testing for
all participants. Patients are urged to see their physicians promptly if
they experience any menstrual irregularities, abnormal vaginal discharge,
change in vaginal discharge, or pelvic pain or pressure. The drug is still
indicated for the treatment of breast cancer, but the NCI emphasizes that
tamoxifen should not be taken as a breast cancer preventive outside of a
clinical trial. Nevertheless, physicians are already prescribing tamoxifen
as a prophylactic agent for women with a family history of breast cancer. 


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