Here's NCI's Q&A on the trial:
This document describes preliminary results from the Breast
Cancer Prevention Trial. It is divided into three sections:
Background and Study Design (questions 1-12);
Preliminary Trial Results/Notifications (questions 13-24)
Public Concerns (questions 25-37)
Background and Study Design
1. What is the Breast Cancer Prevention Trial?
The Breast Cancer Prevention Trial (BCPT) is a clinical trial (a
research study conducted with people) designed to see
whether taking the drug tamoxifen (Nolvadexr) can prevent
breast cancer in women who are at an increased risk of
developing the disease. The BCPT is also looking at whether
taking tamoxifen decreases the number of heart attacks and
reduces the number of bone fractures in these women. The
study began recruiting participants in April 1992 and closed
enrollment in September 1997; 13,388 women ages 35 and
older are enrolled. Researchers with the National Surgical
Adjuvant Breast and Bowel Project (NSABP) are conducting
the study in more than 300 centers across the United States
and Canada. The study is funded by the National Cancer
Institute (NCI), the United States' primary agency for cancer
research.
2. What is tamoxifen?
Tamoxifen is a drug, taken by mouth as a pill. It has been used
for 25 years to treat patients with advanced breast cancer.
Since 1985 it has also been recommended in the United States
for adjuvant, or additional, therapy, following surgery and/or
radiation for early stage breast cancer. Tamoxifen works
against breast cancer, in part, by interfering with the activity of
estrogen, a female hormone that promotes the growth of breast
cancer cells. For this reason, tamoxifen is often called an
"anti-estrogen." In treatment, the drug slows or stops the
growth of these cancer cells.
3. Why was tamoxifen tested to prevent breast cancer?
Research has shown that taking tamoxifen as adjuvant therapy
for breast cancer not only helps prevent the original breast
cancer from returning but also helps to prevent the
development of new cancers in the opposite breast.
Researchers believed that tamoxifen might have a similar
beneficial effect for women at increased risk of breast cancer.
While tamoxifen acts against the effects of estrogen in breast
tissue, it acts like estrogen in other body systems. Tamoxifen's
estrogen-like effects include the lowering of blood cholesterol
and the slowing of bone loss.
4. Who participated in the BCPT?
Women at increased risk for developing breast cancer
participated in the study. These included women 60 years of
age and older who qualified to participate based on age alone,
and women between the ages of 35 and 59 with an increased
risk of breast cancer equivalent to or greater than that of a
60-year-old woman. At age 60, about 17 of every 1,000
women are expected to develop breast cancer within five
years.
Of the 13,388 women on the trial, about 40 percent were ages
35 to 49, about 30 percent were ages 50 to 59, and about 30
percent were age 60 or older. About 3 percent of the
participants were minorities, including African American, Asian
American, Hispanic, and other groups.
5. Did every woman in the study receive tamoxifen?
No. Participants in the BCPT were randomized (selected by
chance) to receive either tamoxifen or a placebo (an inactive
pill that looked like tamoxifen). In a process known as "double
blinding," neither the participant nor her physician knew which
pill she was receiving. Setting up a study in this way allowed
the researchers to clearly see what the true benefits and side
effects of tamoxifen are without the influence of other factors.
According to the design, all women in the study were to take
two pills a day for five years, either a 20-mg dose of tamoxifen
(two 10-mg pills) or placebo pills.
6. Why were women 60 years of age or older eligible for the
BCPT based on age alone?
Many diseases, including breast cancer, occur more often in
older persons. The risk of developing breast cancer increases
with age, so breast cancer occurs more commonly in women
over 60 years of age. The risk of developing heart disease or
osteoporosis also increases with age, and those diseases are
also being studied in the BCPT.
7. What factors were used to determine increased risk of
breast cancer for the participants aged 35 to 59?
To enroll in the study, women between 35 and 59 years of age
needed to have a risk of developing breast cancer within the
next five years that was equal to or greater than the average
risk for 60-year-old women. This increased risk was
determined in one of two ways. Women diagnosed as having
lobular carcinoma in situ, a condition that is not cancer but
indicates an increased chance of developing invasive breast
cancer, were eligible based on that diagnosis alone. The risk
for other women was determined by a computer calculation
based on the following factors:
Number of first-degree relatives (mother, daughters, or
sisters) who had been diagnosed as having breast cancer;
Whether a woman had any children and her age at her first
delivery;
The number of times a woman had breast lumps biopsied,
especially if the tissue was shown to have a condition known as
atypical hyperplasia; and
The woman's age at her first menstrual period.
For example, a 35-year-old woman would have to have two
or more first-degree relatives with breast cancer AND a
personal history of at least one benign breast biopsy OR a
diagnosis of lobular carcinoma in situ.
A 45-year-old woman would have to have one or more
first-degree relatives with breast cancer AND a personal
history of at least one benign breast biopsy OR a diagnosis of
lobular carcinoma in situ.
A 55-year-old woman would have to have one or more
first-degree relatives with breast cancer OR a personal history
of at least one benign breast biopsy OR a diagnosis of lobular
carcinoma in situ.
8. What proportion of women in the United States are
estimated to be at the level of risk required for participation in
the BCPT?
At age 35, about three women in 1,000 or .3 percent, would
have qualified for the study based on their estimated breast
cancer risk.
At age 40, the proportion is about 27 women in 1,000, or 2.7
percent.
At age 45, the proportion is about 71 women in 1,000, or 7.1
percent.
At age 50, the proportion is about 93 women in 1,000, or 9.3
percent.
At age 55, the proportion is about 125 women in 1,000, or
12.5 percent.
At age 60 and beyond, all women would have met the breast
cancer risk criteria.
9. Did other factors affect eligibility for the study?
Certain existing health conditions affected eligibility for the
study. For example, women at increased risk for blood clots
could not participate. Also, women taking hormone
replacements and women using oral contraceptives ("the pill")
could not take part in the trial unless they stopped taking these
medications. Those who stopped taking these hormones were
eligible for the study three months after they discontinued the
drugs.
Women who were pregnant or who planned to become
pregnant were not eligible to participate. Animal studies have
suggested that the use of tamoxifen during pregnancy might
harm the fetus. Premenopausal women participating in the
BCPT were required to use some method of birth control other
than oral contraceptives. Oral contraceptives may change the
effects of tamoxifen and may also affect the risk of breast
cancer.
10. Were the participants required to have any medical exams?
Participants were required to have blood tests, a pelvic exam,
a mammogram, and a physical exam before being accepted
into the study. Women 55 years of age and older needed to
have an electrocardiogram or ECG (a test to measure the
heart's muscular activity), in addition to the other tests.
Screening endometrial sampling (an examination of cells from
the lining of the uterus) was required at entry for participants
joining the study beginning in October 1994 and was strongly
recommended annually for all women in the study. These tests
were repeated periodically.
11. Who paid for these medical exams?
Most physicians' fees and the costs of medical tests were
charged to the participant as if she were not part of the study;
however, the costs for these tests were often covered by the
participant's insurance company. Screening endometrial
samplings were provided without charge. For women over 55,
the required electrocardiograms were also done at no cost.
Every effort was made to contain the costs specifically
associated with participation in this study, and a fund was
available to cover costs for participants without the ability to
pay.
12. How much did the tamoxifen cost the participants?
There was no charge to participants for the tamoxifen or the
placebo. The company that manufactures tamoxifen, Zeneca
Pharmaceuticals Group, of Wilmington, Del., (formerly ICI
Americas, Inc.) provided both the tamoxifen and the placebo
without charge.
Questions and Answers: Preliminary Trial
Results/Notifications
13. What are the initial results of the BCPT?
At this point (data to Jan. 31, 1998), women on the trial have
been followed on the study for about four years. Results show
45 percent fewer diagnoses of invasive breast cancer in women
who were randomized to take tamoxifen compared to women
who were randomized to take the placebo (85 cases in the
tamoxifen group versus 154 cases in the placebo group).
Women on tamoxifen also had fewer diagnoses of noninvasive
breast cancer, such as ductal carcinoma in situ (31 cases in the
tamoxifen group versus 59 cases in the placebo group). Eight
women have died of breast cancer, three women in the
tamoxifen group and five women in the placebo group.
Women in the tamoxifen group had fewer bone fractures of the
hip, wrist, and spine than women in the placebo group (47
cases in the tamoxifen group versus 71 cases in the placebo
group). There was no difference in the number of heart attacks
between the two groups.
Tamoxifen did increase the women's chances of three rare but
serious health problems: endometrial cancer (cancer of the
lining of the uterus) 33 cases in the tamoxifen group versus 14
cases in the placebo group; pulmonary embolism (blood clot in
the lung) 17 cases in the tamoxifen group versus 6 cases in the
placebo group; and deep vein thrombosis (blood clots in major
veins) 30 cases in the tamoxifen group versus 19 cases in the
placebo group.
14. What were the participants' chances of developing
endometrial cancer?
BCPT participants who were randomized to the tamoxifen
group had more than twice the chance of developing
endometrial cancer compared with women on placebo (based
on 33 cases in the tamoxifen group versus 14 cases in the
placebo group). The increased risk of endometrial cancer was
equal to the risk that was expected and is in the same range as
(or less than) the endometrial cancer risk for postmenopausal
women taking single-agent estrogen replacement therapy.
Estrogens and agents that act like estrogens are known to
increase the risk of endometrial cancer.
All the participants were informed about the possibility of
increased risk of endometrial cancer before they entered the
study. Like all cancers, endometrial cancer is potentially
life-threatening. All but one (in the placebo group) of the
endometrial cancers that occurred during the study were found
at an early stage, when treatment is very effective. However,
one participant (also in the placebo group) died of endometrial
cancer. About 37 percent of BCPT participants in both groups
had a hysterectomy (surgery to remove the uterus) for a variety
of health reasons before joining the study. Therefore, these
women were not at any risk for endometrial cancer.
15. What was done to help diagnose endometrial cancer early?
Pap smears are very effective at detecting cancer in the cervix
but are not useful for detecting endometrial cancer. Therefore a
screening endometrial sampling < removal of cells in the lining of
the uterus for examination under a microscope < was used in
the BCPT to detect abnormalities in the endometrium. Women
who joined the study after October 1994 were required to
have a screening endometrial sampling before entering the
study if their uterus had not been removed. All women in the
study were strongly urged to have screening endometrial
sampling done annually throughout the study (at no cost to
them), but could decline if they chose. In addition to these
annual tests, women in the BCPT were told to see their
physicians if they experienced abnormal vaginal bleeding or
pain. The vast majority of the endometrial cancers that were
diagnosed in the BCPT caused such symptoms.
16. What were the participants' chances of getting blood clots?
Women taking tamoxifen had almost three times the chance of
developing a pulmonary embolism (blood clot in the lung) as
women on placebo (based on 17 cases in the tamoxifen group
versus 6 cases in the placebo group). Two women died from
these embolisms, both in the tamoxifen group. Women in the
tamoxifen group were also more likely to have deep vein
thrombosis (a blood clot in a major vein) than women on
placebo (30 cases versus 19 cases). Blood clots occur more
often in people with high blood pressure (hypertension),
diabetes, smokers, and in those who are obese.
17. Is there a relationship between tamoxifen use and the
development of eye problems?
Women in the tamoxifen group, in general, had no more eye
problems than women taking the placebo. However, women
taking tamoxifen may be at a slightly increased risk for
developing cataracts (a clouding of the lens inside the eye)
according to other research. As women age, they are more
likely to develop cataracts whether or not they take tamoxifen.
Other eye problems, such as corneal scarring or retinal
changes, have been reported in a few breast cancer patients in
tamoxifen treatment trials.
18. Was tamoxifen associated with any other cancers?
Tamoxifen was not associated with an increased risk of any
other cancer other than endometrial cancer.
19. What were the other adverse effects of tamoxifen?
Like most medications, whether over-the-counter medications,
prescription drugs, or drugs in research studies, tamoxifen
causes adverse effects in some women. The effects
experienced most often by women in the tamoxifen group were
hot flashes and vaginal discharge. Women in both groups
reported sometimes having side effects < even though the
placebo itself would not cause any symptoms. The side effects
that some women in both groups reported included: vaginal
dryness, itching, or bleeding; menstrual irregularities;
depression; loss of appetite; nausea and/or vomiting; dizziness;
headaches; and fatigue. Treatments that could minimize or
eliminate most side effects were available to the participants.
20. Did any group of women benefit more from tamoxifen than
others?
It is possible that the breast cancer benefit from tamoxifen
could be greater in women over age 50, but older women are
also at increased risk for some of the serious side effects
(endometrial cancer, pulmonary embolism, and deep vein
thrombosis).
21. Why was the study "unblinded," and who made that
decision?
As part of the study design, the BCPT data were regularly
reviewed by an independent Endpoint Review, Safety
Monitoring, and Advisory Committee (ERSMAC). At its
regularly scheduled meeting on March 24, 1998, the committee
recommended to NSABP that the study be unblinded (inform
the participants and their physicians what pills the participants
had been taking) because of the clear evidence of a reduction
of breast cancer incidence in the tamoxifen group. The NSABP
presented the data and recommendation to the NCI on March
26 and together, NSABP and NCI researchers concurred with
the committee's recommendation. This was based upon the
assessment of all three groups that the effect of tamoxifen in the
reduction of breast cancer had been demonstrated. It was
agreed that any additional information that could be gained
from continuing the study in its current form did not outweigh
the benefits of making the treatment available to the participants
in the placebo group and other women at an increased risk of
breast cancer.
22. How were the participants notified?
At the inception of the study, the NSABP made a commitment
to make every effort to notify the participants of major results
prior to any public announcement. After notification to the
BCPT Participant Advisory Board, a group of 16 women in
the trial, a letter announcing initial results and details for
participant "unblinding" was rapidly sent to BCPT investigators
so that they could convey this information to BCPT
participants.
23. What will the participants do now?
All participants are being asked to continue with their follow-up
examinations. Women who have been randomized to the
tamoxifen group who have not completed five years of
tamoxifen therapy will have the opportunity to continue on
therapy. Postmenopausal women who had been taking the
placebo are being invited to participate in an upcoming trial that
will compare tamoxifen to a different drug that could have
similar breast cancer prevention properties, but might be
associated with fewer adverse effects. Women of any age on
placebo also have the option of seeking tamoxifen from their
private health care providers.
24. Would it be beneficial for women to take tamoxifen for
more than five years?
Not necessarily: Results of another NSABP study in which
women with early stage breast cancer took tamoxifen for 5
years versus 10 years (called the B-14 trial) showed no greater
benefit from the longer duration of tamoxifen and showed a
trend toward more adverse effects.
Questions and Answers: Public Concerns
|
