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Treatment of Estrogen Deficiency Symptoms in Women Surviving Breast Cancer, Part 6

Treatment of Estrogen Deficiency Symptoms in Women Surviving Breast Cancer, Part 6

Proceedings of a ConferenceHeld at the Boar's Head Inn, Charlottesville,Virginia,
September 21-23, 1997

Executive Summary

Problem: Several million women worldwide have survived breast
cancer but are currently advised against the use of estrogen for the
management of menopausal symptoms and for the prevention of early
cardiovascular death and osteoporosis.

Consensus Conference: A unique meeting involving international
experts and breast cancer survivors
was convened to address this problem.

Recommendations:

  • Use “tailored treatment strategies,” which avoid the use of
    estrogens while providing its benefits (short and long term), to
    address individual patients’ needs.

  • Perform research trials to evaluate estrogens or estrogen
    alternatives in selected groups of women in whom the benefits might
    potentially outweigh the risks.

  • Conduct clinical trials to exploit the highly favorable properties of
    selective estrogen receptor modulators (SERMs).

  • Forge a “Partnership for Progress” between patient advocate
    groups and health professionals in order to facilitate research and
    education about treatment options.

  • Further develop the “Partnership for Progress” by exploring
    the establishment of a patient-initiated registry to determine what
    alternatives or standard medical approaches patients are using to
    manage estrogen deficiency symptoms and to prevent cardiovascular
    disease and osteoporosis.

Consensus Statement

Definition of the Problem

Increased patient awareness, mammography screening, and the use of
adjuvant therapy have resulted in earlier diagnosis of breast cancer
and a greater probability of long-term survival. Consequently, a
large and increasing number of women who have survived breast cancer
are alive. In two-thirds of these patients, the onset of menopause
occurred prior to the diagnosis of breast cancer. In many of the
others, ovarian failure resulted from adjuvant chemotherapy or
occurred spontaneously. A large fraction of these women currently
experience symptoms of estrogen deficiency and/or can expect to
develop premature heart disease and osteoporosis.

At present, estrogen replacement therapy is considered by many to be
contraindicated in these menopausal breast cancer survivors since
estrogens may accelerate the growth of occult metastases. How to
treat the range of problems related to estrogen deficiency in these
patients is largely unexplored at present. Both the short-term
effects of estrogen deficiency, such as vasomotor instability and
urogenital atrophy, and the long-term consequences, such as
osteoporosis and heart disease, represent important health and
quality-of-life issues for these breast cancer survivors.

Magnitude of the Problem

There are several million breast cancer survivors worldwide.
Specifically, in the United States, 180,000 women were diagnosed with
breast cancer in 1997. Approximately 97,000 of these women have an
extremely low chance of experiencing a recurrence of their cancer
during their lifetime. With an average age at diagnosis of 60 years
and a 25-year expected survival, the current number of breast cancer
survivors in the United States may approach 2.5 million women. Since
breast cancer is now being detected at an earlier stage than
previously and since adjuvant chemotherapy may cause ovarian failure,
an increasing number of women are postmenopausal at a younger age
after breast cancer treatment.

Purpose of the Conference

This conference was convened to consider how menopausal breast cancer
survivors should be treated at the present time and what future
studies are needed to develop improved therapeutic strategies.

Participants

Patient advocates, as well as experts from a wide range of
disciplines, including medical oncology, surgery, gynecology,
endocrinology, radiology, nursing, epidemiology, and the basic
sciences, were represented (see list of conference participants). The
conference planners wished to fully integrate women with a previous
diagnosis of breast cancer into the schedule of formal talks and
discussions so that the perspective of the patient would receive
appropriate emphasis.

Specific Topics

The conference focused on three specific areas and attempted to reach
consensus or identify areas of divergent opinion in each. The first
addressed the question of initiating clinical trials with estrogen
replacement therapy in subsets of women surviving breast cancer or
using estrogens prior to the completion of trials. The second topic
evaluated the potential for the use of selective estrogen receptor
modulators (SERMs) in treating the problems arising from estrogen
deficiency. The third considered the use of surrogates for estrogen
to treat specific problems related to estrogen deficiency.

Key aspects of each of these topics are considered in this report,
and areas of consensus and divergence are described under each topic.
In addition, a consensus statement was prepared by the patient
advocates to reflect their unique perspective on the various issues discussed.

Topic I: Use of Estrogens as Treatment of
Menopausal Problems

Background

Menopausal women with a previous diagnosis of breast cancer, like
other women, experience a variety of hormonal changes that
potentially affect every aspect of their lives. In addition, many of
the therapies currently recommended following a diagnosis of breast
cancer produce body changes that can worsen this situation.
Lumpectomy, breast irradiation, mastectomy, and axillary dissection
each produce changes in body and body image. Most combination
chemotherapies produce either complete menopause or at least some
degree of ovarian dysfunction. Menopause can be produced abruptly in
this situation, precipitating acute menopausal symptoms, which add to
the anxieties, symptoms, and concerns already associated with the
diagnosis of breast cancer and its surgical, chemotherapeutic, or
hormonal therapy.

A traditional belief of the medical profession holds that estrogen
and/or progesterone therapy represents an unacceptable risk in women
surviving breast cancer. This belief is not unreasonable, as it is
based on much of our knowledge about the causes and treatment of
breast cancer. Estrogen and progesterone exposure are closely related
to the development of breast cancer. In established breast cancer,
removal or reduction of estrogen often results in shrinkage of breast
cancer or in prevention of recurrence. Thus, both physicians and
patients remain extremely cautious about the routine clinical use of
estrogen or progesterone in women who have ever had a diagnosis of
breast cancer.

On the other hand, recent studies in patients without breast cancer
suggest that estrogen replacement therapy can lengthen life. Thus, it
is possible that withholding estrogen from women with a previous
diagnosis of breast cancer could increase their mortality from
cardiovascular disease. Small observational studies in women with
breast cancer receiving estrogen replacement therapy have not shown
more rapid recurrence, but properly randomized studies have not yet
been conducted. Thus, important information is lacking regarding the
safety and benefits of estrogens in women surviving breast cancer.

Consideration of Clinical Trials

The conference participants considered whether any trials of estrogen
replacement should be undertaken in survivors of breast cancer, and,
if so, in which subset of patients. The participants agreed that the
ability to control menopausal symptoms with surrogates for estrogen,
while effective in some patients, was limited in others.

The majority of polled participants, but not all, agreed on the need
to conduct trials of estrogen replacement therapy in selected groups
of women surviving breast cancer. There was agreement that the
currently ongoing trials, such as the Hormone Replacement Study After
Breast Cancer: Is it Safe? (HABITS) trial, a large multi-institution
Scandinavian and European trial coordinated from the Uppsala
University by Dr. Lars Holmberg, and other trials will not provide
all of the information needed.

Those favoring clinical trials of estrogen replacement believe that
an answer to this question is required and that it would not be
ethical to continue to make recommendations to patients without
greater scientific evidence. Those arguing against clinical trials
believe that major difficulty will be encountered in entering a
sufficient number of patients in these trials to answer the safety
questions with acceptable statistical power. One participant
suggested that information regarding safety might be gained from
case-control observational studies resulting from the establishment
of a patient registry.

Most agreed that the initial trials should consist of short-term
studies focusing on relief of symptoms of vasomotor instability and
urogenital atrophy but not on prevention of osteoporosis or heart
disease. Safety issues under these circumstances would involve the
risk of accelerating the growth of occult metastases but not the
initiation of new second primary breast cancers.

One group favored trials in patients at lowest risk of adverse
effects from estrogens, namely, women with estrogen receptor (ER)
negative tumors. Other participants favored trials in women with
receptor positive tumors, arguing that studies in these women would
provide stronger evidence of safety if recurrences were not
increased. The latter women were also thought to provide higher
statistical power to detect significant differences in recurrence.
The pros and cons of these two approaches were felt to represent a
dilemma with no easy resolution.

Review of an ongoing trial and strong opinions expressed by patient
advocates suggested that only a small fraction of breast cancer
survivors would accept the use of estrogen replacement therapy, even
if studies suggested relative safety. Consequently, trials with other
approaches designed to relieve menopausal symptoms should also be
carried out in order to develop safe, acceptable alternatives for
women. Some participants felt that the use of progestins might not be
safe in this setting, even though megestrol acetate is known to be an
effective treatment for advanced breast cancer, albeit at higher
doses than those used for vasomotor instability.

The participants discussed at length, but could not agree on,
specific groups of women to be involved in initial trials of hormone
replacement therapy (HRT). Many reasoned that women undergoing
chemotherapy-induced menopause experience particularly severe
symptoms and should be targeted for initial trials of hormone
replacement. Most agreed that such trials should commence only after
subsidence of chemotherapy-related symptoms in order to avoid
confounding the interpretation of results. Patient advocates and
others expressed the opinion that women in this category would be
most frightened of the adverse effects of estrogen and that accrual
into such trials would be too small to obtain meaningful information.

Substantial discussion addressed clinical trials of the combined use
of tamoxifen (Nolvadex) and replacement estrogen in patients with ER
positive tumors. At the conference, concepts had been formally
presented regarding the stoichiometry between tamoxifen and estrogen
for the ER and the differential agonistic and antagonistic effects of
tamoxifen on various target tissues.

It was noted that tamoxifen is an effective antitumor agent for
advanced breast cancer in cycling premenopausal women with estradiol
levels of 1,000 to 2,000 pmol/L. Based on this observation, tamoxifen
should remain an effective antitumor agent in postmenopausal women
given small amounts of replacement estradiol sufficient to increase
plasma levels only to the 150- to 450-pmol/L range. Under these
conditions, the effects of estrogen might relieve hot flashes and
symptoms of vasomotor instability without stimulating tumor growth.
Preliminary biochemical data were presented to the participants
regarding patients receiving therapy with both tamoxifen and
conjugated estrogens (Premarin).

Based on this information, the participants believed that the
combination of tamoxifen with estrogen or progesterone might
potentially relieve menopausal symptoms without increasing the risk
of tumor recurrence. It was agreed, however, that the data presented
were insufficient to conclude that symptoms would be fully relieved
by this approach.

Most participants agreed that small pilot studies to determine the
efficacy of this approach in relieving symptoms should be followed by
large, randomized, controlled trials to ensure safety. This approach
was favored particularly for women with ER positive tumors.

The conference participants initially attempted to design prototype
clinical trials of HRT during the consensus- building period. This
was found to be impossible and, as expressed by several discussants,
not the purpose of the consensus conference.

The panel then agreed to establish general principles on which such
trials could be based. A consensus was reached that trials of hormone
replacement should initially involve women who are symptomatic,
rather than women in whom the prevention of osteoporosis or heart
disease is the primary goal. Trials should be short term to minimize
concerns about stimulation of occult micrometastases. Only with
long-term estrogen replacement would the initiation of new second
primaries be an important consideration.

Groups of women selected for such trials should have findings
suggesting that the benefits of HRT are likely to outweigh the risks.
These might include women receiving tamoxifen; patients with small,
node-negative or low-histologic tumor grades, in whom the likelihood
of long-term survival is great; women with receptor negative tumors;
and women with a long disease-free survival before treatment with estrogen.

Use of Estrogen Replacement Prior to Completion of Clinical Trials

The participants considered at length whether it might be appropriate
to offer HRT to selected women, as an interim measure, prior to the
completion of clinical trials. All agreed that other established
means of controlling symptoms or preventing osteoporosis or heart
disease should be utilized before considering estrogen therapy.

In those women who do not respond, entry into a clinical trial would
be the preferable approach. However, nearly all agreed that a subset
of women continue to experience severe problems from estrogen
deficiency that might only be controlled by HRT. The participants
agreed that an informed woman, knowing all the potential benefits and
risks of estrogen, could choose to take estrogen and may be supported
in that decision. Under those circumstances, informed consent by the
patient should precede the use of estrogens (most, but not all, felt
this should be written informed consent). The unknown but potential
risks of stimulating occult metastases or of causing a new cancer
should be fully discussed.

A clear distinction was made that there was not a consensus to
recommend estrogen in selected patients, but rather, that a woman is
free to make her own decision provided she is fully informed.
Estrogens or progestins in this setting should be prescribed in the
lowest doses, for the shortest duration of time, and only after full
discussion. This strategy considers the informed patient as the final
decision-maker. The heath care provider serves to guide the patient
through the difficult process of assessing known and unknown risks
and benefits.

To capture the essence of the discussion, a comprehensive statement
was offered to the participants and agreed on:

“In women who have had an established diagnosis of breast
cancer, we should seek other established symptomatic or health
promoting interventions before considering the use of estrogens. When
estrogen is used as a last resort, it should be used in the lowest
dose for the shortest duration of time and only after full discussion
of concerns regarding potential risks with respect to breast cancer
outcomes. When estrogen is being considered, the role of the informed
woman as the final decision maker should be accepted by the health
care practitioner.”

Summary of Consensus Points

  • Studies of a variety of methods to control the short-term effects of
    estrogen deficiency in breast cancer survivors are necessary. One
    approach is to examine the efficacy of surrogates for estrogen. The
    other is the use of estrogen itself, where the primary goal should be
    to examine the efficacy and safety of estrogen and progesterone
    replacement therapy.

  • Initial emphasis should be on trials for relief of menopausal
    symptoms, including hot flashes, vaginal dryness, urinary symptoms,
    and painful intercourse.

  • Carefully designed trials to explore the effectiveness and safety of
    estrogens and/or progesterone in women with a previous diagnosis of
    breast cancer who are also receiving tamoxifen should be undertaken.

  • Well-designed trials, starting with smaller pilot studies to
    determine efficacy and followed by large, randomized, controlled
    trials to ensure safety, will be required to establish the indication
    for combined estrogen and antiestrogen therapy.

  • Since only a small fraction of women surviving breast cancer will
    accept HRT, trials of alternative therapies to relieve symptoms are required.

  • A series of principles intended to guide initial clinical trial
    design included the following:

  1.  Clinical trials should include only symptomatic women and HRT
    given over the short term.

  2.  Well designed, randomized trials are required.

  3.  Studies should involve women in whom the benefits of HRT are
    likely to outweigh the risks. Specifically, this might include: women
    with small, node-negative or low-histologic grade tumors; women
    receiving tamoxifen; women with receptor negative tumors; and women
    with a long disease-free survival.

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