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Other Guidelines
Guidelines on endocrine therapy of breast cancer
Introduction
It was in 1896 in Glasgow that George Beatson published his famous
paper showing that removal of the ovaries had reduced the size of a primary
breast cancer. As the first description of any systemic therapy that affected
any malignant tumour it was a brilliant discovery but it rates even higher, for
the idea followed from the line of Beatson's research. An aspiring surgeon, in
his MD thesis on the control of lactation, he showed that the ovaries
controlled the persistence of lactation an said, "It pointed to one organ
holding the control over the secretion of another and separate organ" -
suggesting endocrine action.
Removal or irradiation ablation of the ovaries were initially slow
to achieve widespread acceptance. Other hormonal methods came into use,
stilbestrol in the 1930s (Haddow), a renalectomy in the 1940s (Huggins),
androgenic steroidsin the 1950s, hypophysectomy or ablation (Forrest) in the
1960s, tamoxifen in the 1970s, aminoglutethimide and goserelin in the 1980s,
new generation aromatase inhibitors in the 1990s and total oestrogen receptor
blockers may be the next.
All these were used in the treatment of advanced disease but, in
the 1940s and 1950s, two trials of ovarian ablation used in early breast cancer
were established: in Manchester by Ralston Patterson and in Norway by
Nissen-Meyer.
Cole reported from the Manchester trial that ovarian ablation prolonged the
disease-free interval, but did not improve survival. However, two later UK
trials of adjuvant tamoxifen gave encouraging results. It was use of
meta-analysis of worldwide trials by Peto that really highlighted the role of
tamoxifen in improving case survival.
At the same time, an understanding of the mechanism of action of
endocrine therapy and together with that a means of predicting response, were
provided by the work of Elwood Jensen in the recognition of the oestrogen
receptor (ER).
During the 1960s, cytotoxic agents were being introduced. The use
of combinations of these agents gave startling results in the haematological
malignancies and on some solid tumours. Chemotherapy was rapidly introduced
into breast cancer, giving promising response rates in advanced disease and
prolongation of the disease-free interval when applie in early disease.
Although the response duration was generally short cytotoxic therapy achieve
predominance over endocrine therapy, especially in the Americas, and combination
chemotherapy became the accepte a juvant treatment for young women.
Nevertheless, tamoxifen became the agent of choice for adjuvant
therapy in older women and in particular for ER-positive tumours. Results in
new clinical trials, together with confirmation by the 1995 meta-analysis of
the Early Breast Cancer Trialists Collaborative Group, show a comparable result
is obtained by ovarian suppression to combination cytotoxic therapy in
premenopausal women with ER-positive tumours. With increasing recognition of
the importance of ER as a predictive factor, with the introduction of the newer
agents and trials of the use of endocrine agents in prevention, carcinoma
in
situ and primary medical therapy, interest in hormonal therapies has been
rekindled.
Whilst cytotoxic and hormonal therapies are complementary, each
with specific roles, hormonal therapy has several advantages:
1. ER gives a prediction of effect, so that endocrine therapy does
not have to be given against tumours that will be unresponsive. This means that
cytotoxic therapies and not hormonal, are indicated in ER-negative tumours.
2. Side-effects are more tolerable, long-term fertility is not
threatened, serious adverse events are less and quality of life is better.
These considerations are particularly important in situations 5-7 below.
3. In advanced disease, although the response rate to endocrine
therapies in an unselecte population is lower than chemotherapy, response
duration is longer. The best chance a woman has of being alive 5 years after
the appearance of symptomatic distant disease is to have an endocrine
responsive tumour.
4. Adjuvant systemic endocrine therapy is the preferred treatment
in postmenopausal women with ER-positive tumours; in premenopausal women with
ER-positive tumours it equals the effect of cytotoxic therapy.
5. Endocrine agents have a marked effect on diminishing the rate
of contra-lateral breast cancer in the short-term and for that reason,
endocrine agents are being tested as preventatives in women at high risk of
developing breast cancer and have demonstrated an apparent lowering of the
incidence of breast cancer in the short term, the fall being dependent upon a
lower incidence of ER-positive tumours.
6. Following surgical removal of ductal carcinoma
in situ, endocrine therapy further diminishes the rate of local recurrence (although
not at present recommended as standar therapy).
7. For primary tumours diagnose in patients unfit for surgery, in
whom the side-effects of cytotoxic therapy also forbid that as an option,
primary endocrine therapy can give very long periods of disease control.
It is therefore a most appropriate moment to determine how to maximise in
clinical practice the benefits of endocrine therapy and that is the intention
of European Society of Mastology (EUSOMA) in producing these Guidelines.
Modern Breast Cancer Units must provide a high quality of clinical
care and service provision and to ensure this there must be a quality assurance
system. The Outcome Measures in these Guidelines may be used for an audit
programme; in general, each Outcome Measure should be met in 90% of cases. This
leaves room for some exceptions, but if it cannot be met, the quality of care
has to be questioned.
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