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Other Guidelines
Guidelines on endocrine therapy of breast cancer
1. Background
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Cytotoxic and endocrine therapy are important parts of the management of most
women with breast cancer. The aims of systemic treatment of metastatic disease
are control of disease progression with relief of symptoms and with the least
toxicity; treatment may also prolong survival.
The use of chemotherapy and endocrine therapy in the management of advanced
breast cancer have recently been analysed by Stockler and co-workers
[1] and whether to use chemotherapy alone or endocrine therapy as the
first option for the treatment of advanced breast cancer has been
analysed in a Cochrane review
[2] . These analyses reviewed the results from nine identified
trials. The conclusion was that in general response rates were higher for
chemotherapy treated patients not selected on the basis of steroid receptors
compared with those treated with endocrine therapy. However, there was a
tendency for prolonged survival in favour of those treated firstly with
endocrine therapies.
Many trials have revealed that in HR-positive patients, those treated with
endocrine therapy have comparable response rates and longer times to
progression, duration of response and survival to those patients treated with
cyto-toxic drugs.
The systemic therapy to be used for the treatment of advanced breast cancer
must be selected on the basis of steroid receptor (HR) determination (see
Section 2).
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The anti-oestrogen tamoxifen has until recently been considered the drug of
choice for first-line endocrine therapy in postmenopausal women, due to
its efficacy and low toxicity. The introduction of specific aromatase
inhibitors
[3] has renewed interest in newer forms of endocrine therapy. Data from
large randomised trials have demonstrated a slight superiority in terms of
response rate and time to progression in favour of these specific
aromatase inhibitors (A.I.s) compared with tamoxifen, even in patients not
previously treated with adjuvant tamoxifen
[4]
[5] . These agents are also well tolerated and do not induce thrombotic
events nor endometrial bleeding.
Tamoxifen is given as 20 mg orally daily. There is no advantage to higher doses
[6] or to a loading dose. Third generation aromatase inhibitors are:
anastrozole 1 mg daily; letrozole 2.5 mg daily; exemestane 25 mg daily.
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In premenopausal women (defined here as currently menstruating or with
FSH levels in the premenopausal range), ovarian ablation or removal was for a
long time the only therapy. LH-RH agonists provide a non-invasive alternative
method
[7] of ovarian suppression, which is reversible, sparing women who fail
to respond the menopausal side-effects.
Goserelin is given as a 3.6 mg 4-weekly subcutaneous injection; other LH-RH
agonists including leuprolide, triptorelin and buserelin are available for the
treatment of breast cancer in certain countries.
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A meta-analysis of four randomised trials
[8] has demonstrated superiority for the use of combined therapy with a
LH-RH agonist plus tamoxifen over a LH-RH agonist alone, in response rate and
particularly in response duration and survival from the time of diagnosis of
advanced disease.
| Quality objective |
Outcome measure
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To determine the optimal first-line systemic therapy for advanced breast
cancer in pre-and postmenopausal patients |
- All ER-positive patients at first appearance of advanced
breast cancer should receive endocrine therapy as part of the first-line
systemic therapy.
- Patients with dyspnoea due to metastases in the lung parenchyma may be given
a course of cytotoxic chemotherapy for symptom relief prior to the application
of endocrine treatment. A similar approach should be taken in the face of
massive liver involvement.
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| Quality objective |
Outcome measure
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To use the optimal first-line endocrine therapy according to menopausal
status |
- Premenopausal women should receive a combination of LH-RH agonist
plus tamoxifen.
- Postmenopausal women should receive either a new generation aromatase
inhibitor or a peripheral antioestrogen such as tamoxifen.
- An A.I. is the mandatory choice if there is a past history of a thrombotic
event.
- An A.I. should be strongly considered if the patient received tamoxifen as
adjuvant therapy (and vice versa).
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An interesting aspect of advanced breast cancer is the possibility of obtaining
a further response by applying another form of endocrine therapy following
progression of disease on the original therapy.
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| Quality objective |
Outcome measure
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| To select patients for second-line
endocrine therapy for advanced breast cancer |
All patients who responded complete response (CR), partial response
(PR) or static disease for at least 6 months to first-line endocrine
therapy should, on relapse, be offered second-line endocrine therapy rather
than cytotoxic therapy.
It follows that evidence of response to the first-line treatment must be
documented (see below).
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The preference for a specific (third generation) A.I. as second-line
endocrine therapy after tamoxifen has been substantiated in several trials in
comparison to progestins. Both lower toxicity and a trend for higher efficacy
than with the progestins favour the use of aromatase inhibitors
[9]
[10]
[11]. Trials have demonstrated improved survival times with
third-generation A.I.s over megestrol acetate
[10]
[11].
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Patient's perception of side-effects is, for obvious reasons, different in
advanced disease than during treatment for early disease. The side-effects are
usually mild and only 2-3% of the patients want to terminate because of
toxicities.
The management of side-effects like nausea, thromboembolic disease and
gastrointestinal isturbance is symptomatic.
Hot flushes can be alleviated by serotonin re-uptake inhibitors
[12] and vaginal dryness treated with local oestrogens (e.g. Vagifem).
| Quality objective |
Outcome measure
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| The optimal second-line endocrine
therapy according to menopausal status |
The treatment of choice for premenopausal patients initially treated
with combined endocrine therapy (LH-RH agonist plus tamoxifen) should be to
continue ovarian suppression with an LH-RH agonist and replace tamoxifen with a
specific aromatase inhibitor.
Post-menopausal patients with a previous response to either tamoxifen or a
specific aromatase inhibitor should be treated with the crossover
therapy.
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Third-line endocrine therapy offers response rates of 20-25% in previous
endocrine therapy responders.
| Quality objective |
Outcome measure
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| To select patients for third-line
endocrine therapy for advanced breast cancer |
All patients with a response (objectively measured with a minimum
duration of 6 months) to second-line endocrine therapy should be offered
further endocrine therapy with either a progestin or a pure anti-oestrogen, in
preference to cytotoxic therapy.
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