|
|
|
prostate cancer treatment: hormone therapy I
Metastatic disease is the cause
of nearly all prostate cancer-related death. Currently incurable, 5-year
survival is 25%; 10% survive <6 months, while <10% survive >10 years.
The mainstay of treatment is hormone therapy, with cytotoxic chemotherapy in
reserve and novel treatments such as growth factor inhibitors, angiogenesis
inhibitors, immunotherapy, and gene therapy in development. The concept of
hormone therapy was realized in 1941 when Huggins and Hodges reported favourable
acid and alkaline phosphatase responses in prostate cancer patients castrated or
given oestrogens.
Hormone dependence of prostate cancer treatment
95%
of circulating androgen, mainly testosterone, is produced by the Leydig cells of
the testes under the influence of luteinizing hormone (LH). The anterior
pituitary synthesises LH, stimulated by LH-releasing hormone (LH-RH) produced by
the hypothalamus. The remaining 5% of circulating androgen is synthesized by the
adrenal cortex from cholesterol, under the influence of pituitary ACTH.
Testosterone is metabolized to the more potent dihydrotestosterone (DHT), by
types 1 and 2 5-α reductase (5AR) enzymes. DHT binds to the androgen receptor,
travels to the cell nucleus, and exerts its positive effect on cell growth and
division. All prostate epithelial cells are dependent on androgens and fail to
grow or undergo programmed cell death in their absence. Similarly, most
previously untreated prostate cancer cells are dependent on
androgens.
Androgen deprivation results in a reduction in PSA and
clinical improvement in >70% of patients. However, most will still die within
5 years due to the development of androgen-independent growth. This is
considered to be due to growth of androgen-independent cell clones rather than a
de-differentiation of previously androgen-dependent cells. The mean time to
disease progression after androgen deprivation is 14 months in men with
metastatic disease.
Prognostic factors
Predictors of poor hormone
therapy response include:
- metastatic lesions at presentation
- Elevated
alkaline phosphatase at presentation
- Anaemia at presentation
- Poor
performance status (level of activity) at presentation
- Low serum
testosterone at presentation
- Failure of bone pain to improve within 3
months of treatment
- Failure of PSA to normalize within 6 months of
treatment (conversely a PSA nadir (= lowest value) of <0.1ng/ml predicts a
long-term response)
prostate cancer treatment : hormone therapy
II
Mechanisms of androgen deprivation
- Surgical castration: bilateral
orchidectomy
- Medical castration: luteinizing hormone-releasing hormone
(LH-RH) agonists, oestrogens; also termed androgen ablation or androgen
deprivation
- Anti-androgens (steroidal or non-steroidal): androgen receptor
blockade at target cell
- Maximal androgen blockade (MAB): medical or
surgical castration plus anti-androgen
- 5 α reductase inhibition (5ARI)
with finasteride or dutasteride
Both forms of castration have equivalent
efficacy, so patients should be given the choice. Oestrogens are no longer used
first-line, due to the significant cardiovascular morbidity observed when they
were the only alternative to orchidectomy. Anti-androgens alone are less
effective in treating metastatic disease, but equivalent for non-metastatic
disease. MAB has a theoretical advantage over castration in blocking the effects
of the adrenal androgens, but significant clinical advantages have not been
demonstrated in trial meta-analyses. 5ARIs are not licenced for the treatment of
prostate cancer, but appear to have a role in prevention.
Bilateral
orchidectomy - prostate cancer treatment
A simple procedure, usually carried
out under general anaesthesia. Through a midline scrotal incision, both testes
may be accessed. The tunica albuginea of each testis is incised and the soft
tissue content is removed, after which the capsule is closed. The epidiymes and
testicular appendages are preserved. Post-operative complications include
scrotal haematoma or infection (both rare). Serum testosterone falls within 8h
to <0.2nmol/l.
LH-RH agonists - prostate cancer treatment
Developed
in the 1980s, giving patients an alternative to bilateral orchidectomy, with
which they are clinically equivalent. They are given by subcutaneous or
intramuscular injection, as monthly or 3-monthly depots. Examples include
goserelin, triptorelin, and leuprorelin acetates. If the anterior pituitary is
overwhelmed with an analogue of LH-releasing hormone (LH-RH), it switches off LH
production, although serum testosterone rises in the first 14 days due to a
surge of LH. This can result in tumour flare , manifest in 20% patients
with increased symptoms, including catastrophic spinal cord compression. To
prevent this, cover with anti-androgens is recommended for a week before and two
weeks after the first dose of LH-RH agonist.
An LH-RH antagonist is in
development which should rapidly reduce serum testosterone.
Side-effects
of bilateral orchidectomy and LH-RH agonists
- Loss of sexual interest
(libido) and ED
- Hot flushes and sweats can be frequent and troublesome
during work or social activity
- Weight gain
- Gynaecomastia
-
Anaemia
- Cognitive (mood) changes
- Osteoporosis and pathological
fracture secondary to osteoporosis may occur in patients on long-term (>5
years) treatment
Anti-androgens - prostate cancer treatment
These are
administered as tablets. Examples include bicalutamide (150mg daily as
monotherapy; 50mg daily for MAB, in combination with LH-RH analogues or
orchidectomy), flutamide, and cyproterone acetate. The first two raise the serum
testosterone slightly, so sexual interest and performance should be maintained,
although many such patients have pre-existing ED due to the advancing disease.
Side-effects include frequent gynaecomastia, breast tenderness, and occasional
liver dysfunction; flutamide also causes frequent GI upset. At its full dose of
100mg tds cyproterone acetate may cause reversible dyspnoea; it may be used at
50mg bd for treatment of castration-induced hot flushes.
Management of
advanced prostate cancer: hormone therapy III
Monitoring prostate cancer
treatment
Typically, patients will have baseline PSA, full blood count, renal
and liver function tests, a renal ultrasound, and a bone scan. The PSA is
repeated after 3 months, 6 months, and 6-monthly thereafter until it rises.
Liver function is checked 3-monthly if anti-androgen monotherapy is used. Renal
function should be checked on disease progression, and bone imaging if
clinically indicated.
While PSA is very useful as a marker for response and
progression, 15% of patients show clinical progression without PSA rise. This
may occur in anaplastic tumours that fail to express PSA.
Advice on exercise,
diet, and treatment of erectile dysfunction is often sought by patients during
treatment.
Early versus delayed hormone therapy
Traditionally, hormone
therapy was reserved for patients with symptomatic metastatic disease. Arguments
against early hormone therapy revolve around its side-effects and
cost.
However, studies of patients with locally advanced and metastatic
disease have demonstrated slower disease progression and reduced morbidity when
treated with androgen deprivation early (i.e. before the onset of symptoms).
Improved survival has also been reported in patients without bone metastases but
including node-positive disease, when treated immediately.
Trials have also
demonstrated slower disease progression in patients given bicalutamide 150mg
daily (compared with placebo) for 2 years after treatment of high-risk,
clinically localized prostate cancer with RP or RT. This benefit is not seen in
patients managed by watchful waiting.
Intermittent hormone therapy
The
potential advantages of stopping hormone therapy when the disease has remitted,
then re-starting it when the PSA has risen again are the reduced side-effects
and cost. However, there are no randomized trials yet demonstrating survival
equivalence or advantage. None of the LH-RH analogues or anti-androgens are
licensed for intermittent therapy. Moreover, it can take up to 6 months after
stopping treatment for the serum testosterone to recover, hence side-effects may
persist into the off-treatment periods.
prostate cancer treatment:
androgen-independent disease
Second-line hormone therapy
When the PSA
rises from its lowest (nadir) value, or if symptomatic progression occurs
despite a favourable biochemical response to first-line hormone therapy, the
disease has entered its androgen-independent phase. In these circumstances,
further treatment is usually considered. Most patients receiving anti-androgen
monotherapy respond after switching to androgen ablation (orchidectomy or LH-RH
analogue). If there is relapse during androgen ablation, 25% respond by adding
an anti-androgen (e.g. bicalutamide 50mg daily) to establish maximal androgen
blockade (MAB). If MAB was used from initiation of hormone therapy, withdrawal
of the anti-androgen paradoxically elicits a favourable response in 25% of
patients.
A further rise in PSA may require third-line hormonal therapy such
as the addition of oestrogens or corticosteroids. For example,
diethylstilboestrol 1mg daily with 75mg aspirin for thromboembolic prophylaxis
elicits a response in up to 60% of these patients. The mean duration of response
is 4 months.
The prognostic factors for survival with androgen-independent
disease are identical to the factors predicting response to hormone therapy,
plus time from initiation of hormone therapy to initiation of chemotherapy and
visceral metastasis status.
Cytotoxic chemotherapy
Systemic
chemotherapy is offered to appropriate patients with androgen-independent
metastatic disease, by the medical oncologist. Men with low-volume disease who
have failed radical local treatment and hormone therapy are also candidates for
chemotherapy. Elderly, frail, and infirm patients with significant bone disease,
renal impairment, haematological and clotting abnormalities are unsuitable.
Correction of renal and bone marrow dysfunction is necessary prior to
treatment.
Symptom palliation
Symptom improvements are reported with
cytotoxic chemotherapy. In a randomized trial of mitoxantrone plus prednisolone
versus prednisolone alone, 29% in the combination group experienced a reduction
in pain and analgesic use compared with 12% in the prednisolone alone group. PSA
response did not predict palliative response. In another study, docetaxel plus
prednisolone produced a pain reduction in 35% compared to 22% of patients given
mitoxantrone and prednisolone, resulting in improved quality of life
scores.
Cancer control
There are several reports of single-agent
chemotherapy in the PSA era, most defining response as >50% decrease in PSA.
Responses are reported in 20 - 40% of patients with haematological toxicity
(especially neutropenia) for most agents. Better responses (up to 75%) reported
with newer combination regimes (e.g. estramustine phosphate plus docetaxel) but
with greater toxicity. The median survival following chemotherapy ranges from 24
to 44 weeks. Results of two randomized studies comparing docetaxel with
mitoxantrone plus prednisolone have shown a 2.4 - 3 months median survival
advantage in favour of docetaxel.
Hit: 20452 times
 Print Health Information
 Send to a Friend
Related Health Information in Urology :
|
Bookmark Health Information
Make Health Information Homepage
As a 
Advertise with Health Information