Download Hormone therapy in the management of prostate cancer: treating the

R e v i e w
o n c o l o g y
Hormone therapy in the management
of prostate cancer: treating the cancer
without hurting the patient
A u tho rs
B. Tombal, A. Stainier
Key wo rds
Prostate cancer, hormone therapy, LHRH agonists, antiandrogens, side-effects
Summary
Hormone therapy (HT) is the mainstay systemic
treatment of prostate cancer (PCa). Hormone
therapy can be delivered by androgen deprivation therapies (surgical castration or LHRH
agonists) or by antiandrogens. Conventionally,
hormone therapy is considered as a palliative
treatment since it rapidly alleviates cancer related symptoms such as pain or urinary obstruction
but modestly improves survival. However, recent
publications demonstrate that HT improves survival when it is used in adjuvant to exter-
Introduction
Despite sixty years of intense use, hormone therapy
(HT) basically still is used as described by Charles
Huggins in the 1940s.1 Since then, Luteinising Hormone Releasing Hormone (LHRH) agonists have
replaced surgical castration as the main modality of
androgen deprivation therapy (ADT) and peripheral antiandrogens have been introduced.
With the introduction of prostate specific antigen
(PSA) screening, men are often diagnosed when
still asymptomatic. HT is rarely prescribed, primarily to alleviate symptoms. Nowadays, HT is
more frequently started at diagnosis in every patient
who is not eligible for radical treatment or wants
to postpone this treatment. However, there is no
clear evidence that HT prolongs survival in all settings. Inconclusive recommendations and intense
commercial support result in wide variations in indications of HT between urologists, and radiation
specialists or medical oncologists.2 Recent surveys
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nal beam radiotherapy or radical prostatectomy in young patients with aggressive disease.
However, treating asymptomatic men for long
periods of time also raises new concerns on sideeffects. Recent data indicate an increased risk of
developing severe complications such as metabolic syndrome, diabetes and cardiovascular
events. This implies that physicians have to
adapt to these new indications and learn to
deliver HT in a more holistic approach in compliance with today’s challenges.
(BJMO 2008;vol 2;4:205-11)
confirm that indications of HT depend more on
personal characteristics of the urologist (e.g. board
certification, academic affiliation) than on tumour
or patient characteristics. Non-academic urologists for example, more frequently prescribe HT for
localized PCa, a setting in which the benefits are
uncertain.3 This stresses the need for a better postgraduate education to let physicians keep up with the
rapidly evolving evidence and to oppose the intense
marketing of LHRH agonists and antiandrogens
with validated recommendations. In this review paper the more recent evolutions and the challenges
that need to be tackled, will be addressed.
Hormone therapy
Fewer indications to use HT upfront as single
modality, especially in localized prostate cancer
Many asymptomatic men receive HT for a localized
PCa (T1-2 N0 M0), obviously to avoid or postpone
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radical therapy. Kawakami et al reviewed the files
of 7,045 men with localized PCa and found that
14.1% were treated primarily with HT.4 After 5
years, 67.3% of the patients were still receiving HT
and only 13.8% had received radical treatment. It
is disturbing to know that in localized disease early
HT is not only inefficient but can lead to a paradoxical increase in mortality. This was clearly demonstrated by the EPC trial that included 8,113
men with non-metastatic PCa (all M0) to assess
the efficacy of early treatment with bicalutamide
150mg.5 At a median follow-up of 7.4 years, there
was a clear trend (Hazard Ratio (HR): 1.16; p=0.07)
towards shortened survival in patients with localized disease treated with immediate HT.
Moreover, this paradigm does not only apply to localized disease. A recent EORTC trial suggests that HT
can also be postponed in patients with locally advanced
PCa (T1-2 N+ M0 or T3-4 Nx M0) who are not eligible for
radical treatment. In EORTC trial 30891, 985 patients
unfit for radical therapy were randomly assigned to
receive immediate HT or were deferred until symptomatic disease progression was observed.6 Overall survival was modestly increased in patients receiving immediate ADT (HR: 1.25; p>0.1) as a result of fewer
non PCa related deaths. The time from randomization
to progression of hormone-refractory disease did not
differ significantly between immediate versus delayed
ADT nor did PCa-specific survival. The median time
to start deferred treatment was 7 years and 26% of
patients in the delayed ADT group died without ever
needing treatment. Further analysis of this EORTC
trial suggests that only men with PSA level > 50ng/
ml or with PSA doubling time <12 months are at risk
of progression.7
Taken together, these data suggest that in many
patients with asymptomatic locally advanced PCa,
HT can be delayed, avoiding adverse effects of longterm treatment. Careful selection of patients based
on age, PSA kinetics, imaging and Gleason score
could help the identification of patients needing immediate ADT.
More arguments to use HT as adjuvant therapy
to radical therapies
The only randomized trial showing a substantial advantage for immediate HT is the ECOG trial which
compared immediate versus deferred HT in patients
with positive lymph nodes who underwent radical
prostatectomy and pelvic lymph node dissection.8
At a median follow-up of 11.9 years, immediate
ADT significantly improved overall survival (HR:
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1.84; p=0.04) and PCa-specific survival (HR: 4.09;
p=0.0004). However, the patients in this study had
higher tumor burden (e.g. seminal vesicle involvement, positive surgical margins, Gleason score 8-10)
than most of the contemporary patients and recent
radical prostatectomy series suggest that not all patients with a positive lymph node dissection require
immediate HT.9
The modest benefit obtained when HT is used as
monotherapy contrasts with the super-additive results observed when HT is combined with external
beam radiotherapy (EBRT). In the EORTC 22863
trial, 3-years of adjuvant LHRH agonist added to
EBRT in patients with locally advanced PCa decreased the risk of death by 49% vs. EBRT alone.10
In the RTOG 85-31 trial, lifelong administration
of an LHRH agonist decreased the risk of death
by 23% vs. EBRT alone.11 In the EPC subgroup of
305 patients with locally advanced PCa treated with
EBRT, adding bicalutamide 150mg once daily to
EBRT reduced the risk of death by 35% compared
to EBRT alone (HR: 0.65, p=0.03).12 The exact duration of adjuvant HT for locally advanced PCa is
still unclear, although a recent EORTC trial suggested that it should be prolonged to at least 3 years
in order to improve survival.13
A shorter adjuvant HT treatment is also beneficial for patients with high-risk localized PCa (i.e.
Gleason score > 7 or PSA > 20 ng/mL or stage T2c)
who are primarily treated with EBRT. In a trial conducted by D’Amico et al, 206 patients were randomized to receive EBRT alone or combined with
6-months HT.14 After a median follow-up of 4.5
years, patients randomized to receive EBRT + HT
had a significantly higher survival rate (88%) vs.
EBRT alone (78%; p=0.04).
Which treatment modality to choose?
A shared decision based on the patient’s
expectations
HT can be achieved by lowering testosterone levels
(androgen deprivation therapy) or by direct blockage of the androgen receptor by steroidal (SAA;
cyproterone acetate) or non-steroidal (NSAA;
flutamide and bicalutamide) anti-androgens. Antiandrogens are primarily prescribed to protect the
patient against the initial testosterone surge induced
by LHRH agonists but they can be prescribed continuously with LHRH agonists to increase the efficacy of medical castration (Maximal Androgen
Blockade; MAB).15 High-dose bicalutamide can also
be prescribed alone as an alternative to castration to
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reduce the side-effects of androgen deprivation.16
The question of which treatment modality is most
suited has fuelled passionate debates and produced
more reviews than original research articles. There
have been very few attempts to match modalities to
the expectations of the patient. To do this, patients
should receive comprehensive information to decide
which treatment modality fits best to their personal
“philosophy of life”. This is a fair and reasonable approach as demonstrated by Nyman et al.17 When patients are fully informed they can play an active role
in the treatment choice and they are usually satisfied
with their decision.
If we agree that continuous administration of LHRH
agonists is the standard of care, then the following information should be given to the patients to investigate whether they prefer an alternative strategy.
Maximum androgen blockade (MAB) should be
advised to patients who are looking for improving the efficacy of the treatment and who are
willing to accept the increased side-effects
Several meta-analyses have shown that MAB
provides a significant but limited survival advantage (2-3%) when compared to LHRH agonist
monotherapy.18 The PCTCG meta-analysis demonstrates that MAB increases 5-year survival by
1.8% (p=0.11) compared to LHRH agonists alone,
depending on the class of anti-androgen used.
MAB with nilutamide and flutamide decreases the
risk of death over castration alone by 8%, which
translates into a 2.9% increase in 5-year survival.
In contrast, MAB with cyproterone acetate significantly increases the risk of death by 13%, therefore
reducing 5-year survival by 2.8%. Although this
inferiority is clearly stated in the practice guidelines, 35% of the patients treated with MAB in
Belgium still receive cyproterone acetate as antiandrogen. NSAAs increase the rate of several side-effects vs. castration alone: diarrhoea (10% vs. 2%),
gastrointestinal pain (7% vs. 2%), and non-specific
ophthalmologic events (29% vs. 5%).
None of the meta-analyses performed so far have incorporated studies with bicalutamide 50mg, which
is the most frequently used antiandrogen because of
its daily dosing and low gastrointestinal and ophthalmologic adverse effects. Klotz et al calculated
that bicalutamide in MAB improves survival by
20% over castration alone.19 They calculated that
for a patient with a hypothetical survival of 5 years,
adding bicalutamide 50mg to a LHRH agonist
could increase his survival by 1.5 years.
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Patients worrying about the side-effects of
androgen deprivation therapy and valuing
quality of life (QoL) over survival should be
informed about monotherapy with highdose bicalutamide
One meta-analysis has demonstrated that monotherapy with an NSAA was equivalent to castration
in terms of survival, but led to less toxicity, particularly with respect to loss of libido and physical capacity. However, this doesn’t hold true for cyproterone acetate which is inferior to castration in terms
of time to disease progression.20
Bicalutamide, at the higher dose of 150mg, has been
extensively compared to castration in patients with
locally advanced T3/T4 non-metastatic disease (M0)
or metastatic disease (M1).16,21 The first analysis was
performed at a median follow-up of 100 weeks and
showed that the median survival of metastatic (M1)
patients treated with bicalutamide 150mg was 6
weeks shorter than the median survival of patients
treated by castration (HR: 1.30). Based on these
earlier results, bicalutamide 150mg is not an EMEA
or Belgian recognized therapy for metastatic PCa.
The definitive analysis for non-metastatic patients
(M0) was performed after a median follow-up of 6.3
years.16 In that setting, the study showed that there
was no difference between bicalutamide 150mg and
castration in overall survival (HR: 1.05; p=0.70)
or time to progression (HR: 1.20; p=0.11). In contrast, there was a statistically significant benefit in
the bicalutamide monotherapy group with respect
to sexual interest (p=0.029) and physical capacity
(p=0.046). Bicalutamide 150mg was well tolerated,
with breast pain and gynecomastia being the most
frequent side effects. Further studies confirmed that
bicalutamide 150mg induces fewer bothersome side
effects than LHRH agonists and in addition does
not decrease bone mineral density and has less impact on lipid metabolism.22.23
Is it safe to suspend temporarily androgen
deprivation therapy in patients complaining
of side-effects?
Another alternative for men who are not candidate
for anti-androgen monotherapy is intermittent androgen deprivation (IAD). Several phase II trials
have demonstrated the feasibility of alternating onand off-therapy periods.24 Prospective phase III trials are still underway and data on survival endpoints
and QoL are not yet fully available. However, it appears that with regard to survival, continuous ADT
and IAD are equivalent.25 Awaiting data from the
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phase III trials, IAD is widely offered to patients
with PCa in various clinical settings. However, its
status should still be regarded as investigational.
Side effects of ADT: when the treatment
becomes a silent killer
Because testosterone is the principal male hormone,
its withdrawal is associated with a series of side effects.26 Until recently, most studies on ADT have focused on the ‘‘symptomatic’’ toxicity of testosterone
withdrawal, such as hot flushes, loss of libido, emotional instability, or fatigue. The morbidity of ADT,
however, mainly results from devious toxicities such
as the induction of the metabolic syndrome leading
to increased cardiovascular risk and osteoporosis. In
a cross-sectional study with 58 men, Braga-Brasaria
et al have demonstrated that a metabolic syndrome
was present in > 50% of the men treated with longterm ADT, predisposing them to an increased cardiovascular risk.27 In an observational populationbased cohort study including 73,196 men, Keating
et al showed that ADT increased the risk of diabetes
by 44%, coronary heart disease by 16%, myocardial infarction by 11%, and sudden cardiac death
by 16%.28 This increased risk of developing co-morbidities seems to be higher in patients with localized disease and in those with advanced disease and
moderate to severe co-morbidities.29,30
Loss of bone mineral density is another complication induced by ADT. Significant loss of bone mineral density occurs within 12 months of therapy initiation.31 ADT significantly increases the risk of any
clinical bone fracture, hip fractures, and vertebral
fractures in men with PCa.32 Physicians should take
care that appropriate calcium and vitamin D supplements are administered, and that the development
of bone loss is monitored by means of osteodensitometry and bisphosphonates are prescribed when
bone loss is documented.33
Promoting wellness and proactive management
of side effects in patients receiving ADT
Although the side effects of ADT are well recognised, no proactive management of these side effects
has been recommended so far. A physician prescribing ADT should spend sufficient time explaining
the side effects of ADT to the patient, for example in
clarifying the reasons why libido decreases and emotions change. The physician should be aware of early
signs of depression and look for advice of a specialized colleague if needed. Sexual side effects are the
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best-recognized adverse effects of ADT and include
loss of libido and erectile dysfunction (ED). Loss of
libido is distressing for many men. Urologists often
present it as an ineluctable consequence of androgen suppression, so that men normally potent before
treatment seldom request specific treatment. However, ancient and modern history contains sufficient
evidence that a sexual life is still possible for men
deprived from testosterone.34
Hot flushes are another side effect of ADT. These
are perceived as very bothersome but can be reduced
by simple lifestyle changes such as wearing light
clothes, avoiding abrupt temperature changes and
spicy food. The physician should point out these
simple tricks to the patient. When the hot flushes
are becoming too much of a bother they can be
treated with a variety of therapies, including phytotherapy (sage extracts, alfala), clonidine, velaxafine
or a small dose of estrogens.35
In any case, the physician should encourage patients to adopt a lifestyle that is adapted to ADT.
Osteoporosis and metabolic syndrome are classical
features of other frequent conditions, such as menopause or diabetes. Adopting a better diet and increasing the level of physical activity can minimise
the side-effects of ADT.36,37 In addition, regular exercise may help fighting against fatigue, muscular
weakness, and to a certain extent, help restoring a
better mood. Physical activity should be tailored
to the pre-existing physical activity of the patient,
should include regular resistance exercise, and
should be associated with correct supplementation
of calcium and vitamin D.38 Finally, specific recommendations should be directed towards the patient’s
general practitioner so that he/she can adapt his/her
practice to patients treated with ADT and monitor
on a regular base blood pressure, serum lipid, haemoglobin, and fasting serum glucose.37
Conclusions
Despite sixty years of intensive use, ADT is still the
reference systemic therapy for advanced PCa. However, the situation has changed over the years. Indications for ADT are shifting to earlier stage PCa,
especially in combination with EBRT, where it results in the largest survival benefit. In the future,
new treatment modalities might emerge and new
combinations will probably be evaluated. Moreover,
the patient’s choice and expectations regarding QoL
are more than ever considered of vital importance in
the management of PCa.
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Key messages for clinical practice
1.Modern indications of hormone therapy of PCa are following:
- Immediate treatment of symptomatic patients
- Immediate treatment of metastatic disease
- Immediate treatment of locally-advanced disease with PSA > 50ng/ml or PSA doubling-time
< 12 months
- Treatment of PSA recurrences after radical treatment if PSA doubling time < 12 months
- Long-term adjuvant treatment (2-3 years) to external beam radiation for locally advanced PCa
- Immediate treatment of patients with bulky positive lymph nodes after radical
prostatectomy
2.Summary of treatment modalities:
- Androgen deprivation therapy by surgical castration or LHRH agonist is the Gold
Standard treatment.
- Maximal Androgen Blockade with a non-steroidal antiandrogen increases survival by 5 to
20% and should be recommended to patients looking for maximum efficacy.
- Bicalutamide 150mg monotherapy is equivalent in term of survival to castration in patients
with M0 disease, with a better tolerability profile.
3.Patients receiving androgen deprivation therapy must be stimulated to adapt their diet
and increase daily exercise to minimize the effects of changes in lipid metabolism and osteoporose. Doctors must monitor lipid profile, fasting serum glucose and bone mass density in
addition to oncological parameters.
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Correspondence address
Authors: B. Tombal, A. Stainier
Cliniques Universitaires Saint-Luc, Université
Catholique de Louvain, Brussels, Belgium
Please send all correspondence to:
Prof. B. Tombal
Cliniques Universitaires Saint-Luc
Université Catholique de Louvain
Avenue Hippocrate 10
1200 Brussels
Belgium
Tel: 0032 (0)2 7645540
Fax: 0032 (0)2 7648919
E-mail: [email protected]
Conflicts of interest: Bertrand Tombal is an investigator and consultant for Astellas, AstraZeneca, SanofiSynthélabo and Cougar.
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