Home 
Prostate Cancer BJUI Mini Reviews - Treating Asymptomatic Patients with Hormone-Refractory Prostate Cancer: Hormonal Manipulations for the Urologist
Prostate Cancer BJUI Mini Reviews - Treating Asymptomatic Patients with Hormone-Refractory Prostate Cancer: Hormonal Manipulations for the Urologist | BJUI Mini Reviews - Treating Asymptomatic Patients with Hormone-Refractory Prostate Cancer: Hormonal Manipulations for the Urologist |
|
|
|
|
|
| Tuesday, 11 March 2008 | ||
|
BJUI Mini Reviews - The reviewers attempt to provide the practicing clinician with therapeutic manoeuvres (hormonal manipulations) and an understanding of the different methods that can be used to treat the asymptomatic patient with HRPC and with an increasing PSA level.
More BJUI Mini Reviews and Archives on UroToday.com
Please log-in or register in order to submit comments. Powered by AkoComment! |
||
![Treating asymptomatic patients with hormone-refractory
prostate cancer: hormonal manipulations for the urologist
Kelly J. Boudreaux and Sam S. Chang
Vanderbilt University Medical Center, Nashville, TN, USA
Accepted for publication 24 August 2007
These agents include leuprolide acetate,
goserelin acetate, triptorelin pamoate and
histrelin acetate. Most of these medications
are administered in 1-, 3- or 4-month, or
annual intervals in depot preparations or as
injectable implants (Table 1). The dosing
schedule is suited to the needs of each
patient. Well established side-effects from
this treatment include fatigue, anaemia,
suppression of libido, osteoporosis, hot
flashes and cognitive dysfunction [1]. There is
also the ‘flare’ phenomenon when using LHRH
agonists. Initial tonic stimulation of the LHRH
receptors in the pituitary leads to a transient
increase in LH and testosterone before
castrate levels are achieved. This initial surge
might exacerbate bone pain or urinary
obstruction in men with metastatic disease.
Most patients will have a palliative and
biochemical response to ADT, but a significant
majority of patients who are treated with ADT
are destined to have a limited remission with
this therapy. Patients with limited or no
metastatic disease have had a response
duration of
>
5 years [2], whereas responses to
ADT last
≈
3 years in patients with evidence of
metastatic disease to bone [2,3].
Patients who have progressive prostate
cancer despite ADT should have testosterone
at castrate levels (
<
50 ng/dL) before
classifying them as having ‘castrate-resistant’
disease. If the patient does not have a
testosterone level of
<
50 ng/dL the initial
therapeutic approach should be targeted at
testosterone reduction or blockade. Even in
the setting of disease progression despite
castration, ADT should be continued, as
administration of exogenous testosterone has
been shown to worsen the patients’
symptoms [4].
ANTIANDROGENS
Once castrate testosterone levels have been
confirmed, the first manoeuvre for the patient
on ADT and with an increasing PSA level is to
use maximum androgen blockade (LHRH
agonist and antiandrogen), but this has only a
modest survival advantage over LHRH agonist
therapy alone [5–7]. Antiandrogens fall into
two classes, i.e. steroidal and nonsteroidal.
The steroidal compounds, cyproterone acetate
and megesterol, are seldom used. Cyproterone
acetate is not available for use in the USA.
The nonsteroidal antiandrogens include
bicalutamide, flutamide and nilutamide
(Table 2).
Of the antiandrogens, flutamide and
bicalutamide have been better studied and
more frequently used than nilutamide.
However, patients might respond differently
to various antiandrogens, and no comparative
trials are available to suggest that one might
be better than another. Responses are clearly
possible for patients in who one antiandrogen
has failed and are then treated with another
[8,9].
All antiandrogens carry an inherit risk of
hepatoxicity due to their ability to induce the
cytochrome P-450 hepatic enzyme pathway
INTRODUCTION
In men managed with androgen-deprivation
therapy (ADT), prostate cancer that is
advancing clinically and/or biochemically is a
difficult problem for the practising urologist.
The advent of PSA assays in the 1980s
brought with it a new responsibility for the
urologist, as it has allowed the biochemical
progression of disease to be determined
during hormonal therapy. When deciding on
how to best manage this heterogeneous
group of individuals, specific questions about
efficacy, side-effects and the financial burden
of each proposed treatment must be
considered, along with their subsequent
impact on the quality of life. In this review we
attempt to provide the practising clinician
with therapeutic manoeuvres (hormonal
manipulations) and an understanding of the
different methods that can be used to treat
the asymptomatic patient with hormonerefractory
prostate cancer (HRPC) and with an
increasing PSA level.
MANAGEMENT OPTIONS FOR HRPC
ADT
At some point during their care, men with
prostate cancer who have disease progression
are likely to receive ADT, most commonly with
LHRH agonists with or without antiandrogen
therapy. LHRH agonist monotherapy is
commonly used due to the high cost and the
possible additional side-effects of combined
therapy.
B O U D R E A U X a n d C H A N G
©
2 0 07 T H E A U T H O R S
6 7 2
J O U R N A L C O M P I L A T I O N
©
2 0 07 B J U I N T E R N A T I O N A L
[10]. It is generally recommended that all
patients on antiandrogens receive serial liverfunction
tests for the early detection of
abnormalities. All of the antiandrogens also
have associated gastrointestinal side-effects.
Diarrhoea is more pronounced with flutamide
than with the other agents [11].
Bicalutamide has been extensively studied;
the dose is 50 mg once per day when used in
conjunction with a LHRH agonist, due to its
long half-life of 6 days. The most pronounced
side-effect of this agent is gynaecomastia in
70–80% of patients [12,13]; associated breast
tenderness is also common. Tamoxifen
(20 mg/day) has been shown to be effective in
reducing breast-related complications
stemming from bicalutamide therapy while
not affecting disease control [14]. External
beam irradiation of the breasts has also been
shown to reduce these complications. Di
Lorenzo
et al.
[15] found tamoxifen to be
more effective than radiation or placebo
in preventing bicalutamide-induced
gynaecomastia and breast pain, while
preserving sexual function and quality of life.
The usual dose of flutamide is 250 mg three
times/day; it has a short half-life of 6 h,
requiring this schedule. The most feared sideeffect
of flutamide is hepatotoxicity. This drug
has been shown on rare occasions to induce
severe acute hepatitis, with associated
jaundice, anorexia, nausea and elevated
aminotransferase and bilirubin, early in the
course of its administration (mean of 140 and
151 days into therapy) [16,17].
The dose of nilutamide is 300 mg daily for the
first month of treatment, followed by 150 mg
daily thereafter. The medication is uniquely
associated with visual disturbances (delayed
adaptation to darkness) and in rare incidences
(1%) interstitial pneumonitis, which can
progress to pulmonary fibrosis [18].
ANTIANDROGEN WITHDRAWAL
The current molecular mechanisms by which
prostate cancer cells become hormoneresistant
have not been fully elucidated,
despite intensive research. Likewise, the
mechanism for the antiandrogen withdrawal
response is incompletely understood. One
potential mechanism involves mutation of
the androgen receptor that enables the
antiandrogen to function as an androgen
receptor agonist [19].
If there is biochemical progression while the
patient is on complete androgen blockade, the
antiandrogen can be withdrawn. The decline
in PSA level after such a manoeuvre is well
recognized, and there have been occasional
radiographic responses; 15–30% of men will
have a decline in serum PSA level by more
than half, simply by withdrawing the
antiandrogen. This PSA decline is transient
and lasts 3–5 months [20–22].
The kinetics of the antiandrogen withdrawal
response vary with the half-life of the
antiandrogen used. Flutamide (half-life
≈
6 h)
withdrawal responses typically occur within
28 days, whereas those with bicalutamide
(half-life
≈
6 days) might take up to 8 weeks
[4]. Withdrawal responses are not restricted to
nonsteroidal antiandrogens but have been
described for megestrol acetate [8,23],
diethylstilbestrol (DES) [24] and ketoconazole.
Given that low-dose megestrol acetate is
sometimes used for hot flashes, clinicians
should be aware that stopping even low doses
of megestrol acetate might be associated with
PSA responses in patients who might
otherwise be considered as having HRPC.
HORMONAL MANIPULATION: SECOND-LINE
HORMONAL AGENTS
Second-line hormonal agents can be
considered in the asymptomatic patient
before more toxic chemotherapy is instituted.
As these agents are relatively well tolerated,
they are a reasonable choice for patients with
only biochemical (PSA) progression. The
benefits from these agents remain limited,
with a median duration of response
of 2–6 months. However, individual
responses can vary considerably from the
median, and some patients might show a
prolonged benefit. Notably, only a few
TABLE 1
LHRH agonists approved for treating prostate cancer
Generic name Trade name
Route of
administration
Dosages,
mg
Dosing
interval, days
Leuprolide acetate
Depot suspension Lupron depot i.m. 7.5 28
22.5 84
30 112
Injectable suspension Eligard s.c. 7.5 28
22.5 84
30 112
Implant Viadur s.c. 65 365
Goserelin acetate implant Zoladex s.c. 3.6 28
10.8 84
Triptorelin pamoate
Injectable suspension Trelstar depot i.m. 3.75 28
Trelstar LA 11.25 84
Histrelin acetate implant Vantas s.c. 50 365
TABLE 2
Antiandrogens: dosing information and side-effects
Drug Half-life Dosage, mg Side-effects
Bicalutamide 7 days 50 Gynaecomastia breast tenderness nausea
diarrhoea
Flutamide 5–6 h 250 three times/day Hepatotoxicity (can occur with all of the
antiandrogens, but more frequently
with flutamide) diarrhoea
Nilutamide 2 days 100 three times/day
for 1st months then
150/day thereafter
Visual disturbances alcohol intolerance
interstitial pneumonitis nausea
Cyproterone acetate 30–40 h 100 mg three times/day Cardiovascular toxicity suppressed libido
H O R M O N A L T H E R A P I E S F O R H O R M O N E - R E F R A C T O R Y P R O S TAT E C A N C E R
©
2 0 07 T H E A U T H O R S
J O U R N A L C O M P I L A T I O N
©
2 0 07 B J U I N T E R N A T I O N A L
6 7 3
multi-institutional controlled trials have
assessed the activities and toxicities of
secondary hormonal manipulations.
Adrenal suppressants such as ketoconazole or
aminoglutethimide might have benefit in
selected patients with prostate cancer,
although they do not have a USA Food and
Drug Administration (FDA) indications for
such. Ketoconazole at 400 mg three times/day
plus hydrocortisone 20 mg twice daily has
been used in subsets of patients. Oral steroid
replacement is essential due to the resultant
adrenal suppression. In single-institution
phase II trials this combination had a high
response rate in terms of PSA level reduction
and a potential reduction in symptoms [25].
However, data from the Cancer and Leukemia
Group B indicate that combinations of
ketoconazole, hydrocortisone, and
antiandrogen withdrawal are associated
with only a 27% response rate when using
consensus PSA response criteria [20].
Randomized trials in cooperative group
settings do not indicate that combining
ketoconazole with antiandrogen withdrawal
is more beneficial than these agents given
in sequence. In addition, toxicity from
ketoconazole at these high doses might be
problematic; gastrointestinal distress, fatigue
and liver function abnormalities are not
uncommon. Low-dose ketoconazole (200 mg
three times/day) has also been described
to have comparable PSA responses while
minimizing the side-effects noted above [26].
Due to the drug’s effect on the cytochrome P-
450 system, metabolism of other concurrent
medications dependent on hepatic processing
(coumadin) might be adversely affected.
Ketoconazole must be administered
≥
2 h
before medications designed to treat peptic
ulcer disease (histamine blockers, protonpump
inhibitors), as an acidic stomach
environment is essential for its absorption.
Aminoglutethimide is an adrenal suppressant
that blocks the conversion of cholesterol
to pregnenolone, causing concurrent
deficiencies in glucocorticoids and
mineralocorticoids and thus requiring their
replacement during the therapy. Treatment
consists of aminoglutethimide 1000 mg/day
and hydrocortisone acetate 40 mg/day.
Patients have had clinical responses, with
a reduction in PSA level lasting 9 months
[27]. Side-effects include gastrointestinal
discomfort, anorexia, rash, lethargy,
vertigo, hypothyroidism, depression and
nystagmus.
Glucocorticoids such as hydrocortisone,
prednisone, and dexamethasone are known to
be active agents in prostate cancer, although
they too, like the adrenal suppressants, do not
have an FDA indication for treating prostate
cancer. Well-defined side-effects include
glucose intolerance, redistribution of body fat,
easy bruising, and steroid myopathies. Sideeffects
appear to be dose-related, but doseresponse
curves for treating prostate cancer
have not been established. Palliation of
symptoms and declines in PSA level have been
described in about a third of cases treated
with low-dose (10–20 mg/day) prednisone
[28]. Higher PSA response rates have been
described with dexamethasone, a more potent
glucocorticoid [29]. The dose of the
glucocorticoid in use should be tapered at the
end of therapy, as abrupt discontinuations
might render the patient adrenally
insufficient and precipitate an Addisonian
crisis.
Oestrogens are also used as second-line
agents; they are active in patients with both
symptomatic and asymptomatic HRPC, by
mechanisms of action that are not clearly
understood. The high risk of thromboembolic
events while using high doses of oestrogens
(e.g. intravenous fosfestrol) have substantially
limited the use of these agents. Lower doses
of oestrogens (e.g. oral DES at 1–3 mg) remain
effective and are typically well tolerated,
except for nipple tenderness and
gynaecomastia. DES at oral doses of 3 mg/day
is associated with declines in PSA level in
≈
42% of patients [30]. Although adding 2 mg
of coumadin and 325 mg of daily aspirin to
oestrogen therapy might be effective in
reducing thromboembolic events, controlled
studies are not available. Transdermal
oestrogen administration reduced
cardiovascular complications, and improved
bone density and quality of life, while
maintaining castrate levels of testosterone
[31]. Randomized trials evaluating oestrogens
in the second-line setting are not currently
available.
SUMMARY
The urologist has the unique opportunity
among clinicians to use both surgical and
pharmacological interventions for their
patients. Many options are available, in the
form of LHRH agonists, antiandrogens and
adjunctive therapies for men with advancing
prostate cancer. Each treatment option has it
own unique side-effect profile that requires
clinical monitoring during its administration,
and both the clinician and the patient must be
aware of the side-effects and benefits from
each therapy. As the treatment of prostate
cancer develops the urologist must be
prepared to tailor treatment options to fit the
needs of each patient.
CONFLICT OF INTEREST
Sam S. Chang has a financial relationship to
competitors of Saufi-Aventis.
REFERENCES
1
Holzbeierlein JM.
Managing
complications of androgen deprivation
therapy for prostate cancer.
Urol Clin
North Am
2006;
33
: 181–90
2
Oefelein MG, Agarwal PK, Resnick MI.
Survival of patients with hormone
refractory prostate cancer in the prostate
specific antigen era.
J Urol
2004;
171
:
1525–8
3
Oefelein MG, Ricchiuti VS, Conrad PW
et al.
Clinical predictors of androgenindependent
prostate cancer and survival
in the prostate-specific antigen era.
Urology
2002;
60
: 120–4
4
Schellhammer PF, Venner P, Haas GP
et al.
Prostate specific antigen decreases
after withdrawal of antiandrogen therapy
with bicalutamide or flutamide in patients
receiving combined androgen blockade.
J Urol
1997;
157
: 1731–5
5
Prostate Cancer Trialists’ Collaborative
Group.
Maximum androgen blockade in
advanced prostate cancer: an overview of
the randomised trials.
Lancet
2000;
355
:
1491–8
6
Amling CL.
Advanced prostate cancer
treatment guidelines: a United States
perspective.
BJU Int
2004;
94
(Suppl. 3):
7–8
7
Aprikian AG, Fleshner N, Langleben A,
Hames J.
An oncology perspective on the
benefits and cost of combined androgen
blockade in advanced prostate cancer.
Can J Urol
2003;
10
: 1986–94
8
Sartor O, Eastham JA.
Progressive
prostate cancer associated with use of
megestrol acetate administered for
control of hot flashes.
Southern Med J
1999;
92
: 415–6
9
Scher HI, Liebertz C, Kelly WK
et al.
Bicalutamide for advanced prostate
cancer: the natural versus treated history
of disease.
J Clin Oncol
1997;
15
: 2928–
38
B O U D R E A U X a n d C H A N G
©
2 0 07 T H E A U T H O R S
6 7 4
J O U R N A L C O M P I L A T I O N
©
2 0 07 B J U I N T E R N A T I O N A L
10
Thole Z, Manso G, Salgueiro E, Revuelta
P, Hidalgo A.
Hepatotoxicity induced by
antiandrogens. A review of the literature.
Urol Int
2004;
73
: 289–95
11
Han M, Nelson JB.
Non-steroidal antiandrogens
in prostate cancer – current
treatment practice.
Expert Opin
Pharmacother
2000;
1
: 443–9
12
Tyrrell CJ, Payne H, See WA
et al.
Bicalutamide (‘Casodex’) 150 mg as
adjuvant to radiotherapy in patients with
localised or locally advanced prostate
cancer: results from the randomised Early
Prostate Cancer Programme.
Radiother
Oncol
2005;
76
: 4–10
13
Wirth M, Tyrrell C, Delaere K
et al.
Bicalutamide (‘Casodex’) 150 mg in
addition to standard care in patients with
nonmetastatic prostate cancer. Updated
results from a randomised double-blind
phase III study (median follow-up 5.1 y) in
the early prostate cancer programme.
Prostate Cancer Prostatic Dis
2005;
8
:
194–200
14
Fradet Y, Egerdie B, Andersen M
et al.
Tamoxifen as prophylaxis for prevention
of gynaecomastia and breast pain
associated with bicalutamide 150 mg
monotherapy in patients with prostate
cancer: a randomised, placebo-controlled,
dose–response study.
Eur Urol
2007;
52
:
106–14
15
Di Lorenzo G, Perdona S, De Placido S
et al.
Gynecomastia and breast pain
induced by adjuvant therapy with
bicalutamide after radical prostatectomy
in patients with prostate cancer: the role
of tamoxifen and radiotherapy.
J Urol
2005;
174
: 2197–203
16
Kraus I, Vitezic D, Oguic R.
Flutamideinduced
acute hepatitis in advanced
prostate cancer patients.
Int J Clin
Pharmacol Ther
2001;
39
: 395–9
17
Garcia Cortes M, Andrade RJ, Lucena
MI
et al.
Flutamide-induced
hepatotoxicity: report of a case series.
Rev
Esp Enferm Dig
2001;
93
: 423–32
18
Pfitzenmeyer P, Foucher P, Piard F
et al.
Nilutamide pneumonitis: a report on eight
patients.
Thorax
1992;
47
: 622–7
19
Heinlein CA, Chang C.
Androgen
receptor in prostate cancer.
Endocr Rev
2004;
25
: 276–308
20
Small EJ, Srinivas S.
The antiandrogen
withdrawal syndrome. Experience in a
large cohort of unselected patients with
advanced prostate cancer.
Cancer
1995;
76
: 1428–34
21
Scher HI, Kelly WK.
Flutamide
withdrawal syndrome: its impact on
clinical trials in hormone-refractory
prostate cancer.
J Clin Oncol
1993;
11
:
1566–72
22
Figg WD, Sartor O, Cooper MR
et al.
Prostate specific antigen decline
following the discontinuation of
flutamide in patients with stage D2
prostate cancer.
Am J Med
1995;
98
:
412–4
23
Dawson NA, McLeod DG.
Dramatic
prostate specific antigen decrease in
response to discontinuation of megestrol
acetate in advanced prostate cancer:
expansion of the antiandrogen
withdrawal syndrome.
J Urol
1995;
153
:
1946–7
24
Bissada NK, Kaczmarek AT.
Complete
remission of hormone refractory
adenocarcinoma of the prostate in
response to withdrawal of
diethylstilbestrol.
J Urol
1995;
153
: 1944–
5
25
Small EJ, Halabi S, Dawson NA
et al.
Antiandrogen withdrawal alone or in
combination with ketoconazole in
androgen-independent prostate cancer
patients: a phase III trial (CALGB 9583).
J Clin Oncol
2004;
22
: 1025–33
26
Nakabayashi M, Xie W, Regan MM,
Jackman DM, Kantoff PW, Oh WK.
Response to low-dose ketoconazole and
subsequent dose escalation to high-dose
ketoconazole in patients with androgenindependent
prostate cancer.
Cancer
2006;
107
: 975–81
27
Kruit WH, Stoter G, Klijn JG.
Effect of combination therapy with
aminoglutethimide and hydrocortisone
on prostate-specific antigen response in
metastatic prostate cancer refractory to
standard endocrine therapy.
Anti-Cancer
Drugs
2004;
15
: 843–7
28
Tannock I, Gospodarowicz M, Meakin
W, Panzarella T, Stewart L, Rider W.
Treatment of metastatic prostatic cancer
with low-dose prednisone: evaluation of
pain and quality of life as pragmatic
indices of response.
J Clin Oncol
1989;
7
:
590–7
29
Nishimura K, Nonomura N, Yasunaga Y
et al.
Low doses of oral dexamethasone for
hormone-refractory prostate carcinoma.
Cancer
2000;
89
: 2570–6
30
Smith DC, Redman BG, Flaherty LE, Li L,
Strawderman M, Pienta KJ.
A phase II
trial of oral diethylstilbesterol as a
second-line hormonal agent in advanced
prostate cancer.
Urology
1998;
52
: 257–
60
31
Ockrim JL, Lalani EN, Laniado ME,
Carter SS, Abel PD.
Transdermal estradiol
therapy for advanced prostate cancer –
forward to the past?
J Urol
2003;
169
:
1735–7
Correspondence: Kelly Boudreaux, Urology,
Vanderbilt University, A-1302 Medical Ctr
North 21st Ave South and Garland Ave.,
Nashville, TN 37232, USA.
e-mail:
<script language='JavaScript' type='text/javascript'>
<!--
var prefix = 'ma' + 'il' + 'to';
var path = 'hr' + 'ef' + '=';
var addy38212 = 'kelly.boudreaux' + '@';
addy38212 = addy38212 + 'vanderbilt' + '.' + 'edu';
document.write( '<a ' + path + '\'' + prefix + ':' + addy38212 + '\'>' );
document.write( addy38212 );
document.write( '<\/a>' );
//-->\n </script><script language='JavaScript' type='text/javascript'>
<!--
document.write( '<span style=\'display: none;\'>' );
//-->
</script>This email address is being protected from spam bots, you need Javascript enabled to view it
<script language='JavaScript' type='text/javascript'>
<!--
document.write( '</' );
document.write( 'span>' );
//-->
</script>
Abbreviations:
ADT
, androgen-deprivation
therapy; HRPC, hormone-refractory prostate
cancer; DES, diethylstilbestrol; FDA, Food and
Drug Administration.](http://urotoday.com/images/stories/bjui_march2008.gif)
| < Prev | Next > |
|---|
|
UroToday, 1802 Fifth Street, Berkeley CA 94710 510.540.0930 (fax), info@urotoday.com ISSN 1939-4810
Privacy Policy | © 2008 UroToday ® All Rights Reserved |
