Blackwell Science, LtdOxford, UKBJUBJU International1464-4096BJU InternationalJune 2004939
COMBINED THERAPY FOR ADVANCED PROSTATE CANCERL. KLOTZ et al. Combined androgen blockade is a A re-assessment of the role of controversial topic, which has arguments both for and against. It combined androgen blockade for is revisited by the authors of this advanced prostate cancer mini-review, with a full discussion on the benefits and cautions with L. KLOTZ, P. SCHELLHAMMER* and K. CARROLL† Sunnybrook & Women’s College Health Sciences Centre, University of Toronto, Canada, *Eastern this approach. A wide range of Virginia Medical School, Norfolk, Virginia, USA, and †AstraZeneca, Macclesfield, UKother issues is also addressed in this section: bilateral testicular cancer, male-factor infertility, and buccal mucosa urethroplasty. All of these are of interest to general KEYWORDS
glands continue to produce the androgens, androsterone and dehydroepiandrosterone.
urologists, as well as to those with
combined androgen blockade, bicalutamide,
a more specific area of interest.
antiandrogen, prostate cancer, advanced,
the peripheral tissues and in the prostate
gland (Fig. 1). After castration minimal amounts of testosterone may persist, derived from the adrenal and residual testicular secretion. INTRODUCTION
It is well established that antiandrogens act
The addition of an antiandrogen to surgical or
through competition with the testosterone
medical castration, termed combined therapy,
metabolite dihydrotestosterone and other
was first described in 1979. Twenty-five years
androgens for binding sites on the androgen
later, much debate still surrounds the benefits
receptors in the prostate cell nucleus. Their
blockade of the androgen receptor activation
by nonsteroidal growth factors, cytokines,
question ‘Does combined therapy have a role
and other nonligand dependent activators
is less well recognized [2]. This latter
prostate cancer?’. We review pertinent study
nonsteroidal antiandrogen bicalutamide and
present an analysis combining historical trial
data that provides an estimate of the benefit
antagonists’. The combination of medical
or surgical castration plus an antiandrogen
blocks the action of androgens produced by both the testes and adrenal glands. Androgen-dependent genes responsible for prostate cell function and division are
THE RATIONALE FOR COMBINED THERAPY
activated by the androgen receptor (Fig. 2). Therefore, inhibiting receptor activation
(either by androgen or ligand independent
testosterone and the adrenal glands produce
the remaining androgens [1]. After castration
(whether surgical or medical), the adrenal
2 0 0 4 B J U I N T E R N A T I O N A L | 9 3 , 11 7 7 – 11 8 2 | doi:10.1111/j.1464-410X.2004.04803.x
WHICH ANTIANDROGEN FOR COMBINATION THERAPY?
Both steroidal antiandrogens, e.g. cyproterone
factor; IGF-1, insulin-like growth
acetate (CPA) and chlormadinone acetate, and
factor-1; IL-6, interleukin-6; KGF,
the nonsteroidal antiandrogens bicalutamide,
investigated in clinical trials as part of
cancer. A survival disadvantage for combined
therapy with the steroidal antiandrogen CPA compared with castration alone has been demonstrated in a subset analysis of data from the Prostate Cancer Trialists’ Collaborative Group (PCTCG) meta-analysis
[3] (discussed in more detail later). Functional regions of the androgen receptor. AF, activation
The properties of the three nonsteroidal antiandrogens differ in several important
respects. One such property is their blockade
of nonandrogenic activation of androgen receptors. These factors include cytokines, e.g. interleukin-6, growth factors such as
IGF and epidermal growth factor, and signal transduction factors such as protein kinase A. These factors are capable of activating
was 2.4–4 times greater in LNCaP-abl cells
normal androgen receptors. In the presence of
than in LNCaP cells. For bicalutamide, the
androgen-receptor mutations the androgen
antiandrogens are their androgen receptor
receptor may become ‘promiscuous’ and
lower than that seen with flutamide. The
binding affinities and potencies, clinical
efficacies and tolerability profiles.
androgen receptor activity were 2–2.5-times
The nonsteroidal antiandrogens differ in
greater in LNCaP-abl cells than in LNCaP
In vitro studies show that the binding affinity
independent activation [4]. Flutamide has
prostate androgen receptor is 2–4 times
been shown to activate cells with specific
greater than that of flutamide and twice that
androgen receptors identified from patients
showed greater potency than flutamide in
with androgen insensitivity syndrome [4].
suppressors and co-activators. For example,
reducing intact rat ventral prostate and
Similarly, nilutamide caused transcription
bicalutamide has been shown to activate the
nuclear androgen receptor co-suppressor N-
CoR and inhibit the co-activator SRC-1. Both
a point mutation in the same codon as the
these effects would result in inhibition of
comparison trial in 813 men with metastatic
mutation in the androgen-independent cell
cell growth signals by activated androgen
prostate cancer [8] there was a trend to
line LNCaP, while bicalutamide maintained
receptors. However, the effect of flutamide in
improved overall survival with bicalutamide
plus an LHRH agonist than with flutamide
novel cell subline, LNCaP-abl, which has
plus an LHRH agonist (median survival 180 vs
a hypersensitive proliferative response to
148 weeks), although the difference did not
achieve statitical significance (hazard ratio,
effects on androgen-receptor transactivation
nonsteroidal antiandrogens in the androgen-
HR, 0.87; 95% CI 0.72–1.05; P = 0.15). This is
activity and was unable to block androgen
the only trial comparing two nonsteroidal
effects [5]. Flutamide also exerted stimulatory
bicalutamide may be superior to flutamide
effects on androgen receptor activity that
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C O M B I N E D T H E R A P Y F O R A D V A N C E D P R O S T A T E C A N C E R
FIG. 3. Overall survival data as HRs for combined therapy compared with castration alone from published
significantly reduces the power to detect
meta-analyses. Figure reproduced with permission from [4]. Derived from information in [3]; †Relative risks
differences in any analysis/study with a
using data from [3]; CPA, cyproterone acetate; FLUT, flutamide; NILUT, nilutamide; NSAA, nonsteroidal antiandrogen; NSAA(LH), relative risks (log HR) from P values; NSAA(PH), relative risks (proportional hazards) from discrete proportional hazards model.
COMBINED THERAPY VS CASTRATION ALONE: META-ANALYSES
In an attempt to better understand this large
volume of trial data there have been several
meta-analyses [3,12,13]. The benefits and
limitations of the various meta-analyses of
castration alone were reviewed previously
evidence is the meta-analysis published in
2000 by the PCTCG, which assessed data from
27 trials (including a total of 8275 patients)
and incorporated individual patient data [3].
The PCTCG meta-analysis found an overall trend for improved overall survival in patients
The nonsteroidal antiandrogens also have
different tolerability profiles. Flutamide is
castration alone for treating metastatic
with castration alone, although this was not
associated with diarrhoea [9,10] and liver
statistically significant (HR 0.958; SEM 0.026;
toxicity [10]. High rates of visual disturbances
improvements in progression-free (median
P = 0.11, two-sided) (Fig. 3); the survival
and alcohol intolerance have been reported
16.5 vs 13.9 months; P = 0.039) and overall
with nilutamide [10]. Bicalutamide is better
(median 35.6 vs 28.3 months; P = 0.035)
tolerated [1,10]. In the trial by Schellhammer
et al. [8] the incidence of diarrhoea was
compared with leuprolide plus placebo.
disaggregated, combined therapy with the
nonsteroidal antiandrogens flutamide and
bicalutamide plus an LHRH agonist than with
The largest randomized trial of combined
nilutamide was associated with a statistically
flutamide plus an LHRH agonist (12% vs 26%;
therapy vs. monotherapy conducted to date
significant 8% decrease in the risk of death
P < 0.001). In that study, haematuria was the
studied bilateral orchidectomy plus either
only adverse event to occur significantly more
flutamide or placebo in 1387 patients with
P = 0.005, two-sided); this translated into a
frequently with bicalutamide plus agonist
metastatic prostate cancer [9]. There was a
2.9% absolute improvement in 5-year survival
than with flutamide plus agonist (12% vs 6%;
trend for improved survival (a survival benefit
(Fig. 3) [14]. However, combined therapy with
P = 0.007); in most cases this was mild to
moderate, unrelated to treatment (96%), and
castration alone, but this was not statistically
associated with a statistically significant 13%
did not lead to treatment withdrawal. Overall,
increase in the risk of death compared with
the incidence of withdrawal from therapy due
flutamide vs placebo, 0.91, 90% CI 0.81–1.01;
castration alone (95% CI 0–27; P = 0.04, two-
P = 0.14). The trial was powered to detect the
sided), and this equated to a 2.8% reduction
bicalutamide plus agonist (10%) than with
25% difference that had been observed in the
study by Crawford et al. [11]. At progression, the treatment arm was unblinded and
In the PCTCG meta-analysis [3] the results
patients who had been on placebo could then
appeared to be independent of patient age,
CLINICAL EVIDENCE FOR THE
receive open-label flutamide; therefore, the
disease stage or whether surgical or medical
EFFECTIVENESS OF COMBINED THERAPY
trial actually compared initial with delayed
castration was used. Although the results of
the trials differed, such variation could be
Evidence for the effectiveness of combined
expected by chance (the test of treatment-
by-trial interaction was not significant,
comes from individual trials, meta-analyses of
(treatment for > 1 year) trials in >8000 men
trial results and, in the case of combined
therapy using bicalutamide, from the latest
investigated the effectiveness and tolerability
of combined therapy, with variable results [3].
Differences between therapies are unlikely to
be detected during the early follow-up, as most deaths within 1–1.5 years from
As bicalutamide was not available when most
Crawford et al. [11] reported the first large
diagnosis of advanced cancer are likely to
2 0 0 4 B J U I N T E R N A T I O N A L
available for inclusion in the meta-analysis
bicalutamide 50 mg with castration alone. A
double-blind randomized trial is currently
ongoing in Japan of bicalutamide 80 mg (the
registered dose in Japan) combined with an
LHRH agonist vs an agonist plus placebo in
New analysis:
Preliminary data at a median follow-up of
bicalutamide plus castration versus castration alone
15 months indicate that combined therapy with bicalutamide has significant benefits
over LHRH agonist monotherapy; there was
an improvement in PSA normalization rate (79.4% vs 38.6%; P < 0.001); reduction of the risk of treatment failure (median time to
metastatic disease) upon which the size of the
failure 22.1 vs 15.6 months; P = 0.038) and
leucovorin and a meta-analysis of trials
effect of bicalutamide relative to flutamide
comparing 5-fluorouracil plus leucovorin to
would differ, and that patients in the trials
P = 0.015); and improvement in quality of life
5-fluorouracil alone. Fisher et al. [17]
(P < 0.001). There were too few events to
described a similar application to estimate the
effect of clopidogrel relative to placebo in
ischaemic stroke or symptomatic peripheral
combining data across studies is that it is
arterial disease. Results from an active-
impossible to completely verify the above
nonsteroidal antiandrogen, flutamide, in the
controlled trial comparing clopidogrel with
combined therapy setting (HR 0.87; 95% CI
aspirin were used with data from 40 trials of
consistency of the effect of flutamide in the
0.72–1.05) [8]. At the time this trial was
aspirin vs placebo to obtain an estimate of the
PCTCG analysis [3] provides some reassurance
designed a direct comparison of combined
therapy using bicalutamide with castration alone was considered unethical, as combined
THE FUTURE OF COMBINED THERAPY
therapy was considered standard care and
therapy using bicalutamide vs castration
superior to monotherapy. To understand the
alone is estimated by multiplying the HR for
role of bicalutamide in combined therapy we
bicalutamide combined therapy vs flutamide
used data from the Schellhammer trial [8] in
combined therapy with the HR for flutamide
When considering therapeutic options the
conjunction with the PCTCG meta-analysis
combined therapy vs castration alone (i.e.
clinician and patient must consider many
data [3] for flutamide plus castration vs
factors. These include the patient’s disease
castration alone (HR 0.92, 95% CI 0.86–0.98)
status, benefits of therapy, treatment side-
to calculate an estimate of the likely benefit of
On applying this analysis the balance of
effects, quality-of-life issues and cost.
bicalutamide combined therapy vs castration
probability (98.5%) that bicalutamide as part
suggest that there is a modest improvement
in overall survival with combined therapy
Conventional wisdom dictates that data from
advantage over castration alone. The HR is
0.80, indicating a 20% reduction in the risk of
death, with a 95% CI of 0.66–0.98, indicating
although these do not appear until after
validated technique has evolved to integrate
that this benefit could range from an absolute
2 years. An overall survival benefit, although
the results of trials which share a common
benefit of 2% to 34% (Fig. 4). These CIs are
modest, in the aged population where there is
arm (in this case, flutamide as MAB) but differ
calculated from the combined SEM, which was
a high competing risk of death from other
in the alternate arm. Typically, this is
larger than the SEM from either [8] or the
causes is noteworthy. The analysis reported
employed where a placebo arm may no longer
here using historical data estimates the
be feasible or ethical. Stringent criteria
greater uncertainty when combining results
benefit of bicalutamide combination therapy
(see Appendix). The key assumptions made
as a 20% reduction in the risk of death (HR
populations must be met. The PCTCG trials
when estimating the effect of bicalutamide
0.8; 95% CI 0.66–0.98) over castration alone.
and the Schellhammer trial, both of which
are that the effect of flutamide in the trials in
enrolled D2 patients from the pre-PSA era,
the PCTCG meta-analysis [3] was of a similar
Compared with other cancer interventions the
appear to meet these criteria. Rothmann et al.
magnitude to that in the study population of
[16] applied the method to estimate the effect
Schellhammer et al. [8]. This would require
prostate cancer is reasonable [18]. Using
of capecitabine relative to 5-fluorouracil
there to be no important prognostic factors
alone for metastatic colorectal cancer, by
which were represented differently between
4–7-month survival benefit with combined
combining the results from a trial comparing
the study populations (such as the extent of
therapy in advanced prostate cancer, the
2 0 0 4 B J U I N T E R N A T I O N A L
C O M B I N E D T H E R A P Y F O R A D V A N C E D P R O S T A T E C A N C E R
therapy into context with previously reported
Culig Z, Hoffmann J, Erdel M et al.
bicalutamide per month of survival benefit is
meta-analyses. An estimate of the benefit of
Switch from antagonist to agonist of the
combined therapy with bicalutamide suggests
there is a high probability (estimated to be
gained are higher with other cancer therapies
progression in a new model system. Br J
therapy provides a survival advantage over
Cancer 1999; 81: 242–51
castration alone. The HR for survival in this
Hu X, Lazar MA. Transcriptional
analysis was 0.80, indicating a 20% reduction
repression by nuclear hormone receptors.
benefit) the cost is calculated as Can$1241
in the risk of death with combined therapy
Trends Endocrinol Metab 2000; 11: 6–10
per month of survival gained. For metastatic
using bicalutamide over castration alone
Kolvenbag GJCM, Furr BJA, Blackledge
colorectal cancer, irinotecan added to 5-
(with 95% CI indicating that the absolute
GRP. Receptor affinity and potency of
fluorouracil and leucovorin provides a 2–3-
survival benefit of 2–34%). When using
non-steroidal antiandrogens: translation
combined therapy other properties of the
of preclinical findings into clinical activity.
calculated to be Can$11 214 per month of
nonsteroidal antiandrogens should also be
Prostate Cancer PD 1998; 1: 307–14
considered, i.e. tolerability, binding affinity
Schellhammer PF, Sharifi R, Block NL et al. Clinical benefits of bicalutamide
RESEARCH NEEDS
Trial data suggest that patients with minimal
metastatic disease may have the greatest
ACKNOWLEDGEMENTS
randomized trial. Br J Urol 1997; 80: 278
benefits from combined therapy. It may also
Eisenberger MA, Blumenstein BA,
be possible to use molecular markers, e.g.
Laurence Klotz and Paul Schellhammer are
Crawford ED et al. Bilateral orchiectomy
with or without flutamide for metastatic
prostate cancer. New Engl J Med 1998;
derive the greatest benefit from combined
supported by AstraZeneca Pharmaceuticals. 339: 1036–42
therapy. Further research is warranted to
10 McLeod DG. Tolerability of nonsteroidal CONFLICT OF INTEREST
advanced prostate cancer. Oncologist
L. Klotz is a study investigator for AstraZeneca
1997; 2: 18–27
and a paid member of the advisory board.
11 Crawford ED, Eisenberger MA, McLeod
administration in combined therapy is an
P. Schellhammer is a study investigator for
DG et al. A controlled trial of leuprolide
important consideration. Can the benefit of
AstraZeneca. K. Carroll is an employee of
combined therapy be obtained by initiating
carcinoma. New Engl J Med 1989; 321:
antiandrogens at the time of progression? To
date, no trial comparing early vs delayed
12 Agency for Health Care Policy and
combined therapy has been conducted. PSA
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APPENDIX Can J Urol 2003; 10: 1986–94
19 Kassouf W, Tanguay S, Aprikian AG.
Combination of uncertainty in estimates of
the likely benefit of bicalutamide combined
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