What are the benefits of adding bicalutamide (CasodexTM) to standard care for non-metastatic prostate cancer?
Artykuł opublikowany w Urologii Polskiej 2007/60/3.
- Department of Urology, Rigshospitalet, Copenhagen, Denmark
prostate, prostatic neoplasms, bicalutamide, androgen antagonists, radiotherapy, prostatectomy, stercz, nowotwory stercza, bikalutamid, antagoniści receptorów dla androgenów, radioterapia, prostatektomia
- Adjuvant castration therapy using goserelin (ZOLADEXTM) prolongs survival in men with locally advanced prostate cancer who undergo radiotherapy or in those with node-positive disease who undergo radical prostatectomy. However, castration is associated with side effects that limit its use in patients for whom sexual function and physical ability are priorities. The addition of bicalutamide (CASODEXTM) 150 mg to standard care for localised or locally advanced, non-metastatic prostate cancer is being investigated in the Early Prostate Cancer programme. This paper reviews the data from the third analysis of the programme at a median 7.4 years' followup. One finding was that patients with localised disease do not benefit from the addition of bicalutamide 150 mg to standard care. However, bicalutamide 150 mg improved objective progression-free survival in patients with locally advanced disease, irrespective of the standard care received (hazard ratio [HR] 0.65; 95% CI [confidence interval] 0.57, 0.74; p<0.001). In patients with locally advanced disease receiving radiotherapy, the addition of bicalutamide 150 mg significantly reduced the risk of death by 35% (HR 0.65; 95% CI 0.44, 0.95; p=0.03). This is the first evidence of an overall survival benefit with a non-castration-based hormonal therapy in this setting and, importantly, the magnitude of this benefit is comparable with that of adjuvant goserelin in a similar population. As bicalutamide 150 mg is associated with quality-of-life advantages including maintenance of sexual function and physical ability, it offers an attractive alternative to castration for patients with locally advanced disease who wish to maintain an active lifestyle.
Men with localised or locally advanced prostate cancer typically
receive radiotherapy, radical prostatectomy or watchful waiting
as standard care . There is scope for improvement on
each of these standard care options, however, as disease progression
and survival outcomes can be unsatisfactory [2-6].
Patients undergoing radiotherapy for locally advanced disease
are often given adjuvant luteinising hormone-releasing hormone
agonist therapy based on the proven survival benefit of
goserelin (ZOLADEXTM) in these settings [2,7]. Likewise, adjuvant
hormone ablation has been associated with a marked survival
benefit in patients found to be node positive during radical prostatectomy
for clinically localised disease . However, castration-
based therapies, which exert their therapeutic effect by suppressing
testosterone levels, are associated with a number of
pharmacologically predictable side effects. These include impotence,
loss of libido and decreased vitality , as well as reductions
in bone mineral density and lean muscle mass, which may
lead to an increased risk of osteoporotic bone fractures [9,10] Although
many of these side effects are manageable to an extent
[1,11,12], they may limit the use of castration in patients for
whom quality-of-life issues such as maintenance of sexual function
and physical ability are a high priority.
Non-steroidal antiandrogens such as bicalutamide (CASODEXTM)
do not suppress testosterone levels and offer potential quality-
of-life advantages over castration. Pooled data from two
randomised trials have shown that there is no significant difference
between bicalutamide 150 mg and castration in terms of
prolonging overall survival in patients with non-metastatic disease
 (Figure 1). In this same analysis, bicalutamide 150 mg was
associated with significant advantages over castration with regard
to maintaining sexual interest and physical capacity. There
is also evidence from other studies that bicalutamide 150 mg
preserves bone mineral density and lean muscle mass compared
with castration [10,13]. Bicalutamide 150 mg may, therefore, be
an attractive alternative hormonal therapy for patients with non-
-metastatic disease who wish to maintain an active lifestyle.
The role of adding bicalutamide 150 mg to standard care (radiotherapy,
radical prostatectomy or watchful waiting) for localised
or locally advanced, non-metastatic prostate cancer is being
evaluated in the world's largest prostate cancer treatment programme
to date – the Early Prostate Cancer (EPC) programme.
This article provides an overview of the data from the recently
published third analysis of the entire EPC programme  and
the separate analysis of the Scandinavian Prostate Cancer Group
Study No. 6 trial (SPCG-6, also known as Trial 25) . Using
these data, the underlying question of which patients are likely
to benefit from bicalutamide 150 mg therapy is explored.
The EPC programme
The ongoing EPC programme comprises three complementary,
double-blind, randomised, placebo-controlled trials  (Figure
2). A total of 8113 patients with localised or locally advanced,
non-metastatic prostate cancer were enrolled and randomised in
a 1: 1 ratio to receive standard care plus either bicalutamide 150
mg (n=4052) or placebo (n=4061). The primary end points of
the EPC programme were overall survival and objective progression-
free survival (PFS); tolerability was a secondary end point.
The EPC programme was designed to have 90% power to detect
a 15% reduction in the rate of objective progression and overall
survival for bicalutamide 150 mg compared with standard care
alone . To achieve this, overall recruitment of at least 7500
patients was required . The three trials were set up in various
geographical locations so that the required number of patients
could be enrolled and also to reflect variation in clinical practice
worldwide. Trial 23 was conducted in North America (n=3292
from 96 centres), Trial 24 in Europe, South Africa, Australia, Israel
and Mexico (n=3603 from 196 centres), and SPCG-6 in Scandinavia
(n=1218 from 61 centres). The effect of bicalutamide
150 mg was to be determined through a combined analysis of all
three trials, as stated in each individual trial protocol. To identify
where the effects of bicalutamide 150 mg were the greatest, examination
of outcomes in the individual trials, as well as in prospectively
defined subgroups (for example, disease stage at study
entry and standard care received), were intended from the outset.
The third analysis of the EPC programme was pre-planned
and took place at 7.4 years' median follow-up .
Findings from the EPC third analysis
The two treatment arms were well balanced in terms of patient
demographics and disease characteristics at baseline  (Table
1). Differences in disease prognosis and management were evident
across individual trial populations, with prognosis worsening
from Trial 23 to 24 to SPCG-6; this reflects the different clinical
practices across the continents. Consistent with North American
practice, most patients in Trial 23 were treated with radical prostatectomy
and, unlike in Trials 24 and SPCG-6, those with lymph-node
involvement or who were candidates for watchful waiting were
excluded. Conversely, in accordance with Scandinavian practice,
most patients in SPCG-6 were managed with watchful waiting
. As the differences between the trials apply equally to both
treatment arms, they do not bias the size of treatment effects.
Overall efficacy results
Across the entire EPC programme, bicalutamide 150 mg significantly
reduced the risk of objective progression by 21%
compared with standard care alone (hazard ratio [HR] 0.79; 95%
confidence interval [CI] 0.73, 0.85; p<0.001) . There was no
significant difference in overall survival between the treatment
groups, with 23% of patients having died in both arms (HR 0.99;
95% CI 0.91, 1.09; p=0.89).
These findings suggest that at least some patients benefit
from bicalutamide 150 mg therapy. Further investigation of outcomes
in individual trials and prospectively defined subgroups
were, therefore, warranted to identify where the benefits of bicalutamide
therapy were greatest.
Identifying which patients benefit most from
bicalutamide 150 mg therapy
In the subgroup of patients with localised disease,
the addition of bicalutamide 150 mg to standard
care provided no significant benefit in terms of
overall survival or objective PFS, irrespective of the
standard care received . Moreover, there was
a statistically insignificant trend towards decreased
overall survival in bicalutamide-treated patients who
would otherwise have undergone watchful waiting
(HR 1.16; 95% CI 0.99, 1.37; p=0.07). The accumulation
of several small imbalances in various causes
of death, rather than one specific cause, appears to
account for the increased number of deaths with bicalutamide
in this patient subgroup. Nevertheless,
these data suggest that, in patients with localised
disease treated with bicalutamide, there is a level of
tumour burden below which hormonal therapy may
be harmful. Bicalutamide 150 mg should not, therefore,
be used as immediate hormonal therapy for
patients with localised disease.
In contrast with the results in patients with localised
disease, the benefits of bicalutamide 150 mg
were clearly demonstrated in those with locally advanced
disease. When patients with locally advanced
disease in the adjuvant and watchful waiting
populations were considered, bicalutamide 150 mg
significantly improved objective PFS, irrespective of
the standard care received (HR 0.65; 95% CI: 0.57,
0.74; p<0.001), although there was no significant
overall survival benefit. The objective PFS benefit
extended into the radiotherapy (HR 0.56; 95% CI
0.40, 0.78; p<0.001), radical prostatectomy (HR
0.75; 95% CI 0.61, 0.91; p=0.004) and watchful
waiting (HR 0.60; 95% CI 0.49, 0.73; p<0.001)
subgroups (14) (Figure 4). Differences between the
three standard care subgroups were found, however,
in terms of overall survival.
For patients who received radiotherapy for locally
advanced disease, adjuvant bicalutamide 150 mg
significantly improved overall survival (HR 0.65; 95%
CI 0.44, 0.95; p=0.03; Figure 3) compared with radiotherapy
alone . The difference in mortality
was driven by a lower risk of prostate-cancer-related
deaths with adjuvant bicalutamide 150 mg relative
to radiotherapy alone (16.1% versus 24.3%, respectively).
This is the first time that an overall survival
benefit has been observed for any non-castrationbased
hormonal therapy given as adjuvant treatment
to patients with prostate cancer. Although
this finding arises from a subgroup analysis and the
risk of a false-positive result must be acknowledged,
the results are unlikely to be due to chance given
that they were driven by reduced prostate cancer
mortality and because a highly significant objective
PFS benefit was observed. Moreover, the magnitude
of the overall survival benefit seen with bicalutamide
150 mg in this patient group (35% reduction in
the risk of death) compares favourably with that reported
with goserelin in the Radiation Therapy Oncology
Group (RTOG) 85-31 trial, which comprises
a near contemporary series of patients . At 7.6
years' median follow-up, which is similar to the current
length of follow-up in the EPC programme (median
7.4 years), goserelin adjuvant to radiotherapy
significantly reduced the risk of death by 23% in patients
with locally advanced disease compared with
radiotherapy alone (HR 0.77; p=0.001).
In patients with locally advanced disease undergoing
radical prostatectomy, there was no significant
difference in overall survival between the adjuvant
bicalutamide and standard care alone groups
(HR 1.09; 95% CI 0.85, 1.39; p=0.51). However, in
patients with locally advanced disease who would
otherwise have undergone watchful waiting, a trend
towards improved overall survival with bicalutamide
150 mg was observed (HR 0.81; 95% CI 0.66, 1.01;
p=0.06). This survival trend was largely accounted
for by findings in Trial 25, which included 359 of the
657 patients in the locally advanced, watchful waiting
subgroup of the overall population; the watchful
waiting patients in Trial 25 had a worse prostate
cancer prognosis than the corresponding patients in
Trial 24 as shown by higher PSA levels at trial entry.
In Trial 25, there was statistical evidence that bicalutamide
150 mg improved overall survival (p=0.007)
in this subset of patients .
Safety and tolerability of bicalutamide 150 mg
The latest data from the EPC programme confirm
the good tolerability of bicalutamide 150 mg,
consistent with findings from earlier analyses
[17,18]. As expected with a non-steroidal antiandrogen,
the most common adverse events with bicalutamide
150 mg were gynaecomastia (68.8%) and breast pain (73.6%)
, which reflect the pharmacological action in blocking androgen
receptors. These events were, however, of mild to moderate
intensity in most cases (>90%) and were associated with a relatively
low withdrawal rate (16.8%). Other adverse events were
reported at low incidences, including impotence (9.3% with bicalutamide
150 mg versus 6.5% with standard care alone), decreased
libido (3.6% versus 1.2%, respectively), hot flushes (9.2%
versus 5.4%, respectively) and abnormal liver function tests
(3.1% versus 1.7%, respectively).
Although not offered to patients in the EPC programme, effective
options for the management of bicalutamide-induced gynaecomastia
and breast pain are available. Data from randomised
studies have demonstrated that radiotherapy is successful in suppressing
these adverse events when used prophylactically (19)
and in reducing their intensity when used therapeutically . Tamoxifen
has also shown efficacy in preventing and treating gynaecomastia
and breast pain in randomised trials with no apparent
detrimental effects on PSA control [21,22], but before it can be
recommended in routine clinical practice, the impact of antioestrogen
therapy on cancer control remains to be determined.
When compared with the tolerability profile of castration, bicalutamide
150 mg offers clear advantages, including maintenance
of sexual and physical activity and preservation of bone
mineral density and lean muscle mass [8,10,23]. The good tolerability
profile of bicalutamide 150 mg means that this agent represents
an attractive alternative to castration, particularly for
patients who wish to maintain an active lifestyle.
The third analysis of the EPC programme, conducted at
a median follow-up of 7.4 years, suggests that bicalutamide
150 mg is a valuable hormonal treatment option for patients
with locally advanced disease, but not for those with localised
disease. These data represent the first evidence of a significant
overall survival benefit for a non-castration-based hormonal
therapy as adjuvant to radiotherapy in patients with locally advanced
disease, with findings comparable to those reported
with goserelin as adjuvant to radiotherapy in the RTOG 85-31
trial. As bicalutamide 150 mg offers tolerability advantages over
castration, particularly regarding maintenance of sexual and
physical activity, it represents an attractive alternative hormonal
therapy for men wishing to maintain an active lifestyle. In studying
the effects of bicalutamide 150 mg in such a large number
of patients, the EPC programme has improved our understanding
of not only the role of bicalutamide 150 mg but also
hormonal therapy as a concept in the management of non-metastatic
We thank Dr Sharon Gladwin from Complete Medical Communications,
who provided medical writing support funded by
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Peter Iversen MD
Department of Urology D-2112
University of Copenhagen, Rigshospitalet
Blegdamsvej 9, 2100
tel. +45 3545 2314, fax +45 3545 2158