Prostate Cancer and Prostatic Diseases (2005) 8, 194–200
& 2005 Nature Publishing Group All rights reserved 1365-7852/05 $30.00
www.nature.com/pcan
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
M Wirth1*, C Tyrrell2, K Delaere3, M Sánchez-Chapado4, J Ramon5,
DMA Wallace6, J Hetherington7, F Pina8, C Heyns9, T Borchers9,
T Morris10 & J Armstrong10 on behalf of the ‘Casodex’ Early
Prostate Cancer Trialists’ Group
1
Technical University of Dresden Medical School, Dresden, Germany; 2Plymouth
Oncology Centre, Derriford Hospital, Plymouth, UK; 3Atrium Medical Centre, Heerlen,
The Netherlands; 4Hospital Principe de Asturias, Alcala de Henares, Madrid, Spain;
5
Department of Urology, Chaim Sheba Medical Center, Tel-Hashomer, Israel; 6Queen
Elizabeth Medical Centre, Edgbaston, Birmingham, UK; 7Princess Royal Hospital, Hull,
UK; 8Servico de Urologica, Hospital de São Joao, Porto, Portugal; 9Tygerberg Hospital
and Faculty of Health Sciences, University of Stellenbosch, Cape Town, South Africa;
and 10AstraZeneca, Macclesfield, UK
Trial 24 is one of three placebo-controlled trials within the ongoing bicalutamide
(‘Casodex’w) Early Prostate Cancer (EPC) programme evaluating bicalutamide
150 mg/day in addition to radical prostatectomy, radiotherapy or watchful waiting
for T1b–4, any N, M0 prostate cancer. In Trial 24, at 5.1 y median follow-up, the
addition of bicalutamide significantly (Po0.0001) improved objective progressionfree survival (PFS) and prostate-specific antigen PFS compared with standard care
alone. There was no significant difference in overall survival (P ¼ 0.746). In the
context of the whole EPC programme, long-term bicalutamide is not appropriate
for localised disease, yet provides advantages in delaying disease progression in
patients with locally advanced prostate cancer.
Prostate Cancer and Prostatic Diseases (2005) 8, 194–200. doi:10.1038/sj.pcan.4500799
Keywords: nonsteroidal antiandrogen; prostatic neoplasms; clinical trial; bicalutamide
Introduction
In patients with prostate cancer, disease progression can
have serious clinical consequences, such as painful bone
*Correspondence: M Wirth, Department of Urology, Technical
University of Dresden Medical School, Fetscherstrasse 74, Dresden
D-01307, Germany.
E-mail: [email protected]
w
‘Casodex’ is a trademark of the AstraZeneca group of companies
Received 1 March 2005; accepted 23 March 2005
metastases, spinal cord compression, pathological fractures and urinary dysfunction.1 Patients and their
carers/family members can suffer depression and
anxiety at signs of advancing disease, which impacts
on their quality of life.2 Furthermore, metastatic and
prostate-specific antigen (PSA) progression pose a significant economic burden.3,4 The ongoing bicalutamide
(‘Casodex’) Early Prostate Cancer (EPC) programme is
evaluating whether the addition of bicalutamide 150 mg/
day to standard care can reduce the risk of disease
progression as well as improve overall survival in
Bicalutamide 150 mg in addition to standard care
M Wirth et al
patients with localised (T1–2, N0 or Nx, M0) or locally
advanced prostate cancer (T3–4, any N, M0 or any T,
N þ , M0). This programme, the largest prostate cancer
study to date, consists of three randomised, doubleblind, placebo-controlled trials (Trial 23, 24 and 25).5,6
Although the three trials in the EPC programme were
prospectively designed and powered for a combined
analysis, it is important to consider each trial separately
as well as in the context of the overall results. In Trial 25,
conducted in Scandinavia, over three-quarters of patients
were untreated before entry; therefore, findings essentially reflect those of immediate hormonal therapy vs
watchful waiting.7 Trial 23, a North American trial, is
evaluating the benefit of early antiandrogen therapy,
predominantly in patients with localised prostate cancer
undergoing radical prostatectomy.
This manuscript reports the results from Trial 24,
which is being conducted primarily in Europe. The
results from the first planned analysis of Trial 24,
performed at 2.6 y median follow-up, showed that
bicalutamide significantly improved objective progression-free survival (PFS), irrespective of primary therapy
and disease stage. The tolerability profile was closely
linked to the pharmacology of bicalutamide, with
gynaecomastia and breast pain the most frequently
reported adverse events (mild to moderate in most
cases).8 Trial 24 is ongoing and this article reports the
findings of the second planned analysis of this Trial,
performed at 5.1 y median follow-up.
Methods
The methods for Trial 24 have been previously described8 and are presented here in brief.
Trial design
Trial 24, a randomised, double-blind, placebo-controlled
trial, recruited 3603 patients between September 1995
and July 1998 from 191 centres in non-Scandinavian
Europe (n ¼ 2925), South Africa (n ¼ 394), Israel (n ¼ 193),
Mexico (n ¼ 77) and Australia (n ¼ 14).
Men aged X18 y diagnosed with clinically or pathologically confirmed nonmetastatic prostate cancer
(T1b–4, any N, M0), who gave written informed consent,
were included in the trial. These patients would have
otherwise not received hormonal therapy following
standard care.
Following standard care, patients included in the trial
were randomised 1 : 1 to receive either bicalutamide
150 mg or placebo once daily. For radical prostatectomy
and radiotherapy patients, it was recommended that
randomised treatment should continue until objective
disease progression or up to a maximum of 5 y. In
watchful waiting patients, randomised therapy was
recommended until objective disease progression with
no maximum duration. Alternative therapy upon disease
progression was initiated at the investigators’ discretion.
Patients are being followed for objective progression and
death.
The trial was conducted in accordance with the
Declaration of Helsinki and Good Clinical Practice
guidelines, and with Independent Ethics Committee
approval at each centre.
195
Assessments and end points
Assessments for patients receiving randomised treatment were made at 12-weekly intervals for local and
regional disease, distant metastases, clinical symptoms,
PSA level, liver biochemistry and other clinical laboratory parameters. Patients withdrawn from therapy were
followed every 24 weeks until death.
The primary end points in Trial 24 were objective PFS
and tolerability. Objective PFS was defined as the time
from randomisation to the earliest sign of objective
progression (confirmed by bone scan, computed tomography, ultrasound or magnetic resonance imaging scan,
or histological evidence of distant metastases), or to
death from any cause without progression. Tolerability
was assessed by examining the number of patients who
reported adverse events, classified using the Coding
Symbols for Thesaurus of Adverse Reaction Terms
(COSTART) system.
Secondary end points were overall survival (time from
randomisation to death) and PSA PFS (time from
randomisation to the earliest point of PSA doubling,
objective progression or death). Serum PSA levels were
measured every 12 weeks using the Hybritech assay
(Hybritech Inc., San Diego, USA). Patients with baseline
PSA levels below the limit of quantification (1.0 ng/ml)
were considered to have reached PSA doubling if their
PSA level increased to X2 ng/ml.
Statistical analyses
The timing of this second preplanned analysis of Trial 24
was based on the accrual of sufficient deaths across the
whole EPC programme to allow detection of a 15%
reduction in the overall mortality rate in the overall
population with 80% power and 5% two-sided significance. It was estimated that by 31 December 2002 (4.5 y
minimum follow-up), the required number of events
(1200) across the whole EPC programme would have
occurred. The predicted statistical estimates were met at
the time of the second analysis (4.5 y minimum followup) as 1236 patients had died across the whole
programme.6 The statistical methods used have been
described previously.8
Efficacy data for the overall Trial 24 population were
analysed on an intent-to-treat basis using a Cox proportional hazards regression model, which estimates the
hazard ratio (HR) for the reduction in the risk of an event
for bicalutamide relative to standard care alone. As part
of the Statistical Analysis Plan, a statistical test was
performed that examined whether the relative effect of
bicalutamide on overall survival was dependent on
certain prespecified baseline prognostic factors, such as
baseline PSA level, Gleason score and disease stage.
Results
Patients
Of the 3603 men recruited into Trial 24, approximately
two-thirds had received surgery or radiotherapy and
Prostate Cancer and Prostatic Diseases
Bicalutamide 150 mg in addition to standard care
M Wirth et al
196
approximately one-third had received no primary treatment. A total of 1798 patients were randomised to
receive bicalutamide and 1805 patients were randomised
to receive placebo. The two treatment groups were well
balanced in terms of patient demography and baseline
disease characteristics (Table 1).
Following the first analysis of the full EPC programme
data set,5 the study blind was broken due to a
significantly lower risk of objective disease progression
with the addition of bicalutamide to standard care
compared with placebo. Investigators and patients were
informed of the results and patients had the option of
breaking their blind and switching to bicalutamide as
open-label therapy. A total of 12% of patients broke their
blind in Trial 24; 300 patients (8.3%) were still receiving
randomised therapy when the blind was broken, of
which 214 changed to open-label bicalutamide (94 had
been previously randomised to bicalutamide and 120 to
placebo). All patients continue to be followed for
progression and survival.
Efficacy
The median follow-up at this analysis was 5.1 y. The
median duration of randomised therapy according to
underlying standard care is given in Table 1.
Overall survival At the time of analysis, 17.8% (320/
1798) of patients randomised to bicalutamide and 17.5%
(316/1805) randomised to placebo had died. There was
no significant difference in overall survival between the
two treatment groups across the Trial 24 population (HR
1.03; 95% confidence intervals [CI] 0.88, 1.20; P ¼ 0.746)
(Figure 1). The statistical interaction test to determine
Table 1 Patient demographics and baseline tumour characteristics
Bicalutamide 150 mg/day
plus standard care
(n ¼ 1798)
Placebo plus standard care
(n ¼ 1805)
68.6 (42–93)
68.7 (46–93)
Country of origin (%)
Europe (excluding Scandinavia)
South Africa
Israel
Mexico
Australia
81.3
11.0
5.3
2.0
0.4
81.1
11.0
5.4
2.3
0.4
Race (%)
Caucasian
Black
Other
95.3
0.9
3.7
94.7
0.7
4.6
Stage of diseasea (%)
T1–T2
T3
T4
64.2
33.2
2.6
66.2
31.2
2.5
Nodal status (%)
N0
Nx
N+
61.3
36.0
2.6
60.4
36.9
2.7
Tumour grade (Gleason score) (%)
Well differentiated (2–4)
Moderately differentiated (5–6)
Poorly differentiated (7–10)
Unknown
31.0
40.5
26.7
1.8
31.2
41.1
26.1
1.6
Standard care (%)
Radical prostatectomy
Radiotherapy
Radical prostatectomy plus radiotherapy
Watchful waiting
44.9
18.6
1.6
34.9
43.4
18.0
1.6
36.9
Median prerandomisation PSA level (ng/ml)
1.3
1.3
Median duration of treatment, patient yearsb
Radical prostatectomy
Radiotherapy
Watchful waiting
3.8
3.8
3.5
4.0
3.7
4.4
3.3
3.2
Mean age (range) (y)
PSA, prostate-specific antigen.
a
Disease stage determined pathologically for radical prostatectomy patients, but clinically for radiotherapy and watchful waiting patients.
b
For those patients who received trial treatment.
Prostate Cancer and Prostatic Diseases
Bicalutamide 150 mg in addition to standard care
M Wirth et al
Po0.0001) and 63% (HR 0.37; 95% CI 0.32, 0.43;
Po0.0001), respectively, compared with placebo.
whether the relative effect of bicalutamide on overall
survival was dependent on the prespecified baseline
prognostic factors was not significant (P ¼ 0.57).
197
Safety and tolerability
Objective progression-free survival Across Trial 24, the
objective disease progression end point was met by
22.5% (405/1798) of patients randomised to bicalutamide
(103 confirmed by bone scan, 66 confirmed by objective
measures, 236 deaths in the absence of progression) and
28.1% (507/1805) of patients randomised to placebo (172
confirmed by bone scan, 134 confirmed by objective
measures, 201 deaths in the absence of progression). The
addition of bicalutamide significantly improved objective PFS, reducing the risk of objective progression by
27% (HR 0.73; 95% CI 0.64, 0.83; Po0.0001) compared
with placebo (Table 2 and Figure 2). A significant
difference in favour of bicalutamide treatment was seen
for both the subgroup of patients randomised to
adjuvant therapy and the subgroup of patients undergoing watchful waiting (Table 2).
A total of 3585 patients were included in the safety
population (1790 randomised to bicalutamide and 1795
randomised to placebo). In all, 18 patients who did not
receive randomised therapy were excluded from the
safety analyses.
Adverse events The tolerability of bicalutamide was
consistent with that observed at the first analysis of Trial
248 and the combined analysis.6 The most common
adverse events associated with bicalutamide treatment
were gynaecomastia (67.9%) and breast pain (66.3%)
(Table 3) and were of mild to moderate intensity in most
(X85%) cases. Few patients (o3%) received prophylactic
breast irradiation or surgery for gynaecomastia and
breast pain. The incidence of other adverse events was
low in both treatment groups (Table 3).
Prostate-specific antigen progression-free survival In the
overall Trial 24 population, 29.4% (529/1798) of patients
randomised to bicalutamide and 50.1% (905/1805) of
patients randomised to placebo met the criteria for PSA
progression. Bicalutamide significantly improved PSA
PFS, reducing the risk of PSA progression by 57% (HR
0.43; 95% CI 0.39, 0.48; Po0.0001) compared with
placebo (Figure 3). Bicalutamide also significantly improved PSA PFS in the subgroup of patients randomised
to adjuvant therapy as well as in the subgroup of patients
who had undergone watchful waiting, reducing the risk
of PSA progression by 52% (HR 0.48; 95% CI 0.41, 0.55;
Withdrawals In Trial 24, withdrawal rates from randomised treatment were similar for bicalutamide and
placebo (64.5 vs 69.0%). The withdrawal rates due to
adverse events were greater for patients receiving
bicalutamide than those receiving placebo (29.4 vs
10.9%); 17.8 and 0.9% withdrew due to gynaecomastia
and/or breast pain, respectively. Fewer patients receiving bicalutamide withdrew due to objective progression
than those receiving placebo (5 vs 14.5%, respectively).
Figure 2 Kaplan–Meier curve of objective PFS in the overall Trial 24
population.
Figure 1 Kaplan–Meier curve of overall survival in the overall Trial 24
population.
Table 2 Analysis of objective PFS for the overall Trial 24 population and by primary therapy
Population
Trial 24
Adjuvant
Watchful waiting
No. patients
3603
2308
1294
HR (95% CI; P-value)
No. events (%)
Bicalutamide 150 mg
plus standard care
Placebo plus
standard care
405/1798 (22.5)
204/1170 (17.4)
201/628 (32.0)
507/1805 (28.1)
275/1138 (24.2)
232/666 (34.8)
0.73 (0.64, 0.83; o0.0001)
0.66 (0.55, 0.79; o0.0001)
0.82 (0.67, 0.99; ¼ 0.03)
CI, confidence intervals; HR, hazard ratio.
Prostate Cancer and Prostatic Diseases
Bicalutamide 150 mg in addition to standard care
M Wirth et al
198
Table 4 Most common causes of death (incidence X0.7% in either
treatment arm)
COSTART term
No. patients who died (%)
Bicalutamide
150 mg/day
plus standard
care (n ¼ 1790)
Figure 3 Kaplan–Meier curve of PSA PFS in the overall Trial 24
population.
Table 3 All adverse events with an incidence of X5% in either
treatment group showing a difference in incidence of 41% between
groups
No. patients (%)a
COSTART-term
Bicalutamide
150 mg/day
plus standard
care (n ¼ 1790)
Gynaecomastia
Breast pain
Back pain
Constipation
Urinary tract infection
Vasodilation (hot flushes)
Arthralgia
Impotence
Urinary incontinence
Pain
Rash
Hernia
Hypercholesterolaemia
Accidental injury
Weight gain
Haematuria
Somnolence
1216
1186
186
173
173
172
157
150
148
132
130
114
106
104
104
96
95
(67.9)
(66.3)
(10.4)
(9.7)
(9.7)
(9.6)
(8.8)
(8.4)
(8.3)
(7.4)
(7.3)
(6.4)
(5.9)
(5.8)
(5.8)
(5.4)
(5.3)
Placebo plus
standard care
(n ¼ 1795)
150
107
239
133
139
84
183
107
115
166
96
146
77
127
53
134
57
(8.4)
(6.0)
(13.3)
(7.4)
(7.7)
(4.7)
(10.2)
(6.0)
(6.4)
(9.2)
(5.3)
(8.1)
(4.3)
(7.1)
(3.0)
(7.5)
(3.2)
a
Patients may appear in more than one category; COSTART, Coding Symbols
for Thesaurus of Adverse Reaction Terms.
Deaths There was no difference in overall survival in
Trial 24 between patients receiving bicalutamide and
those receiving placebo. Fewer patients died of prostate
cancer in the bicalutamide group compared with those in
the placebo group (76 [4.2%] vs 101 [5.6%]), while the
converse was true for nonprostate-cancer-related deaths
(243 [13.6%] vs 215 [12.0%]). The most common causes of
death were examined (Table 4) and no consistent pattern
of nonprostate-cancer-related deaths was identified.
Discussion
Consistent with the earlier findings (at a median followup of 2.6 y), this second analysis of Trial 24 (at 5.1 y
median follow-up) continues to show that the addition of
Prostate Cancer and Prostatic Diseases
Prostatic carcinoma
Myocardial infarction
Cause unknown
Cerebrovascular accident
Gastrointestinal carcinoma
Pneumonia
Heart arrest
Carcinoma of the lung
76
33
18
18
18
13
13
11
(4.2)
(1.8)
(1.0)
(1.0)
(1.0)
(0.7)
(0.7)
(0.6)
Placebo plus
standard care
(n ¼ 1795)
101
30
16
14
14
18
9
12
(5.6)
(1.7)
(0.9)
(0.8)
(0.8)
(1.0)
(0.5)
(0.7)
COSTART, Coding Symbols for Thesaurus of Adverse Reaction Terms.
bicalutamide 150 mg/day significantly improves objective and PSA PFS in patients who otherwise would not
have received hormonal therapy following standard
care. These differences were also observed irrespective
of whether patients received adjuvant bicalutamide or
would have otherwise undergone watchful waiting.
There was no difference in overall survival in Trial 24
between bicalutamide and standard care alone.
As Trial 24 is one of the three trials making up the EPC
programme, it is important to consider these results in
the context of the other two trials (Trials 23 and 25). The
ongoing EPC programme comprises over 8000 men and
the second analysis of this programme was conducted at
a median follow-up of 5.4 y. This analysis demonstrated
that, in patients receiving adjuvant therapy, long-term
bicalutamide significantly improved objective PFS in
those with locally advanced prostate cancer (T3–4, any
N, M0 or any T, N þ , M0) disease, but not in those with
localised (T1–2, N0 or Nx, M0) disease.6 In those patients
who underwent watchful waiting, the improvement was
significant irrespective of disease stage, and most
pronounced in patients with locally advanced disease.6
An important finding from Trial 25 undertaken in
Scandinavia,7 where more than 80% of patients recruited
underwent watchful waiting, was that the relative effect
of bicalutamide on overall survival was dependent on
disease stage. In patients with localised disease, survival
appeared to be improved in those randomised to
standard care alone and, conversely, survival appeared
to favour bicalutamide therapy in patients with locally
advanced disease.
In contrast to Trial 25, the statistical interaction test
between randomised treatment and the prespecified
baseline prognostic factors on overall survival in Trial
24 was not significant (P ¼ 0.57), suggesting that within
Trial 24, baseline prognostic factors, such as disease
stage, did not influence the relative effect of bicalutamide
on overall survival. However, in light of the survival
findings from Trial 25, it is important to investigate
whether these trends were also seen in the watchful
waiting patients of Trial 24 (there were no watchful
waiting patients in Trial 23). In the watchful waiting
subgroup of Trial 25, the HR for overall survival in
patients with localised disease was 1.36 (95% CI 0.97,
1.91; P ¼ 0.07) for bicalutamide compared with standard
care alone, and in patients with locally advanced disease
Bicalutamide 150 mg in addition to standard care
M Wirth et al
the HR was 0.68 (95% CI 0.48, 0.97; P ¼ 0.03). In
comparison, the results for Trial 24 watchful waiting
patients were 1.15 (95% CI 0.89, 1.49; P ¼ 0.28; n ¼ 996)
and 0.96 (95% CI 0.66, 1.40; P ¼ 0.84; n ¼ 298), respectively. While the HRs for bicalutamide compared with
standard care alone in Trial 24 are in the same direction
as for Trial 25 (ie both are below one for locally advanced
watchful waiting patients and above one for localised
watchful waiting patients), the trends are much clearer in
Trial 25 than in Trial 24. However, the two results are not
statistically inconsistent and consequently, the combined
data6 provide the best estimate of the effect of bicalutamide.
The combined analysis of Trials 23, 24 and 25 showed
that in the watchful waiting population there was a trend
towards reduced survival with bicalutamide in patients
with localised disease (HR 1.23; 95% CI 1.00, 1.50;
P ¼ 0.05) and a trend towards improved survival with
bicalutamide in patients with locally advanced disease
(HR 1.04; 95% CI 0.81, 1.33; P ¼ 0.78).6
The findings from the EPC programme overall suggest
that bicalutamide provides advantages to patients with
locally advanced disease, while long-term early or
adjuvant hormonal therapy for patients with localised
disease is not appropriate in light of the current data.
Bicalutamide, therefore, significantly reduces the risk
of disease progression in patients with locally advanced
disease. The clinical relevance of this has been shown in
a recent Medical Research Council study in the United
Kingdom involving 938 patients with locally advanced
or asymptomatic metastatic prostate cancer. This study
reported that immediate hormonal therapy was associated with lower incidences of spinal cord compression,
pathological fractures, ureteric obstruction and the
development of extraskeletal metastases, compared with
deferred treatment.9 Furthermore, preventing or delaying disease progression is likely to have quality-of-life
benefits for patients, and their families, as many
experience physical, social and psychological problems
at signs of advancing disease.2,3,10,11 PSA and metastatic
progression also pose a significant additional economic
burden4 and delaying disease progression with antiandrogen therapy can delay and reduce both the costs and
suffering associated with advancing disease.12
The benefits of adding hormonal therapy to standard
care in patients with locally advanced prostate cancer are
further supported by previous findings of other randomised trials with castration-based therapy.13–15 Medical
and surgical castration, however, can often be associated
with adverse events such as decreased libido, sexual
dysfunction, fatigue and vasodilation (hot flushes).16
Furthermore, long-term therapy is associated with loss of
bone mineral density, which can lead to osteoporotic
fractures.17–19 Data from two open-label, multicentre
studies (studies 306 and 307), which were prospectively
designed for pooled analysis, have demonstrated that
in patients with locally advanced prostate cancer requiring immediate hormonal therapy, bicalutamide is
similar to castration in terms of objective PFS and overall survival.16 Studies 306 and 307 also demonstrated
significant advantages in favour of bicalutamide in
terms of maintaining sexual interest and physical
capacity.16 Other randomised trials indicate that in
contrast to castration, bicalutamide preserves bone
mineral density.18,19
In Trial 24, bicalutamide was associated with low
incidences of decreased libido, impotence and hot
flushes. The most common adverse events of bicalutamide treatment in Trial 24 were gynaecomastia and
breast pain, which were of mild to moderate intensity in
the majority of cases. Withdrawal rates due to these
events were relatively low, suggesting that many patients
are prepared to tolerate these symptoms given the
improvements in objective and PSA PFS. However, there
are also various prophylactic and therapeutic strategies
available for the management of gynaecomastia and
breast pain, including tamoxifen20,21 and breast irradiation.22,23
There is a potential concern that patients with early
prostate cancer who show evidence of disease progression following first-line antiandrogen monotherapy will
not respond to subsequent hormonal manipulation.
However, recent evidence from a subset of patients
within the EPC programme, reveals that approximately
55% of those who progressed on bicalutamide showed a
PSA response (defined as a reduction in PSA X20% at
X3 months post initiation of second-line therapy) to
second-line hormonal therapy, mostly castration-based
therapies.24 Furthermore, the response rate for those
patients who had objective progression did not differ
from that of the patients who commenced second-line
therapy for PSA progression. This suggests that patients
who progress on bicalutamide may also respond to
subsequent treatment with castration.
199
Conclusions
Consistent with the second analysis of the EPC programme as a whole,6 the results of Trial 24, conducted at
a median follow-up of 5.1 y, demonstrate that bicalutamide 150 mg/day following standard care significantly
improved objective and PSA PFS in the overall Trial 24
population. No significant difference in overall survival
was observed between bicalutamide and standard care
within this study at the time of the analysis. Altogether,
the results from the EPC programme suggest that based
on the current evidence, long-term use of bicalutamide is
not appropriate in patients with localised (T1–2, N0 or
Nx, M0) disease, yet provides advantages in delaying
disease progression in patients with locally advanced
(T3–4, any N, M0 or any T, N þ , M0) disease. The EPC
programme is ongoing and continued follow-up will
provide further valuable information on the role of
bicalutamide in the management of prostate cancer.
Acknowledgements
Editorial support was provided by Sarah Goodger,
PhD; AstraZeneca provided financial assistance for this
support.
References
1 Smith Jr JA, Soloway MS, Young MJ. Complications of advanced
prostate cancer. Urology 1999; 54 (Suppl 6A): 8–14.
Prostate Cancer and Prostatic Diseases
Bicalutamide 150 mg in addition to standard care
M Wirth et al
200
2 Pitceathly C, Maguire P. The psychological impact of cancer on
patients’ partners and other key relatives: a review. Eur J Cancer
2003; 39: 1517–1524.
3 Rosenfeld BD et al. Differences in health-related quality of life of
prostate cancer patients based on disease stage. Proc Am Soc Clin
Oncol 2003; 22: 438; abstract 1758.
4 Penson DF et al. The economic burden of metastatic and prostate
specific antigen progression in patients with prostate cancer:
findings from a retrospective analysis of health plan data. J Urol
2004; 171: 2250–2254.
5 See WA et al. Bicalutamide as immediate therapy either alone or
as adjuvant to standard care of patients with localized or locally
advanced prostate cancer: first analysis of the early prostate
cancer program. J Urol 2002; 168: 429–435.
6 Wirth MP et al. Bicalutamide 150 mg in addition to standard
care in patients with localized or locally advanced prostate
cancer: results from the second analysis of the early prostate
cancer program at median follow up of 5.4 years. J Urol 2004;
172: 1865–1870.
7 Iversen P et al. Bicalutamide (150 mg) versus placebo as
immediate therapy alone or as adjuvant to therapy with curative
intent for early nonmetastatic prostate cancer: 5.3-year median
followup from the Scandinavian Prostate Cancer Group study
number 6. J Urol 2004; 172: 1871–1876.
8 Wirth M et al. Bicalutamide (Casodex) 150 mg as immediate
therapy in patients with localized or locally advanced prostate
cancer significantly reduces the risk of disease progression.
Urology 2001; 58: 146–151.
9 Kirk D, on behalf of the Medical Research Council Prostate
Cancer Working Party Investigators Group. Immediate vs.
deferred hormone treatment for prostate cancer: how safe is
androgen deprivation? BJU Int 2000; 86 (Suppl 3): 220; abstract
MP6.1.07.
10 Ullrich PM et al. Cancer fear and mood disturbance after radical
prostatectomy: consequences of biochemical evidence of recurrence. J Urol 2003; 169: 1449–1452.
11 Zietman AL et al. Conservative management of prostate cancer
in the prostate specific antigen era: the incidence and time course
of subsequent therapy. J Urol 2001; 166: 1702–1706.
12 Moeremans K, Caekelbergh K, Annemans L. Cost-effectiveness
analysis of bicalutamide (Casodext) for adjuvant treatment of
early prostate cancer. Value Health 2004; 7: 472–481.
Prostate Cancer and Prostatic Diseases
13 Bolla M et al. Long-term results with immediate androgen
suppression and external irradiation in patients with locally
advanced prostate cancer (an EORTC study): a phase III
randomised trial. Lancet 2002; 360: 103–108.
14 Messing E et al. Immediate hormonal therapy compared with
observation after radical prostatectomy and pelvic lymphadenectomy in men with node positive prostate cancer: results at 10
years of EST 3886. J Urol 2003; 169: 396; abstract 1480.
15 Pilepich MV et al. Phase III trial of androgen suppression
adjuvant to definitive radiotherapy. Long term results of
RTOG study 85-31. Proc Am Soc Clin Oncol 2003; 22: 381;
abstract 1530.
16 Iversen P et al. Bicalutamide monotherapy compared with
castration in patients with nonmetastatic locally advanced
prostate cancer: 6.3 years of follow up. J Urol 2000; 164: 1579–
1582.
17 Daniell HW et al. Progressive osteoporosis during androgen
deprivation therapy for prostate cancer. J Urol 2000; 163: 181–186.
18 Sieber PR et al. Bicalutamide 150 mg maintains bone mineral
density during monotherapy for localized or locally advanced
prostate cancer. J Urol 2004; 171: 2272–2276.
19 Smith MR et al. Bicalutamide monotherapy versus leuprolide
monotherapy for prostate cancer: effects on bone mineral
density and body composition. J Clin Oncol 2004; 22: 2546–2553.
20 Eaton AC, Makris A, Makris A. Once weekly tamoxifen in the
prevention of gynaecomastia and breast pain secondary to
bicalutamide therapy. J Urol 2004; 171: 282; abstract 1069.
21 Boccardo F et al. Tamoxifen (T) is more effective than anastrozole
(A) in preventing gynecomastia induced by bicalutamide (B)
monotherapy in prostate cancer (pca) patients (pts). Proc Am Soc
Clin Oncol 2003; 22: 400; abstract 1608.
22 Tyrrell CJ et al. Prophylactic breast irradiation with a single dose
of electron beam radiotherapy (10 Gy) significantly reduces the
incidence of bicalutamide-induced gynecomastia. Int J Radiat
Oncol Biol Phys 2004; 60: 476–483.
23 Van Poppel H et al. Efficacy and tolerability of radiotherapy as
treatment for bicalutamide-induced breast pain and gynaecomastia in prostate cancer. Eur J Cancer 2003; 1 (Suppl 5): S265;
abstract 881.
24 Wirth M et al. Response to second-line hormonal therapy
following progression on bicalutamide (‘Casodex’) 150 mg
monotherapy. Eur Urol Suppl 2004; 3: 58; abstract 223.