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european urology supplements 5 (2006) 640–646
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The Prostate Cancer Prevention Trial and Its Implications
for Clinical Practice: A European Consensus
Pierre Teillac a,*, Per-Anders Abrahamsson b
a
b
L’Hôpital Saint-Louis, Paris, France
Malmö University Hospital, Lund University, Malmo, Sweden
Article info
Abstract
Keywords:
Benign prostatic hyperplasia
Chemoprevention
Finasteride
Medical Therapy of Prostatic
Symptoms (MTOPS) Study
Prostate cancer
Prostate Cancer Prevention
Trial (PCPT)
The findings from the Prostate Cancer Prevention Trial (PCPT) and how
they relate to the management of prostate disease were reviewed by
leading European urologists during a meeting held in December 2005.
The consensus opinions that were reached were endorsed by the European Association of Urology and are documented here. The key points
of the consensus are as follows: (1) The overall results from the PCPT are
of importance to the urologic community. (2) The PCPT data provide
additional support for the use of finasteride in the management of men
with lower urinary tract symptoms (LUTSs)/benign prostatic hyperplasia (BPH). (3) It is recommended that prostate management guidelines be
updated to include the results from both the Medical Therapy of Prostatic Symptoms (MTOPS) Study and the PCPT. (4) The increased incidence of diagnosed high-grade cancer in the finasteride group compared
with placebo is probably a consequence of improved detection. (5) For
men who are concerned about prostate cancer, it may be appropriate to
discuss chemoprevention with finasteride. (6) Urologists are encouraged to disseminate these recommendations among other health care
professionals.
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# 2006 European Association of Urology. Published by Elsevier B.V. All rights reserved.
* Corresponding author. Department of Urology, L’Hôpital Saint-Louis, 1, Avenue ClaudeVellefaux 75475 PARIS Cedex 10, France. Tel. +33 1 42 49 96 14; Fax: +33 1 42 49 96 16.
E-mail address: [email protected] (P. Teillac).
1.
Introduction
The landmark Prostate Cancer Prevention Trial
(PCPT) is the largest completed and published study
conducted in the urologic community and reported
for the first time that medical intervention reduced
the incidence of diagnosed prostate cancer to a
clinically meaningful extent. Although the data
clearly demonstrate a reduction in the incidence
of prostate cancer in men treated with finasteride,
controversy surrounds the incidence of tumours of
Gleason grades 7–10 in the active treatment group.
New data have been generated that aim to clarify
this issue and the focus should now be on how
information from the PCPT should be translated into
clinical practice and shared with patients.
To this end, a European consensus meeting
endorsed by the European Association of Urology
was held in Paris, France on 19 December 2005. The
invited group of experts included 10 panelists plus
41 participants from 13 European countries. The
objective of the meeting was to produce a consensus
1569-9056/$ – see front matter # 2006 European Association of Urology. Published by Elsevier B.V. All rights reserved.
doi:10.1016/j.eursup.2006.05.001
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european urology supplements 5 (2006) 640–646
statement based on the most up-to-date and robust
data set and analyses from the PCPT with a view to
providing clear recommendations on its clinical
implications. At the meeting, clinical findings in key
areas were presented by the panelists. Each presentation was followed by audience discussion and,
ultimately, the generation of consensus statements
on each area. This paper presents the consensus
statements plus brief summaries of the background
to the topics discussed.
2.
PCPT update
2.1.
Background
An overview of findings from the PCPT (Akduman and
Crawford [1]) was presented and formed the basis of
discussion. In summary, finasteride significantly
reduced the 7-yr period-prevalence of prostate cancer
by 24.8% compared with men receiving placebo
( p < 0.001) [2]. There was, however, an increased
prevalence of tumours of Gleason scores 7–10 in the
finasteride arm compared with placebo (6.4% vs. 5.1%;
p < 0.001). The increase in high-grade tumours has
been investigated and found to be explained, at least
in part, by the effects of finasteride on prostate gland
size [3]. Median prostate volume was 24% lower in
patients with high-grade tumours in the finasteride
arm compared with placebo, that is, 25.5 versus
33.6 ml. This reduction in size meant that a relatively
larger proportion of the prostate was biopsied and
evaluated histologically, increasing the chances of
detecting tumours of Gleason grades 7–10 in the
finasteride arm. More recently, receiver operating
characteristic (ROC) analyses have been conducted on
the biomarker prostate-specific antigen (PSA). Area
under the curve (AUC) values for placebo and
finasteride-tested patients indicated that PSA performed better in terms of overall detection of prostate
cancer, including high-grade cancers [4] in finasteride-treated patients than those receiving placebo.
2.2.
Consensus statement
The following consensus statement on the PCPT was
prepared:
1. To date, the PCPT is the largest study ever
reported in the urologic community and reported
for the first time that medical intervention may
reduce the prevalence of prostate cancer to a
clinically meaningful extent (level 1b evidence).
This study was funded by the United States
government through the National Cancer Institute (NCI) and administered by the Southwest
Oncology Group (SWOG) at 221 centres across the
United States.
2. The results showed that finasteride reduced the
risk of developing prostate cancer by 25% compared with placebo (24.4% placebo vs. 18.4%
finasteride).
3. However, the finasteride-treated group had a
higher prevalence of tumours with Gleason
grades 7–10 (6.4%) compared with the placebo
group (5.1%).
4. Subsequent analyses have concluded that this
increased prevalence was probably due to a
detection bias caused largely by the reduction
in prostate volume in patients taking finasteride
compared with patients receiving placebo. This
improved detection of high-grade cancer at
biopsy in the finasteride group is further
enhanced by an improved performance of PSA
in the finasteride arm relative to placebo.
3.
Prostate cancer prevention
3.1.
Background
Prostate cancer is a leading cause of cancer death,
with high rates of incidence, prevalence, and death
documented in North European countries, such as
Germany, France, and the United Kingdom (Table 1)
Table 1 – Incidence and death rates associated with prostate cancer in 1998 [5]
Country
Cases
Age-standardised
rate (per 100,000)
Deaths
Age-standardised
rate (per 100,000)
European Union
Denmark
France
Germany
Italy
Spain
Sweden
United Kingdom
144,504
1,627
28,135
30,911
19,258
10,659
6,610
21,056
67.55
53.89
87.10
77.21
52.78
45.33
114.95
60.97
56,035
1,009
9,239
11,417
7,109
5,742
2,480
9,470
25.55
32.11
27.08
26.65
19.12
23.76
37.71
26.41
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european urology supplements 5 (2006) 640–646
[5]. This high prevalence points to the magnitude of
the human cost of the disease and the potential
benefit of a successful preventive strategy. Dietary
modification as a means of preventing prostate
cancer has been explored for some considerable
time and a wealth of literature on the subject is
available [6]. More defined strategies might target
three possible stages in prostate cancer development: initiation, promotion, and progression. The
impact of the reduction in incidence of prostate
cancer using finasteride has been explored in a
hypothetical model based on the findings from the
PCPT [7]. The authors assumed that a 24.8%
reduction in the incidence of prostate cancer for 5
yr among US men aged 55 yr would lead to an
estimated saving of 316,760 person-years due to
finasteride. Even allowing for an absolute increase of
6.9% in the proportion of men with high-grade
tumours (corresponding to the difference between
the rates on the placebo and finasteride arms of the
PCPT), the number of person-years saved would only
be reduced to 262,567. The authors of the report
estimate that for each absolute increase of 5% in the
proportion of patients with high-grade tumours, the
number of person-years saved would be reduced by
approximately 39,000. They concluded that the
results of the PCPT would have a major impact on
population mortality from prostate cancer if they
were applied clinically. The potentially detrimental
effects of an increased rate of patients with prostate
cancer with high-grade Gleason scores would be
outweighed by a reduction in overall incidence.
Risk factors for the development of prostate cancer
have been well documented [8,9]. A sub-analysis of
the PCPT showed that the relative risk of developing
prostate cancer in men treated with finasteride was
reduced in all subgroups analysed, including age, race
or ethnic group, family history, and baseline PSA level
(Table 2) [2]. In terms of the cost of prostate cancer
prevention using finasteride, it has been estimated
that 6 life-years would be gained per 1000 men treated
at a cost of $1,660,000 per life-year gained [10]. It was
also estimated that it would cost $200,000 to gain one
additional quality-adjusted life-year (QALY). The
authors of the report concluded that to achieve an
incremental cost below $100,000 per QALY gained,
the cost of finasteride would have to be reduced by
50% from its current average wholesale price.
One open question regarding prostate cancer
prevention is whether such prevention decreases
prostate cancer mortality. A reduction in the
development of symptomatic disease or prostate
cancer mortality needs to be demonstrated in
clinical trials. Incidence-based statistical models,
although useful, are not sufficient in this setting.
Table 2 – Prostate cancer incidence at 7 yr according to
risk group, in men who underwent biopsy in the Prostate
Cancer Prevention Trial [2]
Risk group
Finasteride
(n = 4368)
Placebo
(n = 4692)
Relative
risk
Age (yr)
55–59
60–64
65
15
18
22
21
24
28
0.72
0.73
0.80
Race
White
African American
Hispanic
Other
18
27
16
9
24
34
20
16
0.75
0.79
0.80
0.60
Prostate cancer in first-degree relative
Yes
25
No
17
30
23
0.81
0.74
PSA (ng/ml)
0–1.0
1.1–2.0
2.1–3.0
16
28
39
0.66
0.77
0.81
11
21
32
PSA = prostate-specific antigen.
3.2.
Consensus statement
The following consensus statement on prostate
cancer prevention was prepared:
1. Prostate cancer is one of the leading causes of
cancer death in Europe.
2. The PCPT showed that finasteride significantly
reduces the prevalence of histologically proven
prostate cancer.
3. For men who are concerned about prostate
cancer (eg, familial disease, abnormal PSA,
increased PSA velocity/doubling time), it may
be appropriate to discuss chemoprevention with
finasteride.
4. In so doing, it is important to highlight both the
benefits and potential side-effects associated
with long-term treatment.
5. Further data on health economic analyses are
required before recommending widespread chemoprevention with finasteride.
4.
BPH management
4.1.
Background
The efficacy of 5a-reductase inhibitors has been
established in a number of randomised controlled
clinical trials and studies also show that these
agents are most effective in men with enlarged
prostates (>30–40 ml) [11,12]. Two 5a-reductase
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european urology supplements 5 (2006) 640–646
Table 3 – Risks and benefits of finasteride
Benefit/risk
Prostate cancer diagnosis
Genitourinary
symptoms and
complications
Sexual dysfunction or
endocrine symptoms
High-grade cancer diagnosis
Absolute
difference (%)
In favour of
6
0.3–0.5
Finasteride
Finasteride
1.7–13.1
Placebo
1.3
Placebo
Reproduced with permission from [18].
Fig. 1 – Genitourinary effects observed in the Prostate
Cancer Prevention Trial [2].
inhibitors are currently marketed: finasteride,
which inhibits type 2 5a-reductase, and dutasteride, which inhibits type 1 and type 2 5a-reductase.
Type 2 is the predominant isoenzyme found in the
prostate. Although dutasteride can reduce serum
dihydrotestosterone (DHT) levels to a greater
degree than finasteride (95% vs. 71%) [13], this
effect has not been shown to translate into superior intraprostatic DHT reduction [14,15] or, more
importantly, additional clinical benefit; both therapies produce similar improvements in symptoms,
flow rates, and prostate volume reduction [11,12].
The Medical Therapy of Prostatic Symptoms
(MTOPS) Study has gone further to demonstrate
that the combination of a 5a-reductase inhibitor
plus an a1-blocker provides greater benefits than
either agent as monotherapy [16] (also see Marberger [17]). Recent analyses of the MTOPS Study
indicate that patients with prostates 25 ml may
benefit from combination therapy, whereas those
with a baseline prostate volume 31 ml are at
significantly greater risk of progression. Combination therapy for this latter patient group represents
optimal therapy for benign prostatic hyperplasia
(BPH).
The PCPT also demonstrated the positive effects
of finasteride in regard to genitourinary symptoms
(Fig. 1), with a significantly ( p < 0.01) lower incidence of BPH, prostatitis, urinary tract infection for
urgency/frequency, urinary retention, and transurethral resection of the prostate procedures compared with patients receiving placebo [2]. These,
along with the additional benefit of the reduced risk
of developing prostate cancer, have to be balanced
against an increase in typical 5a-reductase inhibitor
side-effects, such as reduced ejaculate volume,
decreased libido, and erectile dysfunction, which
were as expected in this study. A risk-benefit
analysis on data from the PCPT has been conducted
and shows areas where finasteride provides a
benefit over placebo (Table 3) [18].
The use of finasteride to treat men with BPH
does not preclude the use of PSA in detecting
prostate cancer. Studies have shown that finasteride decreases PSA by approximately 50% during
the first 12 mo of use [19] and a similar reduction
was seen in the PCPT over the same time period.
Recent analysis of the ROC of PSA in the PCPT
shows that PSA performs better in detecting all
grades of cancer, as well as high-grade cancers in
men treated with finasteride compared with
placebo.
4.2.
Consensus statement
The following consensus statement on BPH management was prepared:
1. Randomised, placebo-controlled trials have
demonstrated the benefit of 5a-reductase inhibitors over placebo in men with clinically
enlarged prostates above 30–40 ml secondary to
BPH (level 1 grade A).
2. The efficacy of combination therapy with 5areductase inhibitors and a1-adrenoceptor antagonists is greater than either agent alone (level 1
grade B)
3. The clinical utility of this combination therapy
should consider the balance between efficacy and
additional side-effects (level 1 grade B).
4. If one assumes a class effect:
All combinations of an a1-adrenoceptor antagonists and a 5a-reductase inhibitor would be
equally effective.
The combination of doxazosin and finasteride
is the best tested regarding safety and efficacy.
5. The evidence currently available from the PCPT
provides additional support for the use of
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finasteride in the management of men with
LUTSs/BPH.
6. Based on current knowledge, a conversion factor
of 2 for PSA is accurate for patients taking
finasteride. Further analysis of the PCPT data
would suggest that finasteride therapy may
enhance detection of high-grade disease.
7. It is recommended that prostate management
guidelines [20] be updated to include the results
from both the PCPT and the MTOPS Study.
5.
Communicating with patients
5.1.
Background
In addition to some very good sites, a brief search on
the Internet using any of the common search
engines will bring up much spurious information
on the subject of prostate cancer. Some of this
‘‘disinformation’’ is simply misleading, but other
sites contain dangerously incorrect data [21].
Patients using the Internet to search for information
on BPH and prostate cancer have the difficult task of
distinguishing fact from fiction. Doctors can assist
in communicating factual information on prostate
cancer to their patients. Compliance with medication is another important issue that needs to be
addressed by doctors with their patients. Urologists
could potentially use the fact that finasteride has
been shown to significantly reduce the incidence of
prostate cancer as an added benefit to improve
compliance among men taking finasteride for BPH.
Uptake of health care provisions by men is another
area that should be addressed. A household survey
conducted in the United Kingdom in 1998–1999
indicates that men were less likely than women to
consult their general practitioner about a medical
problem [22]. This statistic appears to be borne out
by data from the World Health Organization
European ‘‘Health for All’’ database. Across a survey
of 17 European countries in 2003, the incidence of
melanoma in women was found to be higher than in
men, yet more men die of the disease [23]. Clearly,
patients, and in particular men, need to be better
educated and provided with better literature on
health issues to overcome these problems.
The urologist plays a key role in disseminating
accurate information on the benefits of finasteride
in not only BPH but also prostate cancer including
providing reassurance over the high-grade tumour
findings from the PCPT. They should understand the
information, set the standard for counselling
patients, and take charge of what has been learned
from the PCPT. Urologists are well placed to be
important sources of information for general practitioners and patients alike and in so doing have the
potential to make a difference in the health of
millions of men worldwide.
5.2.
Consensus statement
The following consensus statement on communicating with patients on the findings of the PCPT was
prepared:
1. Implications for patient information
Physicians should be aware of the findings
from the PCPT.
This will allow physicians to appropriately
counsel their patients about the potential
benefits and side-effects of treatment with
finasteride.
Patients entering a programme of chemoprevention should be closely followed up and
monitored to ensure that they do not develop
malignant prostate disease that is unrecognised.
2. Implications for education of medical community
This information needs to be discussed in the
urologic and general health care community to
allow a balanced opinion to be provided to
patients.
Urologists are encouraged to disseminate these
recommendations among other health care
professionals, including general practitioners,
who often play a significant role in the
management of BPH/LUTSs.
6.
Conclusions
The PCPT and MTOPS Study have provided information that should change the way urologists manage
prostate disease. Clearly, the chemopreventive
benefits of finasteride demonstrated in the PCPT
provides additional support for the use of finasteride
in the management of patients with BPH. The
MTOPS Study established that combination therapy
is indicated for patients most at risk of clinical
progression, that is, with a baseline prostate volume
>30 ml. There are other important implications of
this new line of management both in terms of the
potential for chemoprevention of prostate cancer
and the need to ensure that the new paradigms are
accessible to and followed by physicians in primary
care. Management guidelines on prostate disease
should be updated to reflect the findings from the
PCPT and the MTOPS Study, so assisting physicians
to adopt and embrace new management practices.
european urology supplements 5 (2006) 640–646
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Appendix A. Consensus meeting panelists &
participants
Panelists
Professor Pierre Teillac, France
Professor Per-Anders Abrahamsson, Sweden
Professor Clément-Claude Abbou, France
Professor Christopher Chapple, United Kingdom
Mr Adrian Joyce, United Kingdom
Professor Jean-Louis Misset, France
Professor Jørgen Nordling, Denmark
Dr Eduardo Solsona, Spain
Professor Andrea Tubaro, Italy
Professor Manfred Wirth, Germany
Panelists from left to right: Jørgen Nordling, Manfred Wirth, Pierre Teillac, Per-Anders Abrahamsson, David Crawford (key note speaker on the PCPT
data), Christopher Chapple, Adrian Joyce, Clément-Claude Abbou, Jean-Louis Misset, Andrea Tubaro, Eduardo Solsona.
Participants
Professor Michael Marberger, Austria
Professor Stephan Madersbacher, Austria
Dr Wolfgang Loidl, Austria
Professor Fred Saad, Canada
Dr Laurence Klotz, Canada
Professor Ognjen Kraus, Croatia
Professor Benoit Feuillu, France
Professor Jean-Jacques Rambeaud, France
Professor Klaus Höfner, Germany
Professor Ulf Tunn, Germany
Dr Richard Berges, Germany
Professor Bernd Schmitz-Dräeger, Germany
Mr Thanos Anastasios, Greece
Mr Gerasimos Alivizatos, Greece
Dr Tommaso Prayer-Galetti, Italy
Professor Roberto Mario Scarpa, Italy
Professor Domenico Prezioso, Italy
Professor Alessandro Sciarra, Italy
Dr Giario Conti, Italy
Professor Theo M. de Reijke, Netherlands
Dr Carlos Rabaca, Portugal
Dr Fernando Manuel Pinto Faria, Portugal
Dr Kutaiba El-Metwally, Saudi Arabia
Professor Bojan Trsinar, Slovenia
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european urology supplements 5 (2006) 640–646
Dr Carlos Allepuz Losa, Spain
Dr Juan Morote Robles, Spain
Dr Jose Marı́a Alonso Dorrego, Spain
Dr Joaquı́n Carballido Rodrı́guez, Spain
Dr David Castro-Dı́az, Spain
Professor Pär Stattin, Sweden
Professor Patrice Jichlinski, Switzerland
Professor Rāto Strebel, Switzerland
Mr Mark Speakman, UK
Mr Simon Holmes, UK
Mr Mike Swinn, UK
[11]
[12]
[13]
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