RICHIE
The New England Journal of Medicine rarely
publishes follow-up studies for articles
previously published in that prestigious
journal. The excellent randomized prospective
study of radical prostatectomy (RP) vs
watchful waiting from the Scandinavian
Prostate Cancer Group Study [1], with an
additional 3 years of follow-up, has yielded
statistically significant differences in both
primary endpoint of death from prostate
cancer and the secondary endpoints of death
from any cause, distant metastases, and local
progression. This study, which accumulated
695 men from 14 centres from 1989 to 1999,
included patients with clinical stage T1 or T2
prostate cancer, a PSA level of <50 ng/mL and
negative bone scans. The patients were
stratified according to tumour grade and
randomization centre, and were randomly
assigned to undergo either RP or watchful
waiting. Analysis was by intention to treat,
with a 5% crossover in the RP group and a
10% crossover in the watchful-waiting group.
There were significant advantages in the RP
group in terms of death from prostate cancer
(30 vs 50 men, P = 0.01) and deaths from any
cause (83 vs 106 men, P = 0.04). Importantly,
although there was no difference in the
incidence of distant metastases in the two
groups during the first 5 years of follow-up,
an additional 3-year follow-up yielded an
absolute risk reduction of 10% in favour of
the RP group, with a relative risk of 0.60.
Likewise, the difference in cumulative
incidence of local progression, although
statistically significant at 5 years of follow-
up, increased markedly in the additional
3 years, with a relative risk of 0.33 in the RP
group. These differences cannot be explained
by hormonal therapy, as this was used less
often in the RP group than in the watchful-
waiting group.
This randomized prospective study is the first
to show a clear advantage to RP over
watchful waiting in a cohort of patients with
clinically localized prostate cancer, either well
© 2 0 0 5 B J U I N T E R N A T I O N A L | 9 6 , 9 5 1 – 9 5 7 | doi:10.1111/j.1464-410X.2005.05793–05797.x
RADICAL PROSTATECTOMY VS WATCHFUL WAITING IN EARLY
PROSTATE CANCER JEROME P. RICHIE – Brigham and Women’s Hospital,
Boston, MA, USA
Accepted for publication 22 July 2005
or moderately differentiated. Several lessons
can be learned from this important study. First
and most important, the 5-year follow-up
data in treatments for prostate cancer have
limited value; 8- or preferably 10-year
data are necessary to discern important
differences. The greater incidence of local
progression and distant metastases in the
watchful-waiting group would also suggest
that relative risks may be further improved in
the RP group by a longer follow-up. The
subgroup analysis would suggest that the
reduction in disease-specific mortality was
greatest among patients aged <65 years. This
observation is hypothesis-generating because
subgroup analyses are not powered to ensure
a balance of all known and unknown
prognostic factors between the age cohorts.
Nonetheless, this subgroup analysis would
suggest that younger patients would benefit
more from intervention rather than watchful
waiting.
Should this study sway the clinician to
abandon watchful-waiting techniques?
Clearly, selected patients will benefit from
active surveillance or watchful waiting and
avoid the potential side-effects from RP or
other interventions with curative intent.
Generally, older patients, especially those with
comorbid diseases and lower Gleason sum
prostate cancers, would seem to be
reasonable candidates for active surveillance
protocols. The use of PSA velocity, in
particular a >2-point rise during the year
before diagnosis, will be an important adjunct
to identify those patients at risk of death from
prostate cancer, in whom intervention may be
preferable [2]. Information can be gleaned
from two important recent studies; that by
Albertsen et al. [3] on causes of death after
observation in the Connecticut series
suggested that younger patients, especially
with higher Gleason sum carcinoma of the
prostate, had a greater likelihood of prostate
cancer mortality with conservative
management. Much of the emphasis on
watchful waiting came from the original
study by Johansson et al. [4]. In their 10-year
follow-up of 223 patients, cause-specific
survival from prostate cancer was excellent.
Interestingly, in their 20-year follow-up,
recently published [5], the mortality from
prostate cancer increased dramatically,
indicating the pitfall of a shorter follow-up in
a disease such as prostate cancer.
Although the present study consisted of
patients with clinical stage T2 disease
(palpable nodules), widespread use of
screening with PSA will identify patients at
earlier stages, most of whom have stage T1
disease, with potentially greater lead-time
bias. Nonetheless, this study [1], and that of
Johansson et al. [5] with a 20-year follow-up,
suggests that with a longer follow-up,
watchful waiting has a significant
disadvantage compared to surgical
intervention, especially in younger healthier
patients with a presumed greater longevity.
Further advantages of surgical intervention
include a lower incidence of local progression
with attendant need for intervention, and
lower likelihood of hormonal treatment, with
its attendant morbidity.
This study adds credence to the concept that
active treatment with effective methods can
significantly reduce cause-specific mortality
and reduce later morbidity for younger
951
 COMMENTS
patients with prostate cancer. Much credit
should go to the Scandinavian Prostate
Cancer Group for the careful design,
recruitment, and follow-up of a large number
of patients in a prospective randomized study
adequately powered to detect differences in
RP vs watchful waiting.
REFERENCES
1 Bill-Axelson A, Holmberg L, Ruutu M
et al. Radical prostatectomy versus
watchful waiting in early prostate cancer.
N Eng J Med 2005; 352: 1977–84
2 D’Amico AV, Chen MH, Roehl KA,
Catalona WJ. Preoperative PSA velocity
and the risk of death from prostate cancer
THE SCANDINAVIAN PROSTATE CANCER GROUP STUDY: THE CASE
FOR CONSERVATIVE MANAGEMENT CHRIS PARKER – Academic Unit of
Radiotherapy & Oncology, The Institute of Cancer Research and Royal Marsden NHS Foundation
Trust, Downs Road, Sutton, Surrey, UK
Accepted for publication 22 July 2005
Unlike other types of cancer, a significant
proportion of prostate cancers will behave in
an indolent fashion, with no effect either on
health or longevity, even in the absence of
treatment. Partly for this reason it has been
difficult to establish whether the radical
treatment of prostate cancer improves
survival, and if so, by how much. The
Scandinavian Prostatic Cancer Group Study
Number 4, which opened in 1989, is the first
good quality randomized controlled trial to
compare the outcome of radical treatment
with that of conservative management [1,2],
and its results were recently updated [3].
The trial randomized 695 men with localized
disease between radical prostatectomy (RP)
and watchful waiting. Patients had a mean
age of 65 years, a mean PSA level of 13 ng/
mL, and the grade mix was 68% Gleason score
<7, 26% of 7 and 6% of 8–10. At a median
follow-up of 8.2 years, randomization to RP
was associated with a benefit both in terms of
disease-specific mortality (hazard ratio 0.56,
95% CI 0.36–0.88, P = 0.01) and overall
mortality (0.74, 0.56–0.99; P = 0.04). This
translated into a 10-year overall survival of
73% vs 68% (P = 0.04) for RP vs watchful
952
after radical prostatectomy. N Eng J Med
2004; 351: 125–35
3 Albertsen PC, Hanley JA, Fine J. 20-year
outcomes following conservative
management of clinically localized
prostate cancer. JAMA 2005; 293: 2095–
101
4 Johansson JE, Adami HO, Andersson
SO, Bergstrom R, Holmberg L, Krusemo
UB. High 10-year survival rate in patients
with early, untreated prostatic cancer.
JAMA 1992; 267: 2191–6
5 Johansson JE, Andren O, Andersson
SO et al. Natural history of early,
localized prostate cancer. JAMA 2004;
291: 2713–9
e-mail: jrichie@partners.org
November 2005
967
Original Article
comment
PARKER
waiting, respectively. This is a very important
result and shows beyond doubt that some
patients with localized prostate cancer benefit
from surgery, as opposed to traditional
watchful waiting. Indeed, if the crossover
from one arm of the trial to the other is taken
into account, and the lack of postoperative
radiotherapy, it is quite possible that the
Scandinavian trial underestimates the true
benefit of radical treatment. However, there
are at least three reasons why immediate
radical treatment should not be uncritically
accepted as the standard of care for all men
with localized prostate cancer.
The choice of treatment depends on
personal values. The survival benefit in the
Scandinavian trial provides a powerful
argument for choosing radical treatment in
preference to traditional watchful waiting.
However, patients need to weigh the
survival benefit against the risk of adverse
consequences of treatment. The 5% absolute
improvement in 10-year survival was
achieved at the expense of a 35% absolute
increase in the risk of erectile dysfunction and
a 28% absolute increase in the risk of urinary
leakage [2]. Faced with these results some
patients would choose surgery, but many
would choose conservative management [4].
An individual’s treatment decision depends
not only on trial results, but also on his
personal values, and in particular the relative
importance he places on prolonging life vs
preserving lifestyle.
The results may not be applicable to screen-
detected prostate cancer. Only 12% of
patients in the Scandinavian trial had stage
T1c disease, and as many as 19% of patients
had a PSA level of >20 ng/mL. How can the
outcome data, based largely on clinically
detected prostate cancer, be applied to men
with screen-detected disease? PSA screening
results in over-detection (of cases that would
not otherwise have been detected within the
patient’s lifetime) and introduces a lead time
(the time difference between screen-
detection and clinical detection in the
absence of screening), which may be
≥ 10 years [5]. It follows that, in the absence
of treatment, the natural history of screen-
detected prostate cancer will be more
favourable than that of clinically detected
prostate cancer. This is an important
consideration for men faced with the choice
between conservative management and
curative treatment. In comparison with
clinically detected disease, men with screen-
detected cancers will have longer to endure
any adverse effects of curative treatment, and
longer to wait for any beneficial effect on
survival to emerge. At present, insufficient
time has elapsed to observe the natural
history of screen-detected prostate cancer,
but it is interesting to compare the 10-year
prostate cancer-specific mortality rate of
14.9% for watchful waiting reported by
Bill-Axelson et al. [3] with the 15-year rate
predicted by Nicholson and Harland [6] for
screen-detected disease, of 7.4–11.6%. Given
the more favourable natural history of
screen-detected disease, it seems likely that
the absolute survival benefit of treatment will
be less than for treatment of clinically
detected prostate cancer. There are two
ongoing randomized trials that will address
this issue [7,8]. The results of these trials will
be important in helping to define the
magnitude of the survival benefit for the
radical treatment of screen-detected, rather
than clinically detected, prostate cancer.
Watchful waiting is not the same as active
surveillance. In terms of 10-year freedom
from distant metastasis, the absolute benefit
of surgery vs watchful waiting was 10%
© 2005 BJU INTERNATIONAL

(84.8% vs 74.6%, P = 0.004) [3]. So it could be
argued that 90% of patients did not benefit
significantly from RP. Is it possible to identify
these patients before surgery? One approach
to this problem is active surveillance, in which
radical treatment is targeted to those patients
with biochemical or histological progression
during a period of close observation [9]. This is
by contrast to traditional watchful waiting, as
specified in the Scandinavian trial, according
to which palliative treatment is given to those
with symptomatic progression. Klotz et al.
[10,11] reported the updated results of the
Toronto experience of active surveillance,
which is the largest such study to date. In all,
299 patients with favourable-risk, localized
prostate cancer were closely monitored with
3-monthly PSA level tests and a repeat
prostate biopsy at 18 months. About 20% of
the patients received radical treatment
because of a rapid PSA doubling time, 10%
because of ‘progression’ on repeat biopsy, and
10% because of patient preference, so that
the remaining 60% avoided the risk of
treatment-related morbidity. Encouragingly,
the 8-year disease-specific mortality was just
1% (in comparison with 10-year disease-
specific mortality of 14.9% for watchful
waiting in the Scandinavian trial). It is possible
that targeted radical treatment, based on an
active surveillance strategy, will be as
effective, and considerably less morbid, than
radical treatment for all cases. An intergroup
phase III trial will soon start that will compare
the long-term outcomes of active surveillance
with those of immediate radical treatment,
and will aim to recruit ≈ 1500 patients.
The Scandinavian trial has finally resolved one
of the key issues in localized prostate cancer;
we now know that radical treatment can
improve overall survival. However, the
trial leaves several important questions
unanswered. How large is the survival benefit
for treating screen-detected prostate cancer?
Is active surveillance, with radical treatment
targeted to those with disease progression,
as effective as a blanket policy of radical
treatment for all? For the present, a patient’s
decision whether or not to have radical
treatment for localized prostate cancer
remains a value judgement, weighing the risk
of treatment-related morbidity against the
possible survival benefit.
REFERENCES
1 Holmberg L, Bill-Axelson A, Helgesen F
et al. A randomized trial comparing radical
© 2005 BJU INTERNATIONAL
prostatectomy with watchful waiting in
early prostate cancer. N Engl J Med 2002;
347: 781–9
2 Steineck G, Helgesen F, Adolfsson
J et al. Quality of life after radical
prostatectomy or watchful waiting.
N Engl J Med 2002; 347: 790–6
3 Bill-Axelson A, Holmberg L, Ruutu M
et al. Radical prostatectomy versus
watchful waiting in early prostate cancer.
N Engl J Med 2005; 352: 1977–84
4 Singer PA, Tasch ES, Stocking C, Rubin
S, Siegler M, Weichselbaum R. Sex or
survival: trade-offs between quality and
quantity of life. J Clin Oncol 1991; 9: 328–
34
5 Draisma G, Boer R, Otto SJ et al. Lead
times and overdetection due to prostate-
specific antigen screening: estimates from
the European Randomized Study of
Screening for Prostate Cancer. J Natl
Cancer Inst 2003; 95: 868–78
6 Nicholson PW, Harland SJ. Survival
prospects after screen-detection of
prostate cancer. BJU Int 2002; 90: 686–
93
7 Wilt TJ, Brawer MK. The Prostate Cancer
RADICAL PROSTATECTOMY VS WATCHFUL WAITING
ROGER S. KIRBY and JOHN M. FITZPATRICK* – The Prostate Centre, 32 Wimpole St.,
London, UK, and * Mater Misericordiae Hospital, Dublin, Ireland
Accepted for publication 22 July 2005
It was a rather unfortunate accident of
timing that the paper by Whelan [1]
arguing that patients with localized
prostate cancer fare just as well with
watchful waiting as with surgery was
published in the same month that a
Scandinavian group reported the results of
their randomized study comparing the two
treatments [2]. Over a 10-year observation
period, radical prostatectomy (RP) reduced
disease-specific mortality, overall mortality
(P = 0.04), and the risks of metastasis and
local progression (P = 0.001) in the surgically
managed group of 347 men (Fig. 1). The
authors concluded that although the absolute
reduction in the risk of death after 10 years is
small, the reductions in the risk of metastasis
and local tumour progression are substantial
[2].
COMMENTS
Intervention Versus Observation Trial
(PIVOT). A randomized trial comparing
radical prostatectomy versus expectant
management for the treatment of
clinically localised prostate cancer. Cancer
1995; 75 (Suppl. 7): 1963–8
8 Donovan J, Hamdy F, Neal D et al.
Prostate Testing for Cancer and Treatment
(ProtecT) feasibility study. Health Technol
Assess 2003; 7: 1–88
9 Parker C. Active surveillance: towards a
new paradigm in the management of
early prostate cancer. Lancet Oncol 2004;
5: 101–6
10 Choo R, Klotz L, Danjoux C et al.
Feasibility study: watchful waiting for
localized low to intermediate grade
prostate carcinoma with selective delayed
intervention based on prostate specific
antigen, histological and/or clinical
progression. J Urol 2002; 167: 1664–9
11 Klotz L. Active surveillance with selective
delayed intervention: using natural
history to guide treatment in good risk
prostate cancer. J Urol 2004; 172: S48–51
e-mail: Chris.Parker@rmh.nhs.uk
November 2005
967
Original Article
comment
KIRBY AND FITZPATRICK
Over 30 000 men are diagnosed annually in
the UK with prostate cancer, and while
watchful waiting is an excellent option for
older men with low-risk, well-differentiated
cancers, as confirmed by the recently
published data of Albertson et al. [3], patients
with higher Gleason scores (≥7) fare much
less well over time [4]. Roehl et al. [5] recently
reported the excellent outcome and low
morbidity in 3478 patients treated by RP with
10 years of follow-up. Not surprisingly,
patients with poorly differentiated tumours
fare less well with surgery [5] and for this
small subgroup external beam radiotherapy
with adjuvant androgen ablation is probably
now the best management option [6].
Currently, the debate about the management
of patients with medium-risk localized
953
 COMMENTS

prostate cancer (i.e. Gleason score 7), who a FIG. 1.

constitute the vast majority of the case load, 40 The cumulative incidence of a,
has moved on from RP vs watchful waiting to P = 0.04 metastases and b, death from any

Cunulative incidence of
RP vs brachytherapy. With excellent long- 30
cause in men treated by watchful
term data now being reported for this

metastasis, %
Watchful waiting waiting or RP over 10 years of
treatment [7], the pertinent question is now follow-up. Reproduced with
20
whether brachytherapy or RP is the right permission from Bill-Axelson et al.
treatment choice for an individual patient. [2].
Moreover, retropubic RP is developing rapidly, 10
with laparoscopic and robotic assistance Radical prostatectomy
promising less morbidity and a shorter 0
hospital stay, and the goal-posts are 0 2 4 6 8 10
continuing to move. With >10 000 deaths Years of follow-up
from prostate cancer each year in the UK, and
347 333 306 254 181 87
far more than this worldwide, watching and
348 332 310 243 156 73
waiting while men progress and eventually
die from this very prevalent disease hardly b
seems the way to turn back the advancing 40 P = 0.04
Cunulative incidence of death

tide. Watchful waiting

from any cause, %

REFERENCES
1 Whelan P. The case against radical
prostatectomy. Ann R Coll Surg Engl 2005;
87: 161–2
2 Bill-Axelson A, Holmberg L, Ruutu M
et al. Radical prostatectomy versus
watchful waiting in early prostate cancer.
N Engl J Med 2005; 352: 1977–84
3 Albertsen PC, Hanley JA, Fine J. 20-year
outcomes following conservative
management of clinically localised cancer.
JAMA 2005; 293: 2095–101
4 Lu-Yao GL, Yao SL. Population-based
study of long-term survival in patients
with clinically localised prostate cancer.
Lancet 1997; 349: 906–10
5 Roehl KA, Han M, Ramos CG, Antenor
JA, Catalona WJ. Cancer progression and
survival rates following anatomical
radical retropubic prostatectomy in 3,478
consecutive patients: long-term results.
J Urol 2004; 172: 910–4
6 Bolla M, Gonzalez D, Warde P et al.
Improved survival in patients with locally
advanced prostate cancer treated with
radiotherapy and goserelin. N Engl J Med
1997; 337: 295–300
7 Langley SE, Laing R. Prostate
brachytherapy has come of age: a review
of the techniques and results. BJU Int
2002; 89: 241–9
e-mail: rogerkirby@theprostatecentre.com
November 2005
967
Comment Article
comment
BARRY
30
20
10
Radical prostatectomy
0
0 2 4 6 8 10
Years of follow-up
347 343 332 284 210 118
348 341 326 279 198 104
REVISITING MY PERSONAL DECISION ABOUT PROSTATE-SPECIFIC
ANTIGEN TESTING IN 2005 MICHAEL J. BARRY – Harvard Medical School,
Boston, MA, USA
Accepted for publication 22 July 2005
Somewhat atypical for older male American attributable to attempting to maintain my
primary-care physicians, amongst whom exercise level despite the ageing process. As
almost 80% have made the personal decision such, my lifetime probability of dying from
to have a PSA test [1], I have not. However, prostate cancer is ≈ 3% (even using statistics
there is new evidence to consider as I ponder from before the advent of PSA testing),
whether I should join the ranks of so many of although my lifetime probability of dying is,
my colleagues and be screened for prostate sadly and inevitably, 100% (with the
cancer, as I approach the age of 52 years in a ultimately tight CI). Moreover, if I am destined
few weeks. to die from prostate cancer, there is a 70%
chance I will do so after age 75, more than
First, some background: I am Caucasian and two decades hence.
have no first-degree relatives with prostate
cancer; I have minor LUTS (IPSS of 6); I have What new evidence should I be considering as
frequent bone pain, but those symptoms are I revisit my personal decision about PSA
migratory and evanescent, and seem easily testing? First and foremost are the updated

954 © 2005 BJU INTERNATIONAL


results from the SPCG-4 trial on radical
prostatectomy vs watchful waiting [2]. This
important trial provides the first evidence that
for men with clinically localized prostate
cancers that are largely discovered the ‘old
fashioned’ way, without PSA screening,
surgery can change the natural history of the
disease. However, the absolute benefits
appear to be fairly small, so that ≈ 20 men
would need to have their prostates removed to
prevent one death over 10 years. How would
this ‘number needed to treat’ (NNT) change for
men with cancer discovered by screening? The
effects of over-diagnosis and lead time would
probably mean that ≈ 40 men would need to
have surgery to save a life over 15–20 years,
which sounds like a very small benefit to me.
However, the NNT would shrink if earlier
detection saved some lives of men who would
otherwise have died in the surgical arm of the
SPCG-4 trial, or even some men not included in
the trial because they initially presented with
high-grade or disseminated disease.
Unfortunately, we do not have the data to
quantify that effect on the NNT, as yet.
Moreover, any benefit would come at the price
of a substantial risk of sexual dysfunction and
incontinence, as documented in the trial;
neither prospect sounds attractive to me.
The work of D’Amico et al. [3] is also a key new
piece to the puzzle. These investigators
documented that there is a group of patients
with prostate cancers characterized by rapidly
rising pre-diagnostic PSA levels that, even
when found relatively early and treated
aggressively, do not fare well, with a 15–20%
risk of dying of prostate cancer within
10 years. Although we cannot determine
whether such men would have fared even
worse without early detection and treatment,
these data suggest there is a subset of cancers
that may simply not be amenable to screening,
and may well be responsible for a
disproportionate share of prostate cancer
mortality.
Another important piece of data for me is the
newest estimate of the lifetime risk of a
prostate cancer diagnosis in the USA, where
PSA screening is widespread. In the ‘pre-PSA
era’, the estimated lifetime risk of a prostate
cancer diagnosis for a man my age in the USA
was ≈ 10%. In the ‘PSA era’, as of 2000–2002,
it was 19% [4], and not all men have been
tested; it would easily be >20% for a man who
has a regular PSA test. That risk will be driven
relentlessly higher in future years as the PSA
threshold for biopsy is lowered and
© 2005 BJU INTERNATIONAL
increasingly many biopsy cores are taken. I
suspect that if epidemiological studies
indicated that regular consumption of a
certain vegetable doubled the risk that a man
would ‘get’ prostate cancer, no one would eat
it. The PSA test is that vegetable. Food for
thought.
The lifetime probability of requiring one or
more sets of prostate biopsies will be much
higher than the lifetime probability of a
cancer diagnosis, and that prospect does not
thrill me either. That cumulative risk has not
been quantified, but the poor discriminating
ability of PSA suggests that it will be high.
Data from the Prostate Cancer Prevention
Trial have allowed the first unbiased receiver-
operating characteristic curve (ROC) to be
drawn for the PSA test, using biopsy as the
diagnostic ‘gold standard’. The ROC area for
PSA (the chance that a man with prostate
cancer on biopsy will have a higher PSA level
than a man without) is only a mediocre 68%
[5], and not much better than that of flipping
a coin (50%). If we feel we must biopsy at
relatively low PSA levels to maintain adequate
sensitivity, the number of biopsies that will be
required given this poor discrimination will be
numerous indeed.
As I contemplate these new data, I am left
fairly certain that if I elect to start PSA testing
now, I will at least double my risk of having to
deal with prostate cancer over my lifetime,
from ≈ 10% to ≈ 20%, and probably even
higher if I have an average life-expectancy. I
will have an even greater lifetime risk of
requiring a prostate biopsy, and even if that
biopsy is initially negative, I will be left
worrying about a false-negative result [6]. I
suspect that if PSA screening is eventually
shown to decrease prostate cancer mortality
in the ongoing randomized controlled trials
(RCTs), and even if it proves more effective
than the mortality reduction of 25% seen
with regular breast-cancer screening, it would
be unrealistic for me to expect to be able to
reduce my risk of dying from prostate cancer
from 3% without testing to much less than
2% with testing, a 33% reduction. Even if I
had data from RCTs now that allowed me to
be confident of this benefit, I am still not sure
I would change my mind about having a PSA
test at age 52, given the substantial
disadvantageous risks. Therefore, I will
continue to eschew screening for now, but
watch the literature carefully for new
developments.
COMMENTS
I stress that I do not consider myself a nihilist
in terms of early cancer detection; in fact,
I decided to undergo a colonoscopy for
colorectal cancer screening two birthdays
ago. However, that early detection can reduce
colorectal cancer mortality has been proven in
RCTs. Moreover, screening for colorectal
cancer reduces, rather than increases, the risk
of colorectal cancer, by detecting and
removing potentially pre-cancerous polyps.
If I am one of the 3% of men destined to die
from prostate cancer, I may regret my
decision. Although those 30-to-1 odds
against are pretty long, is there anything else
I can do to try to reduce my risk of dying from
prostate cancer? Numerous micronutrients
and dietary factors may reduce the risk from
prostate cancer; the most promising, with risk
reductions of up to 50% suggested in studies
thus far, appear to be selenium, low-dose
α-tocopherol, and even red wine (a problem
with finasteride chemoprevention is that
many physicians would feel compelled to
order PSA tests if they prescribe this agent,
negating its chemopreventive advantage)
[7,8]! The benefit of trying to reduce prostate
cancer mortality through these preventive
manoeuvres is if that (if effective), unlike
screening, they would reduce the cumulative
risk of a prostate cancer diagnosis as well as
death, and would therefore be dramatically
less intrusive for people and more cost-
effective for populations than screening.
While the effect of nutritional interventions
on prostate cancer incidence and mortality
needs to be confirmed in large-scale RCTs,
exactly the same thing must be said of PSA
screening. So for now, I will wash down some
vitamins and minerals with a glass of good
red wine for my birthday, and revisit the
decision, if good fortune allows me to do so,
next year.
REFERENCES
1 Chan ECY, Barry MJ, Vernon SW, Ahn C.
United States physicians and their
personal prostate cancer screening
practices with prostate specific antigen.
J Gen Intern Med 2005; in press
2 Bill-Axelson A, Homberg L, Ruutu M
et al. Radical prostatectomy versus
watchful waiting in early prostate cancer.
New Engl J Med 2005; 352: 1977–84
3 D’Amico AV, Chen M, Roehl KA,
Catalona WJ. Preoperative PSA velocity
and the risk of death from prostate cancer
955
 COMMENTS
after radical prostatectomy. New Engl J
Med 2004; 35: 125–35
4 National Cancer Institute. SEER Cancer
Statistics Review. http://seer.cancer.gov/
csr/1975_2002/results_merged/
topic_lifetime_risk.pdf [Accessed July
2005]
5 Thompson IM, Ankerst DP, Chi C et al.
Operating characteristics of prostate-
specific antigen in men with an initial PSA
level of 3.0 ng/ml or lower. JAMA 2005;
294: 66–70
6 McNaughton-Collins M, Fowler FJ Jr,
HOW (NOT) TO COMMUNICATE NEW SCIENTIFIC INFORMATION: A
MEMOIR OF THE FAMOUS BRINDLEY LECTURE LAURENCE KLOTZ –
Sunnybrook and Women’s College Health Sciences Centre, University of Toronto, Toronto,
Canada
Accepted for publication 22 July 2005
In 1983, at the Urodynamics Society meeting
in Las Vegas, Professor G.S. Brindley first
announced to the world his experiments on
self-injection with papaverine to induce a
penile erection. This was the first time that
an effective medical therapy for erectile
dysfunction (ED) was described, and was a
historic development in the management of
ED. The way in which this information was
first reported was completely unique and
memorable, and provides an interesting
context for the development of therapies for
ED. I was present at this extraordinary lecture,
and the details are worth sharing. Although
this lecture was given more than 20 years
ago, the details have remained fresh in my
mind, for reasons which will become obvious.
The lecture, which had an innocuous title
along the lines of ‘Vaso-active therapy for
erectile dysfunction’ was scheduled as an
evening lecture of the Urodynamics Society in
the hotel in which I was staying. I was a senior
resident, hungry for knowledge, and at the
AUA I went to every lecture that I could. About
15 min before the lecture I took the elevator
to go to the lecture hall, and on the next floor
a slight, elderly looking and bespectacled
man, wearing a blue track suit and carrying a
small cigar box, entered the elevator. He
appeared quite nervous, and shuffled back
and forth. He opened the box in the elevator,
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Caubet JF et al. Psychological effects of a
suspicious prostate cancer screening test
followed by a benign biopsy result. Am J
Med 2004; 117: 719–25
7 Klein EA. Selenium and vitamin E cancer
prevention trial. Ann NY Acad Sci 2004;
1031: 234–41
8 Schoonen WM, Salinas CA, Kiemeny
LA, Stanford JL. Alcohol consumption
and the risk of prostate cancer in middle-
aged men. Int J Cancer 2005; 113: 133–40
e-mail: mbarry@partners.org
November 2005
967
Comment Article
comment
KLOTZ
which became crowded, and started
examining and ruffling through the 35 mm
slides of micrographs inside. I was standing
next to him, and could vaguely make out the
content of the slides, which appeared to be a
series of pictures of penile erection. I
concluded that this was, indeed, Professor
Brindley on his way to the lecture, although
his dress seemed inappropriately casual.
The lecture was given in a large auditorium,
with a raised lectern separated by some
stairs from the seats. This was an evening
programme, between the daytime sessions
and an evening reception. It was relatively
poorly attended, perhaps 80 people in all.
Most attendees came with their partners,
clearly on the way to the reception. I was
sitting in the third row, and in front of me
were about seven middle-aged male
urologists, and their partners in ‘full evening
regalia’.
Professor Brindley, still in his blue track suit,
was introduced as a psychiatrist with broad
research interests. He began his lecture
without aplomb. He had, he indicated,
hypothesized that injection with vasoactive
agents into the corporal bodies of the penis
might induce an erection. Lacking ready
access to an appropriate animal model, and
cognisant of the long medical tradition of
using oneself as a research subject, he began
a series of experiments on self-injection of his
penis with various vasoactive agents,
including papaverine, phentolamine, and
several others. (While this is now
commonplace, at the time it was unheard
of). His slide-based talk consisted of a large
series of photographs of his penis in various
states of tumescence after injection with
a variety of doses of phentolamine and
papaverine. After viewing about 30 of
these slides, there was no doubt in my
mind that, at least in Professor Brindley’s case,
the therapy was effective. Of course, one
could not exclude the possibility that erotic
stimulation had played a role in acquiring
these erections, and Professor Brindley
acknowledged this.
The Professor wanted to make his case in the
most convincing style possible. He indicated
that, in his view, no normal person would find
the experience of giving a lecture to a large
audience to be erotically stimulating or
erection-inducing. He had, he said, therefore
injected himself with papaverine in his hotel
room before coming to give the lecture, and
deliberately wore loose clothes (hence the
track-suit) to make it possible to exhibit the
results. He stepped around the podium, and
pulled his loose pants tight up around his
genitalia in an attempt to demonstrate his
erection.
At this point, I, and I believe everyone else in
the room, was agog. I could scarcely believe
what was occurring on stage. But Prof.
Brindley was not satisfied. He looked down
sceptically at his pants and shook his head
with dismay. ‘Unfortunately, this doesn’t
display the results clearly enough’. He then
summarily dropped his trousers and shorts,
revealing a long, thin, clearly erect penis.
There was not a sound in the room. Everyone
had stopped breathing.
But the mere public showing of his erection
from the podium was not sufficient. He
paused, and seemed to ponder his next move.
The sense of drama in the room was palpable.
He then said, with gravity, ‘I’d like to give
some of the audience the opportunity to
confirm the degree of tumescence’. With his
pants at his knees, he waddled down the
stairs, approaching (to their horror) the
urologists and their partners in the front row.
As he approached them, erection waggling
before him, four or five of the women in the
front rows threw their arms up in the air,
© 2005 BJU INTERNATIONAL

seemingly in unison, and screamed loudly.
The scientific merits of the presentation
had been overwhelmed, for them, by the novel
and unusual mode of demonstrating the
results.
The screams seemed to shock Professor
Brindley, who rapidly pulled up his trousers,
returned to the podium, and terminated the
lecture. The crowd dispersed in a state of
flabbergasted disarray. I imagine that the
urologists who attended with their partners
had a lot of explaining to do. The rest is
history. Prof Brindley’s single-author paper
reporting these results was published about
6 months later [1].
Professor Brindley made a huge contribution
to the management of ED, for which he
deserves tremendous gratitude. He was a true
© 2005 BJU INTERNATIONAL
lateral thinker, and applied his unique mind to
a variety of problems in medicine. These
include over 100 publications that focus on
the areas of visual neurophysiology and
several other aspects of neurophysiology,
including ejaculation and female sexual
dysfunction. He also published one
remarkable paper studying the effect of
17 different drugs used intracorporally
to induce erection [2]. Seven of these
(phenoxybenzamine, phentolamine,
thymoxamine, imipramine, verapamil,
papaverine, naftidrofury) induced an erection.
It is not clear to what degree Brindley’s own
penis served as the test subject for these
studies.
This lecture was unique, dramatic,
paradigm-shifting, and unexpected. It
is difficult to imagine that a similar
COMMENTS
scenario could ever take place again.
Professor Brindley belongs in the pantheon of
famous British eccentrics who have made
spectacular contributions to science. The story
of his lecture deserves a place in the urological
history books.
REFERENCES
1 Brindley GS. Cavernosal alpha-blockade:
a new technique for investigating and
treating erectile impotence. Br J
Psychiatry 1983; 143: 332–7
2 Brindley GS. Pilot experiments on the
actions of drugs injected into the human
corpus cavernosum penis. Br J Pharmacol
1986; 87: 495–500
e-mail: laurence.klotz@sw.ca
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