BJU INTERNATIONAL

Uroscan

NEWS AND INFORMATION RESOURCE FOR THE INTERNATIONAL UROLOGY COMMUNITY

By Kevin D. Blanchet

A Fresh Approach to Prostate Cancer

Physicians should combine imaging studies with focal therapy

Mark Emberton

Has overspecialization in
prostate cancer helped or
hindered progress in its
diagnosis and treatment?
Despite more elaborate
and expensive techniques,
treatment is still associated
with too much toxicity. It also
makes little economic sense
and is unsustainable. Even the
management of prostate cancer
is filled with great uncertainty
and lacks the strategies
employed to treat other types
of cancer. How can prostate
cancer be put on the same
track as breast or renal cancer
in terms of precision diagnosis
and focused therapy? Such
questions are at the forefront
of research being conducted
by Mark Emberton, reader in
interventional oncology at
University College London,
divisional clinical director of its
hospitals Cancer Services and

clinical director of the Clinical

Effectiveness Unit at the Royal
College of Surgeons of England.
With his research into imaging
techniques and focal therapy,
Emberton is rewriting the way
prostate cancer is diagnosed
and treated by precisely
characterizing the disease and
developing targeted therapies.
Recently, he sat down with
UroScan to express
his frustration with
the current state of affairs in
prostate cancer and to share his
thoughts on what is needed to
redefine the way it is diagnosed
and treated.

do this with prostate cancer.

Prostate cancer is the only
cancer where we insist on
removing the whole organ
when there is cancer in it. We
dont do that for anything
else anymore, such as the
kidney or the breast. Its also
the only cancer in which we
treat subclinical disease. Every
other cancer has to manifest
itself in some waywe feel it
or see itbefore it is treated.
In men with high PSA scores
and biopsy, you dont see any
cancer. So, you are treating
microscopic disease. It is the
only cancer where we do this.

Compared with other

types of cancer, how
do we diagnose and
treat prostate cancer differently?
When one thinks about pros
tate cancer, we manage it in
a strange way. The prostate is
the only organ where we use
chance to make the diagnosis.
Men have random biopsies. It
is the only cancer where we do
not use some form of imaging
prior to biopsy. For every other
organ, we target the biopsy,
particularly for the breast with
mammography. Or, we visual
ize the tumour with things
like colonoscopy and gastro
scopy. Its odd that we dont

How did we end up on

this path with prostate cancer? Is there
an explanation for
why things are done
so differently?
With prostate cancer being one
of the more common cancers, we
have to reflect why we treat and
manage it so differently. Why are
we behind the times? A series
of historical occurrences may
explain this. First, we could feel it
with a DRE. Then, we were able
to stick a needle in it and take a
biopsy. Finally, the PSA test was
invented. All of these things con
tributed to the current situation.
The two current problems
everyone agrees upon in prostate

BJUI

UROSCAN

cancer are over-diagnosis and

over-treatment. Could these
two problems be related to
our rather odd diagnostic
evaluation? In other words, is
there a better way to treat the
disease once we know exactly
where it is in the prostate? We
need to start rethinking the way
prostate cancer is diagnosed and
challenge the current diagnostic
pathway.
What do you see
as a better way?
You can see suddenly how image
guided diagnostic strategies
maybe an imaging test to decide
who does and who doesnt get
a biopsywould be sensible. If
we had an imaging test that
could identify men with clini
cally significant prostate cancer
and could be performed before
biopsy, we could save a lot of
men from having unnecessary
biopsies. We call this a triage test,
which is what mammography is.
You dont biopsy every breast on
every woman that walks through
the door! We offer women

Additional Reading
Ahmed HU, Moore C,
Emberton M. Minimallyinvasive technologies in
uro-oncology: The role
of cryotherapy, HIFU and
photodynamic therapy
in whole gland and focal
therapy of localized prostate
cancer. Surg Oncol 2009; 18:
219-232
Ahmed HU, Zacharakis E,
Dudderidge T et al. Highintensity-focused ultrasound
in the treatment of primary
prostate cancer: The first
UK series. Br J Cancer 2009;
101: 19-26
Moore CM, Pendse D,
Emberton M. Photodynamic
therapy for prostate cancer
a review of current status
and future promise. Nat Clin
Pract Urol 2009; 6: 18-30

mammography to help us decide

which ones are worth biopsying.
Why hasnt something like this been
developed yet?
There are societal, economic,
and all kinds of good and bad
reasons why we have had
intellectual laziness in this
area. Some perverse incen
tives exist. At the moment,
rather than point fingers, we
are exploring various options.
What type of imaging
test would be best suited for prostate cancer?
MRI is probably the best
contender. Prostate biopsies
actually perform quite poorly;
they are wrong half the time.
At levels of clinically sig
nificant disease, MRI performs
with about 9095% certainty.
Can an imaging test, such
as MRI, be used to decide
who gets a biopsy? This is an
important research question
with huge public health
implications. In other words,
rather than use chancewhich
seems crazyyou use the
image for targeting rather
than sampling randomly.
Wouldnt using MRI to
screen for prostate
cancer be quite costly?
The greatest cost in prostate
cancer therapy arises from
treating men who dont need
treatment. It has been estimated
in Europe that you need to treat
48 men in order to save one life.
If we could get it down to 20,
wed be saving an awful lot of
money. Remember, it is not just
the cost of treatment but also
the costs of managing erectile
dysfunction, incontinence, etc.
You could argue that an MRI
in a public healthcare setting
is not an expensive test and a
lot less expensive than treat
ing someone unnecessarily.
We are planning a large study

in which men will have an MRI

prior to template biopsies in
order to determine whether
MRI might serve as a triage test
for men with a high PSA level.
Lets talk about treatment. How will imaging
contribute to newer
forms of therapy?
Because our treatments involve
removing or irradiating the
whole gland, we do not cur
rently care about where the
cancer is. With the advent of
active surveillance and the
possibility of focal therapy,
knowing the tumours position
and topography is possibly as
important as knowing that a

man has prostate cancer. Most

cancers only occupy 5% of the
tumour volume. Focal therapy
is at least one strategy whereby
we can address some of the
toxicity issues associated with
treatment. The treatment may
preserve function and treat the
cancer just like lumpectectomy
versus mastectomy and partial
nephrectomy versus total kid
ney removal. It may also be
able to reduce the cost
substantially with a lot
less carbon emission.
When it comes to focal therapy, do you
have a preferred
energy source?

The Best of 2009 Now Available Online

Last year, BJUI published more than 500 peer-reviewed
papers in six sub-specialties of urology. Readers are sure to
have their favourites, but which ones are considered to be
the best of the best? Find out at www.bjui.org, where you
can read these contributions to the field.
BJUIs Editor Prof John Fitzpatrick charged his associ
ate editors (and himself) to create a list of their choices
for the best papers published in 2009. In addition to Prof
Fitzpatrick, making these important selections were Mark
Emberton, Roger Kirby, Alan Partin, Alan Wein, and Mike
Wyllie. Their task wasnt easy. The quality of papers was
quite impressive last year, says Prof Fitzpatrick. Our best
picks really reflect this depth and breadth of excellence.
For example, Prof Fitzpatrick felt the paper by Jhavar et
al on gene expression (Integration of ERG gene mapping
and gene-expression profiling identifies distinct categories
of human prostate cancer) deserved one of his highest
rankings. Not only was the paper well written, but it pre
sented important insights into the genetic basis of prostate
cancer, he says. The graphical presentation of biological
networks and pathways made this paper quite deserving to
be among the best published in 2009.
Wein selected Signal transduction pathways of muscar
inic receptor mediated activation in the newborn and adult
mouse urinary bladder (Ekman et al) as one of his highestranking papers in the research category. Emberton selected
the paper of fellow associate editor Wyllie titled Does the
pharmaceutical industry need urological conferences, and
vice-versa? as one of his top five selections.
Readers of BJUI can access all of the best lists and top
papers in a special feature on the website, www.bjui.org. Ac
cess will be free until early May. I think readers will find our
top picks to be provocative and interesting, Prof Fitzpatrick
says. They offer our readers a glimpse into how our edito
rial team and reviewers think and what they look for in a
good, quality paper.

UROSCAN

At the moment, high intensity

focused ultrasound is a nice
contender. Currently, we are
conducting two clinical trials.
Im not married to it or any oth
er energy source. I suspect that
others are just as convenient
because they are non-invasive
and quick. All you want is an
energy source that you can
control for pinpoint destruction
of a quantity of tissue. Interest
ingly, in the US, they are using
a lot of the old thermal lasers
that were thrown out in the
1990s because they didnt work
for benign prostatic hyperplasia.
These are now being used to
treat men with prostate cancer
in a focal manner because they
are Food and Drug Administra
tion (FDA) approved, so you
dont have to do any long-term
studies. Cryotherapy is also
being used in the US. Here in
the UK, we are using vasculartargeted photodynamic therapy
in a multicenter study.
You are also interested in innovative
trial design. What are
some of your ideas?
Randomized trials are so
expensive and take so long to
mature. The FDA and many
others are concerned about
the length of time it takes for
randomized trials to mature
they are out of date by the time

they do matureand the costs of

undertaking them. You have to
ask the question: why do we do
them? Particularly with technical
innovation, once safety is proven,
you can often gain information
in a quicker way.
When we do go comparative
with focal therapy, one idea is
using pragmatic randomization,
where the physician chooses the
control. This would allow many
more patients to be recruited
more quickly. The surgeon could
express his or her preference
to the control. This is already
being done quite successfully in
breast cancer, but as of yet not
in prostate cancer. Basically, you
would have three arms, with
focal therapy in the middle. The
surgeon would say, This guy,
I really wouldnt do a radical
on him. So, what I will do is
randomize him to focal therapy
against active surveillance.
Thats a coin toss. You cant
control what youd get but you
can control the control. The
surgeon might get another guy
and say, I wouldnt give this
guy active surveillance at all;
Im worried about him. So, it is
focal therapy if thats what the
guy wants. But, for the control,
I want to make sure he gets
surgery. So, you choose surgery
as the control and then you
do the coin toss. The biggest
impediment to trial recruitment

Clinical Trial
Title:

STUDY OF GLOBAL COAGULATION TESTS IN PATIENTS WITH
PAROXYSMAL NOCTURNAL HAEMOGLOBINURIA
Protocol ID:
NCT01020188
Summary:
As a rare disease, paroxysmal nocturnal haemaoglobinuria
(PNH) results in the breakdown of red blood cells, causes
bone marrow failure and is associated with an increased
risk of blood clots. Treatment normally consists of blood
transfusions and blood thinners for those with blood clots.
Eculizumab is now standard for patients who require reg
ular blood transfusions; it prevents the breakdown of red
blood cells. The investigators plan to use specialised blood
tests to assess the stickiness of the blood before starting
eculizumab treatment and monthly after starting treat
ment. They will compare these tests with standard tests of
clotting. The primary outcome measure is to establish the
role of thrombin generation in assessing the prothrom
botic phenotype of PNH.
ELIGIBILITY:
Patients may be male or female and 18 years of age or
older. All must have PNH with the presence of a PNH
clone. Patients on long-term anticoagulation therapy for
previous venous thrombosis are excluded. The study is ex
pected to enroll 60 participants.
LOCATIONS AND CONTACTS:
Dupe Elebute, MB, MD, Kings College Hospital NHS Trust,
London, United Kingdom, 02032995761, dupe.elebute@
nhs.net.

is non-equipoise for the surgeon,

which is overcome because they

Important papers you may have missed

Kupelian V, Araujo AB, Chiu GR et al. Relative
contributions of modifiable risk factors to erectile
dysfunction: Results from the Boston Area Community
Health (BACH) Survey. Prev Med 2010; 50(1-2): 19-25
McClellan WM, Resnick B, Lei L et al. Prevalence
and severity of chronic kidney disease and anemia in
the nursing home population. J Am Med Dir Assoc
2010; 11: 33-41
Boukaramab C, Hannoun-Levib JM. Management
of prostate cancer recurrence after definitive radiation
therapy. Cancer Treat Rev 2010; January 25. [Epub
ahead of print]

choose the control. I think it is

a nice design.

JOURNAL

Williamson SR, Montironi R,

WATCH
Lopez-Beltran A, et al. Diagnosis,
evaluation and treatment of
carcinoma in situ of the urinary
bladder: The state of the art. Crit
Rev Oncol Hematol 2010; January 25. [Epub ahead of print]

Moses KA, Paciorek AT, Penson DF, et al. Impact of

ethnicity on primary treatment choice and mortality in
men with prostate cancer: Data from CaPSURE. J Clin
Oncol 2010; January 25. [Epub ahead of print]

UROSCAN

In this issue...
Urological Oncology
REPEATED BIOPSYING HELPFUL IN PENILE CARCINOMA P1121

GOOD HYGIENE TO WARD OFF

UTI IN CYSTECTOMY PATIENTS
P1107
After undergoing cystectomy for bladder
cancer, patients are at risk for high levels
of bacteriuria. Regardless of the urinary
diversion, the majority (77% to 94%) have
bacteria present in their urine. Each year,
about 25% of these patients experience a
symptomatic urinary tract infection (UTI).
Could practicing good hygiene help these
individuals decrease their risk for acquiring
such infections?
To test this hypothesis, Thulin et al surveyed
patients who had undergone cystectomy and
urinary diversion at seven Swedish hospitals.
Participants filled out a study-specific
questionnaire that inquired about various
hygienic practices, such as hand washing
before catheterization or changing stoma
plates, showering frequency and the use and
frequency of taking baths. Out of 491 patients
contacted, 452 completed the surveys.
During the previous year, 22% of patients
with orthotopic neobladder and cutaneous
continent reservoir had acquired a
symptomatic UTI. The rate was 23% for
non-continent urostomy diversion. Never
washing hands before handling catheters or
stoma plates was associated with a relative
risk (RR) for UTI of 1.1 (0.52.5, 95% CI). Those
patients with diabetes were most at risk for
developing a UTI in the past year with a RR of
2.1 (1.43.2). Given these results, the authors
conclude that focusing on hygiene does not
significantly affect the frequency of UTIs.

In patients with penile squamous cell carcinoma, determining metastasis in inguinal

lymph nodes is an important part of clinical management. Surgeons may opt to use
watchful waiting or elect to perform dissection of the nodes to assess disease spread.
However, a better way may be dynamic sentinel node biopsy (SNB) in patients
with clinically normal lymph nodes.
Graafland et al report their experience in using SNB as a minimally invasive
staging technique since 1994. In their prospectively maintained dynamic sentinel
node database of 304 patients, 12 patients with clinically node-negative
groins underwent repeat dynamic SNB for recurrent invasive penile squamous cell
carcinoma. All had undergone previous penile surgery and SNB. Five of the 12 patients
had undergone unilateral inguinal node dissection for metastases. The median
disease-free interval was 18 months. Both primary and repeat dynamic SNB were
performed in a similar fashion.
The five patients with previous node dissections did not show any sentinel nodes
on preoperative lymphoscintigraphy. Sentinel nodes were seen in 19 undissected
groins; 15 of these had the node identified during surgery. Four groins from three
patients showed metastasis on repeat SNB. Median follow-up was 32 months
after the repeat SNB. One patient had a groin recurrence 14 months after a tumournegative sentinel node procedure. This individual did not have standard preoperative
ultrasonography with fine-needle aspiration cytology.

MANAGING BILATERAL SYNCHRONOUS RENAL TUMOURS P1093

Several options exist for the
management of bilateral
renal masses. These include
radical nephrectomy (RN) or
partial nephrectomy (PN),
ablation and observation. All
of these approaches spark
considerable debate that
produces new questions for
consideration. Although
masses in both kidneys
FIG. 1. Predicted probability of receiving two PNs for
are an indication to use
nephron-sparing surgery, this synchronous disease by year of procedure.
approach is not used as much
as it should be. Instead, RN would be performed on the kidney with the larger tumour,
provided a portion of the other kidney could be preserved.
In their paper, Lowrance et al share their experience with the surgical management
of sporadic synchronous bilateral renal tumours at a major cancer centre. They detail
their preference for staged PN, operating on the more involved kidney first.
Specifically, they report on 2777 patients who underwent PN or RN during a 19-year
period, 73 of whom presented with synchronous bilateral disease.
The probability of patients receiving two PNs for synchronous disease
increased over time. By 2004, 13 of 14 patients underwent bilateral PN. Out of four
possible kidney removal combinations, the most common was bilateral PN. This was
conducted in 32 patients (44%). A total of 45 patients (62%) had their larger tumour
removed during the first operation. Survival of patients with synchronous bilateral
tumours was similar to patients with unilateral disease.