Current Controversies in
Prostate Cancer Screening and Treatment
Mr Stephen Lindsay
Urological Surgeon
Bendigo
www.bendigourology.com
Since the early 1990’s, Prostate Cancer has been the most commonly
diagnosed cancer in Australian men (approx 20,000 new cases/year).
Why the increase?
• Community awareness that testing is available
• Improved risk assessment tools - PSA and TRUS biopsy became
widely available in the early 1990’s
• Improved access to risk assessment – more GP’s and Urologists
• More treatment options available, with less morbidity
• Male life expectancy has increased – more men living longer
It is the second most common cause of cancer death in men. Over 3000
men die of Prostate Cancer each year (4.1% of all male deaths).
WHO Screening Criteria - 1968
The condition sought should be an important health problem.
There should be accepted treatment for patients with recognized disease.
Facilities for diagnosis and treatment should be available.
There should be a recognizable latent or early symptomatic stage.
There should be a suitable test or examination to be used for screening.
The tests should be acceptable to the population.
The natural history of the condition, including development from latent to
declared disease, should be adequately understood.
8. There should be an agreed policy regarding whom to treat as patients.
9. The cost of case-finding (including diagnosis and treatment) should be
economically balanced in relation to possible expenditure on medical care as
a whole.
10.Case-finding should be a continuing process, and not a “once and for all”
project.
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Wilson and Jungner,
“Principles and Practice of Screening for Disease”
• World Health Organization 1968
WHO Screening Criteria – (Revised 2008)
1. The screening programme should respond to a recognized need.
2. The objectives of screening should be defined at the outset.
3. There should be a defined target population.
4. There should be scientific evidence of screening programme effectiveness.
5. The programme should integrate education, testing, clinical services and
programme management.
6. There should be quality assurance, with mechanisms to minimize potential
risks of screening.
7. The programme should ensure informed choice, confidentiality and respect
for autonomy.
8. The programme should promote equity and access to screening for the entire
target population.
9. Programme evaluation should be planned from the outset.
10.The overall benefits of screening should outweigh the harm.
• World Health Organisation 2008
Population-based Screening
• Large scale testing of an entire geographical population of
apparently healthy volunteers for the presence or absence of
disease
eg Breastscreen (screening centres, mailed invitations)
Selective Screening of at-risk populations
• limited testing targeted at high risk populations
eg family history, African-American
Opportunistic testing (or Case Finding)
• investigation of men (with or without symptoms) as part of a
routine medical consultation
Prostate cancer specific survival in Victoria has improved
dramatically over the last 20 years.
"Most men die with, rather than of, their Prostate cancer."
This is misleading, particularly for men in their 50’s and 60’s.
 A man aged 70 has a 38% chance of dying of the cancer
before 80 years of age
 But, a man aged 50 has a 60% chance of dying before 80 years
of age.
So younger men are “More likely to die of, rather than with,
their Prostate cancer.”
Increasing numbers of
older men are surviving
other diseases and living
longer.
There will be a dramatic
increase the numbers of
men diagnosed and living
with Prostate cancer in the
next 20 years.
The Melbourne Consensus Statement on
Prostate Cancer Testing (2013)
Consensus statement:
Older men in good health with over 10 year life expectancy should not be
denied PSA testing on the basis of their age.
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Men should be assessed on an individual basis, particularly as life
expectancy increases.
Urban vs. Rural Comparison
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Men from city and country areas in Australia have the same lifetime risk of
developing Prostate Cancer
Average age at diagnosis is the same at approximately 71 years
but ...
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Men from country areas are 2.6 x more likely to die from Prostate Cancer in
the first 5 years after diagnosis than men in metropolitan areas.
The Natural History of Prostate cancer can vary enormously:
• slow indolent cancers with a long latent period of 10-15 years before they
develop clinical disease (obstructive symptoms, metastases) and need
treatment
• very aggressive cancers with progression to metastatic disease within a few
years despite maximal treatment
The long interval of “latent disease” for less aggressive cancers gives us a large
window of opportunity to diagnose while the cancer is still at a curable stage. But
the life-threatening cancers we need to find and treat are the more aggressive
cancers, with a shorter latent period.
Active surveillance programs use this long interval of “latent disease” in patients
who have less aggressive cancers with a low risk of progression. In Australia now,
around 30% of newly diagnosed men with Prostate cancer are on active
surveillance, with treatment with curative intent offered to those who show signs
of cancer progression.
The Melbourne Consensus Statement on
Prostate Cancer Testing (2013)
Consensus statement:
For men aged 50-69, Level 1 evidence demonstrates that PSA testing reduces
prostate cancer specific mortality and incidence of metastatic prostate
cancer.
ERSPC Trial
• 1991-2003 182,160 men from 7 centres, age 50-74 years
• screening reduced prostate cancer specific mortality by 21% and
progression to metastatic disease by 30% (at 11 years follow-up)
• To prevent one death (at 11 years follow-up) – 936 men would need to be
invited to screen and 33 cancers would need to be diagnosed.
Goteborg Subgroup of ERSPC
• randomised population-based trial (20,000 men screened from age 50
years) showed reduction in prostate cancer mortality by 44% at 14 years
follow-up
• To prevent one death (at 14 years follow-up) – 293 men would need to be
invited to screen and 12 cancers would need to be treated
The Melbourne Consensus Statement on
Prostate Cancer Testing (2013)
Consensus statement:
PSA testing should not be considered on its own, but rather as a part of a
multivariable approach to early prostate cancer detection.
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Age specific PSA (reduces false negatives in young men, false positives
in older men)
PSA Velocity (or doubling time)
Prostate Health Index (phi) – mathematical formula combines total PSA,
free PSA and (-2) pro-PSA (a PSA isoform)
Urinary PCA3, other new biomarkers
Online tools
• ERSPC risk calculator
• Prostate Cancer Prevention Trial risk calculator
The Melbourne Consensus Statement on
Prostate Cancer Testing (2013)
Consensus statement:
Baseline PSA testing for men in their 40s is useful for predicting the future
risk of prostate cancer.
An assessment at 40 years allows risk stratification before BPH-related PSA
elevation occurs.
• Men with PSA levels below the median are less likely to develop Prostate
cancer and need not be tested as often.
• Men with PSA levels above the median are at increased risk and should be
tested more often.
Age Specific Reference Ranges, Median PSA
Digital Rectal Examination (DRE)
Increased firmness, hardness, nodularity, irregularity,
asymmetry, cragginess
Sensitivity of DRE in detecting Prostate cancer
• GP
26.5%
• Specialist Urologist
61.8%
One in four men with a normal PSA have an abnormal
DRE due to Prostate cancer
Health professionals need to be trained to do DRE properly
if they are to competently assess Prostate cancer risk
Who Should be referred to a Urologist?
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Age-specific PSA Elevated
DRE Abnormal
or Both
PSA Velocity
• PSA rising at greater than 0.5ng/ml/year is suspicious for cancer
• PSA doubling time
• <2 years – high risk
• <5 years – intermediate risk
• > 5 years low risk
• Free/Total PSA Ratio – can help to distinguish non-cancer from cancer for PSA in the
range 2-10ng/ml. A FT ratio <10% is suspicious for cancer (a higher level does not
exclude cancer)
50 year old man – Prostate Cancer Risk Assessment
PSA - 5.4 ng/ml (normal <3.5 ng/ml)
DRE - firm prostatic nodule on the right side, with no
extension into the lateral sulcus or seminal vesicle (T2a)
FHx - No
PCPT Risk Calculator
Risk of high grade CaP
Risk of low grade CaP
5%
18%
Likelihood that the biopsy
is negative
77%
50 year old man – Prostate Cancer Risk Assessment
TRUS Biopsy
• Hypoechoic area right side corresponding to nodule
• 5/14 cores involved (2-5mm right side)
• Gleason score 3+3=6
Radiological Staging
• CT Abdomen/Pelvis
• Bone Scan
– N0
– M0
What type of Prostate Biopsy?
Trans-Rectal vs Trans-Perineal Ultrasound-guided Biopsy of the Prostate
Trans-Rectal
Trans-Perineal
• 14-16 cores
• Inadequate sampling of
anterior prostate
• 20+ areas sampled,
multiple cores
• mp-MRI fusion
• Sepsis 2-3% (ESBL)
• Retention <1%
• Bleeding mild
• Sepsis almost 0%
• Retention 2-5%
• Bleeding increased, pelvic
haematoma
• Erectile dysfunction
• Peri-prostatic scarring
• Anaesthetic Risk
• Dramatically increased cost
Low Risk
Intermediate Risk
High Risk
T1 – T2b
Gleason < 7
PSA < 10
T2c – T3a
Gleason 7
PSA 10 - 20
T3b – T4
Gleason > 7
PSA > 20
D’Amico 1998
Multi-parametric MRI
for Prostate Cancer diagnosis
Multiparametric-MRI (mp-MRI) for Risk Stratification
mp-MRI combines diffusion-weighted, dynamic contrastenhanced sequences (or MR Spectroscopy) with conventional
T2 weighted sequences.
This shows anatomy, tissue density and blood supply.
Potential Advantages
• Only detects cancers 7mm or larger with Gleason grade 4
or 5
• It has the potential to offer improved detection and risk
stratification of intermediate/high risk cancers.
• mp-MRI targeted biopsies may lead to
• fewer biopsies, with fewer cores at each biopsy
• reduced detection of clinically insignificant disease
• better representation of disease burden "cancer core
length, Gleason score"
Multi-parametric MRI
for Prostate Cancer diagnosis
Multiparametric MRI (mp-MRI) for Risk Stratification
BUT….
• Mp-MRI is highly technique and operator dependent, requiring two
dedicated Uro-Radiologists for each report. The technique and exact use is
evolving and still in its infancy.
• Mp-MRI should not be considered as a definitive study on its own but
rather one part of a comprehensive assessment. Biopsy must still be
performed to confirm the presence of tumour and to assess Gleason score
We need prospective randomised trials to assess the role of mp-MRI in
Prostate cancer screening.
Mp-MRI is not currently reimbursed by Medicare or private health funds for
prostate imaging.
Patient Factors
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What is his life expectancy?
Will he benefit from treatment?
Is he prepared to accept active surveillance?
What Quality of Life is he prepared to sacrifice to be cured of his
cancer?
Cancer Factors
• Is this Prostate cancer life threatening or likely to cause significant
morbidity?
• Is it curable with the treatment?
Available Treatments
• What are the available treatments options for that patient and that
cancer?
• What are the risks and benefits of each option for this man?
Treatment options for Localised Prostate cancer
Active Surveillance
Radical Prostatectomy
• Open Retropubic, Perineal , Laparoscopic, Robotically-Assisted RP
Radiotherapy
• Intensity Modulated External Beam (IMRT)
• +/- Neo-adjuvant LHRH to downsize
• +/- Adjuvant LHRH for 2-3 years (survival advantage)
• Brachytherapy
• Low Dose Rate Seeds (I125)
• High Dose Rate + EBRT
Hormone Therapy
• LHRH (eg Goserelin, Leuprorelin)
• Antiandrogen (steroidal or non-steroidal)
The Melbourne Consensus Statement on
Prostate Cancer Testing (2013)
Consensus statement:
Prostate cancer diagnosis must be uncoupled from prostate cancer
intervention.
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Active surveillance protocols have been developed and shown to be a
safe option for many men with low volume, low risk prostate cancer.
This does not address the issue of over-diagnosis, but does reduce
excessive intervention.
Active Surveillance/Watchful waiting
Active surveillance is a management strategy for a man who would
benefit from treatment but where the cancer is too small to
recommend active treatment.
• The cancer is closely monitored for change in PSA, size or
aggressiveness (which requires repeat biopsy at defined intervals).
• If the cancer is found to progress, then definitive treatment with
surgery or radiotherapy is offered.
• Currently around 40% of men newly diagnosed with Prostate cancer
in Australia are commenced on Active Surveillance.
Watchful waiting is the no treatment option for elderly men who are
not likely to benefit from definitive treatment.
• Observation of PSA and symptoms, no repeat biopsy.
Intensity Modulated Radiotherapy (IMRT)
• 78Gy in 39 fractions
• 5 treatments/wk = 8 weeks
• Small gold markers or fiducial seeds are
inserted into the prostate (by TRUS) to
improve targeting.
• External Beam Radiotherapy can be
accurately focused onto the Prostate,
minimising radiation toxicity to the
adjacent bladder and bowel
• Neoadjuvant Hormone therapy is often
given to patients with intermediate to
high risk cancers prior to commencing
Radiotherapy
Brachytherapy Seed Implantation
(Low Dose Rate)
Radioactive I125 seeds are implanted
into the prostate by a Urologist and
Radiation Oncologist.
The I125 seeds deliver a precise, high
dose of photons to a small localised
are around the seed.
The I125 seed’s radioactivity decays with
a T½ of 60 days.
Patients are radioactive and radiation
safety precautions must be taken.
Brachytherapy Seed Implantation
(Low Dose Rate) - Technique
A TRUS volume study is performed to
measure prostate size, 3D shape and
the position of bladder, urethra and
rectum. A dose plan is determined.
Implantation Procedure
• TRUS is used to guide seed
placement following the dose plan.
• From 60 to 120 I125 seeds are
inserted
• The procedure takes approx 45
minutes and the patient stays in
hospital overnight.
Radical Prostatectomy - History
1906 – first Radical Prostatectomy at Johns
Hopkins University
Early 1980’s - Dr Patrick Walsh et al published
anatomical studies on pelvic venous and nerve
anatomy.
The Walsh Radical Prostatectomy (or open Radical
Prostatectomy) revolutionised the surgical
technique and dramatically reduced blood loss
and surgical morbidity.
1990’s – now - Subsequent refinements in
technique, including "nerve sparing" Radical
Prostatectomy followed.
Open Radical Prostatectomy - Technique
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Retropubic or Perineal approach
Pelvic LND
Dorsal Venous complex ligated and divided
Nerve sparing prostate dissection
Urethra transected, prostate mobilised
Bladder neck divided
Vesico-urethral Anastamosis
Post-operative complications
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urinary incontinence
sexual dysfunction
5-10%
40-85%
The da Vinci™ Robot-assisted Radical
Prostatectomy (RARP) - Technique
• The console surgeon uses 3D HD images to
drive computer simulation to manipulate the
robotic arms
• The table-side assistant inserts the laparoscope
and 4-5 laparoscopic ports for the robotic arms
• “Endowrist” instruments provide precise
control with increased range of motion and
improved dexterity
• The prostate is removed through a large port
• RARP takes 3-6 hours
• Hospital stay 1-3 days, patient home with
urethral catheter for 2-3 weeks
Controversy - Robotic-Assisted Prostatectomy
a “pseudo-innovation—a technology that increases costs
without improving patients’ health”
a “fake innovation”
Dr Ezekiel Emanuel
Medical Oncologist and former White House Advisor
New York Times May 2012
Urologists worldwide have embraced RARP with enthusiasm, and it is
now well established as a leading treatment for localised Prostate
cancer.
BUT how does it really compare with open Radical Prostatectomy?
• operative bleeding (transfusion rates), longer operation time, earlier
discharge and possibly earlier return to work.
• higher cost (consumables, theatre time, doctors fees)
• achieves equivalent cancer control (surgeon learning curve)
• claimed to improve recovery of urinary continence and erectile
function but this is not yet proven
The da Vinci Robotic-Assisted Radical
Prostatectomy has highlighted the concerns
surrounding the costs of Healthcare and
particularly cancer treatment in the United
States.
In the USA, RARP adds
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$2,200 US to the cost of a Radical Prostatectomy
(increased consumable costs and operating room
time)
additional $400 to $4,800 US per case in capital
costs and maintenance of the da Vinci Robot
Health Administrators are increasingly
analysing the cost/benefit of new therapies to
ensure that they are cost effective and improve
QALY’s.
Why has RARP polarised the debate in health care delivery?
There is an impending crisis affecting the diagnosis and management of prostate
cancer in most Western countries.
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aging and expanding population
new genetic-based screening tests
more sophisticated and expensive imaging tools (eg MRI)
improved treatment technologies
new pharmaceutical developments
Many factors have conspired to drive health expenditures for cancer, especially
Prostate cancer, to unsustainable levels.
We have reached a point where the current paradigm of health care
delivery is changing.
Medical Education and Research has traditionally focused on technical
skills and clinical decision making. Doctors have not had to justify the
costs of treatments that we recommend.
Governments and organisations responsible for paying for health care
are now demanding evidence that therapies we promote truly provide
value to large numbers of patients. Unfortunately, we don’t have wellconstructed randomized trials that demonstrate the cost/benefit of
many of the things we do.
Lifetime Risk
• “Microscopic” Prostate cancer
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- 30%
many of these cancers will be low risk.
• “Clinical” Prostate cancer
- 10%
• Dying of Prostate cancer
- 4.1%
The Challenge
“For a patient with Prostate cancer, if treatment for cure is necessary, is it possible?
If possible, is it necessary?”
Whitmore 1970’s
or to put it another way,
“How do we best find men with significant disease who are going to benefit from
diagnosis and treatment”.
"Treatment or no treatment decisions can be made once a cancer
is found, but not knowing about it in the first place surely burns
bridges"
Dr Joseph Smith, J Urology Editorial 2009