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Prostate cancer

Kate D Linton
James WF Catto
Abstract
Prostate cancer is the second commonest cause of death from malignancy
amongst men in the Western world. Whilst screening for prostate cancer
could reduce this mortality rate, it is controversial as most screen-detected
cancers are low risk and many more men require treatment than lives
saved. Current evidence suggests screening in men with little co-morbidity
is benecial if treatment is stratied to the extent andrisk of the detected dis-
ease. Treatment shouldbe aimedat diseasestage andriskof metastases, and
be balanced against the patients co-morbidities. Observational protocols
(such as active surveillance) should be used for men with low-risk locally
conned tumours or signicant co-morbidity. Radical treatments (such as
radical prostatectomy or radiotherapy) should be used in men with interme-
diate or high-risk disease that is either conned within the prostate or at
risk of local invasion/spread within the pelvis (locally advanced). Less morbid
approaches are being developed for locally conned tumours. These include
radiotherapy through seed implants (brachytherapy) and targeted focal ther-
apy to obliterate regions of the prostate (delivered using high-intensity
focussed ultrasound, cryotherapy or photo-thermal (Tookad) energy). These
approaches are less radical and so are likely to have lower cure rates and
less side effects thanradical treatments. Inhigh-volume, poorly differentiated
or locally advanced tumours, it is likely that multimodal treatments are
needed to obtain the highest rates of disease cure or control. Current combi-
nations include radical surgery followed by adjuvant radiotherapy or neo-
adjuvant androgen deprivation treatment (ADT) before radical radiotherapy.
Ongoing trials are evaluating the benet of adding chemotherapy and other
agents tothesecombinational regimens. Metastatic prostatecancer is initially
treatedwithADTintheformof surgical or medical castration. Thelatter may be
continuous or intermittent. Almost all men with ADT-treated metastatic pros-
tate cancer will develop castrate-resistant disease, if they live long enough.
There are now many options for the treatment of castrate-resistant prostate
cancer, including rst- and second-line chemotherapy, immunotherapy (sipu-
leucel-T), further anti-androgens (abiraterone acetate and enzalutamide) and
specic bone-targetedtreatments. It is likely that there will bemore treatment
options for advanced prostate cancer over the next few years.
Keywords Active surveillance; androgen-deprivation therapy; castrate-
resistant prostate cancer; prostate cancer; prostate specic antigen;
radical prostatectomy; radical radiotherapy
Aetiology and epidemiology
Prostate cancer is the most commonly diagnosed non-cutaneous
cancer and the second most common cause of cancer mortality in
males from the Western world. At the time of writing it is esti-
mated that 241,740 new prostate cancer diagnoses and 28,170
deaths from prostate cancer will have occurred in the USA in
2012.
1
Approximately one in nine men will be diagnosed with
prostate cancer in their lifetime and the lifetime risk of death
from this disease is 2e3% in the USA. These gures will rise with
the increase in life expectancy and widespread use of opportu-
nistic or systematic cancer screening seen in most Western na-
tions. Autopsy series of men dying from other causes show that
the true prevalence of prostate cancer is far higher than these
incidence gures. However, in most men the disease remains
latent or occult during their lifetime.
The aetiology of prostate cancer is not well understood and
appears to involve a complex interaction between ageing, genetic
predisposition, hormonal changes, growth, and environmental
features. Established risk factors include elderly age, ethnicity,
family history and dietary intake (high fat, high red meat and low
vegetable intake). Prostate cancer is rarely seen before the age of
50 (accounting for 0.1% of cases) and rises in incidence
dramatically after the age of 65 years (85% of the cases). The
highest incidence of detected cases occurs in North America,
Australia and Scandinavia, and the lowest in Japan and the Far
East. These demographics reect healthcare practice (e.g. the use
of prostate-specic antigen (PSA) testing) and environmental
factors (men partially acquire the risk of the country they live in
rather than their place of birth). These environmental factors
include pollution, infection, and most importantly dietary con-
tent. It is known that the highest rates of prostate cancer occur in
men whose diet is high in fat, high in red meat (especially
barbecued meat) and low in vegetables (especially cruciferous
and uncooked vegetables, and those high in anti-oxidants). Fat
intake may be related to country of origin, for example the diet of
Japanese men contains less fat than men in the USA, and they
have lower prostate cancer risk. Intake of tomato products con-
taining the anti-oxidant lycopene has been associated with
decreased prostate cancer risks in population studies.
Genetic, familial and racial factors are important in prostate
carcinogenesis. The disease is more common in Africane
American than in Caucasian or Asian (lowest rates) males, and
recent molecular analysis has identied numerous genetic poly-
morphisms that alter an individuals risk of this cancer. Family
risk is stratied (by the number and relationship of cases) into
sporadic (no family history), familial (one or more affected rel-
atives) and hereditary (three or more affected relatives in a nu-
clear family or three successive generations or two affected
individuals before the age of 55) prostate cancer. Many candidate
genes for prostate cancer susceptibility have been identied, for
example hereditary prostate cancer-1 (HPC-1), which is the best
characterized. There is also an increased risk of prostate cancer
in men who carry the BRCA-1 and BRCA-2 genes. It is likely that
more than one gene is involved as well as environmental factors.
Whilst sporadic disease accounts for 85% of all cases, familial
and hereditary cancers are more common in younger patients.
Hormonal factors appear important in prostate carcinogenesis
and may explain the rise in the disease with ageing, with prostate
Kate D Linton MD FRCSEd (Urol) is a Urology Specialist Registrar at
Shefeld Teaching Hospitals, Shefeld, UK. Conicts of interest: none
declared.
James WF Catto MBChB PhD FRCS is a Reader in Urology and Honorary
Consultant Urologist at the Academic Urology Unit and Institute for
Cancer Studies, University of Shefeld, Shefeld, UK. Conicts of
interest: none declared.
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cancer being rarely diagnosed before the age of 50 years, and the
risk increasing with advancing years. Eunuchs and familial
congenital testosterone metabolism defects (such as 5-a-reduc-
tase deciency) do not suffer from prostate cancer, thus impli-
cating testosterone or its derivatives in the disease biology. High
serum androgen levels have been reputed to increase prostate
cancer risk however reported studies have been inconsistent.
Diagnosis
The diagnosis of prostate cancer is usually made through digital
rectal examination (DRE), serum PSA and biopsy (either trans-
rectal ultrasound (TRUS) or trans-perineal). PSA and DRE are
mostly used to limit biopsy to men at elevated risk of the disease
(either high PSA or abnormal feeling prostate gland). In most
men a biopsy is needed to conrm the presence of cancer. Ex-
ceptions to this rule include men with very high PSAs and clin-
ically overt cancer on DRE or staging investigations revealing
metastases typical for this cancer. Recent advances in MRI have
suggested this imaging modality may be introduced before bi-
opsy to identify men with the disease and can be used to monitor
cancer growth (see surveillance section).
Digital rectal examination: before the advent of PSA testing,
DRE was the principal method of prostate cancer detection. DRE
allows the clinician to directly evaluate the prostate but has a
low sensitivity (detects only palpable disease) and low speci-
city (many benign changes may feel similar to cancer). There
is a large amount of inter-observer variability and clinical
experience.
Prostate-specic antigen: PSA is a 34-kDa serine protease pro-
duced by acinar and ductal prostatic epithelium. In health, a
blood:prostate barrier prevents PSA entering the peripheral cir-
culation. Disruption of this barrier through benign, inamma-
tory, traumatic or malignant conditions allows PSA to enter the
bloodstream. As such, serum PSA concentrations alter with age,
benign prostatic enlargement and prostate cancer (related to the
amount in the gland or disseminated elsewhere). PSA was rst
characterized in the early 1970s, and its physiological function is
to prevent coagulation of seminal uid. Serum PSA measurement
is well established as a diagnostic and therapeutic test for the
detection of prostate cancer and in the follow-up of patients with
the disease or who have had radical treatment. However, PSA is
prostate specic and not cancer specic; there are many reasons
that a man may have a raised PSA, such as urinary tract infec-
tion, prostatitis, benign prostatic enlargement etc. and so this test
although very sensitive is not specic enough to have been used
widely as a screening test in the UK. At a PSA level of 4 ng/ml the
test has a specicity of approximately 92% and a sensitivity of
approximately 44%. Age-specic PSA cut-offs improve the
sensitivity in younger men and the specicity of the test in older
men. There is no absolute cut-off for PSA where prostate cancer
cannot be diagnosed, however under 1 ng/ml prostate cancer is
very unlikely.
Prostate biopsy: TRUS is the most commonly used imaging
modality for visualizing the prostate. It allows measurement of
gland volume and targeting for biopsy. The endorectal probe
has two transducers with a frequency of approximately 7 MHz
that allow multiplanar imaging. Periprostatic local anaesthetic
is usually used to reduce pain and antibiotic prophylaxis used
to reduce sepsis. Biopsies are obtained using a spring loaded
gun utilizing an 18-gauge Tru-cut

style needle. Biopsies are


targeted to suspicious lesions and the peripheral zone (10e12
throughout the periphery of the gland). TRUS biopsy carries a
risk of bleeding and infection. The latter is becoming more
problematic with the rise in antibiotic-resistant bacteria and has
led a move to trans-perineal biopsy.
Pathology of prostate cancer
Most (>95%) prostate cancers are adenocarcinomas arising
from the prostatic epithelium in the peripheral zone (75%).
These are made of epithelial cells with varying degrees of
glandular architecture without a basal layer (a critical diag-
nostic feature of prostatic cancer; the basal layer may be
detected immunohistochemically using antibodies against high-
molecular-weight cytokeratin). The accepted standard grading
system for prostatic adenocarcinoma is that developed by
Gleason and is based on the degree of architectural (rather than
cellular) differentiation (Figures 1 and 2). The classication
uses ve growth patterns (1e5) to dene tumour differentiation
(although patterns 1 and 2 are no longer classied as cancer on
biopsy) from the most and second most common patterns. As
the Gleason score increases so the degree of glandular differ-
entiation reduces. In Gleason pattern 5 the tissue does not
resemble glands and can be akin to sheets of undifferentiated
cells. The dominant pattern is the primary pattern and then the
next most common is the secondary pattern. The Gleason score
is the sum of these two patterns, e.g. 3 4 7 (with the
dominant pattern shown rst), however if Gleason pattern 5 is
seen this will also be noted in the pathology report.
Staging
Staging is performed using DRE (indication of local T stage), an
MRI scan (pelvic and abdominal for nodal metastasis) and a bone
Figure 1 Haematoxylin and eosin stained section showing Gleason score 3
prostate adenocarcinoma.
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scan, bone scans utilize metastable technetium-99 attached to a
bisphosphonate to visualize areas of increased osteoblastic ac-
tivity within the bone. The latter may be augmented with plain
radiographs for suspicious areas. Final denitive staging will be
available if the patient undergoes radical prostatectomy with
lymph node dissection. Staging is described using the latest
tumour/node/metastasis (TNM) classication (Table 1).
Screening
In the UK there are no screening programmes for prostate cancer.
This is due to controversy regarding the benets of screening and
economic factors. There have been two large randomized
controlled trials (RCTs) of prostate cancer screening reported.
The largest (ERSPC: European Randomized Screening for Pros-
tate Cancer) and most robust found that PSA-based population
screening (and radical treatment of cases) reduces prostate can-
cer and overall mortality within a population, but at the expense
of overdetection (diagnosis of a cancer that would never have
become apparent within that patients lifetime) and overtreatment
(treatment of an overdetected cancer) for many men (between 24
and 48 men need treatment to prevent one death from prostate
cancer).
2
Regional components of the ERSPC study with longer
follow-up and screening of younger men have suggested that the
numbers needed to treat will drop (to nearer 12 men) with longer
maturation of the trial.
3
In contrast, a North American screening
RCT failed to show a benet of PSA-based population screening
for prostate cancer (the PLCO trial: Prostate, Lung, Colon and
Ovarian). This study was smaller than the ERSPC and was
heavily contaminated (many of the men in the non-screen arm
had PSA testing and had had a PSA test or biopsy before trial
entry).
4
Regardless of this controversy, the benets from
screening are greatest to men with a long life expectancy and
little co-morbidity.
Prevention of prostate cancer
There is interest in chemoprevention of prostate cancer as this
offers a low-morbidity opportunity to reduce the incidence of a
common disease found in elderly men. Of the many compounds
that have been tested, 5-a-reductase inhibitors (5-ARIs) appear
most promising. 5-a-reductase is the enzyme responsible for the
conversionof testosterone tothe more potent dihydrotestosterone.
The prostate cancer prevention trial (PCPT)
5
was the rst RCT of
prostate cancer prevention. Men were randomized to nasteride 5
mg/day, a type 2 5-ARI, or placebo. Prostate cancer was detectedin
18.4% of men in the nasteride arm compared with 24.4% in the
control arm. However tumours of a Gleasongrade 7e10 were more
common in the nasteride group and it is this nding that has
prevented the widespread use of nasteride for prostate cancer
prevention. The Reduction by Dutasteride of Prostate Cancer
Events (REDUCE) trial
7
evaluated dutasteride (a type1 and 2 5-
ARI) and the presence of prostate cancer in biopsies at 24 and 48
months. The study found dutasteride reduced prostate cancer risk
by 5.1%but with increases in high-grade tumours in years 3 and 4
of the trial.
Figure 2 Haematoxylin and eosin stained section showing Gleason score 5
prostate adenocarcinoma.
The UICC 7th edition (2009) tumour/node/metastasis
(TNM) classication is used for staging
6
T-primary tumour
Tx Primary tumour cannot be assessed
T0 No evidence of primary tumour
T1 Clinically unapparent tumour not palpable or
visible by imaging
T1a Tumour incidental histological nding in 5% or
less of tissue resected
T1b Tumour incidental histological nding in more
than 5% of tissue resected
T1c Tumour identied by needle biopsy (e.g.
because of elevated PSA level)
T2 Tumour conned to the prostate
T2a Tumour involves one half of one lobe or less
T2b Tumour involves more than half of one lobe,
but not both lobes
T2c Tumour involves both lobes
T3 Tumour extends through the prostatic capsule
T3a Extra-capsular extension (unilateral or
bilateral)
T3b Tumour invades seminal vesicle(s)
T4 Tumour is xed or invades adjacent structures
other than seminal vesicles: external
sphincter, rectum, levator ani and/or pelvic
wall
N e regional lymph nodes
NX Regional lymph nodes cannot be assessed
N0 No regional lymph node metastasis
N1 Regional lymph node metastasis
M e distant metastasis
M0 No distant metastasis
M1 distant metastasis
M1a Non-regional lymph node(s)
M1b Bone(s)
M1c Other site(s)
UICC, The Union for International Cancer Control.
Table 1
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Management of prostate cancer
The management of the disease is directed towards its differen-
tiation, stage and patient co-morbidity. Radical treatments have
the highest rates of side effects and should be used in men with
sufcient life expectancy to benet and sufciently aggressive
disease to need treatment.
Locally conned disease
Active surveillance: screening and the early detection of prostate
cancer lead to the diagnosis of many prostate cancers that are
insignicant to the patient. One way to mitigate the risk of this over
diagnosis is to offer low-morbidity treatments to men with low-risk
disease. The best evaluated of these is active surveillance. Suitable
tumours include those with Gleasonscore 3 3 6 or 3 4 7 (or
better) differentiation, witha PSAless than10ng/ml, tumour that is
impalpable or in less than half of one lobe (T1c-T2a), in only one or
twopositive cores onbiopsy, less than50%involvement inanyone
core and PSA density less than 0.15. Active surveillance means
deferring radical treatment until there is either evidence of wors-
ening disease on biopsy or MRI, a rising PSA or patient choice to
change treatment. Active surveillance is different to watchful
waiting which is used for older co-morbid men who are monitored
until they develop symptoms of advanced or metastatic disease at
which point they will receive ADT. Men undergoing active sur-
veillance must be prepared to undergo stringent follow-up, with
3-monthly PSAs and re-biopsy at approximately 1 year and then
every 3 years thereafter unless PSA or DRE dictates otherwise.
External beam radiotherapy (EBRT)/brachytherapy: external
beam radiotherapy uses focussed beams of gamma radiation
directed at the prostate (typical doses of 76e80 Gy are used). To
reduce irradiation to the surrounding structures three-dimensional
(3D) conformal radiotherapy and intensity-modulated radiotherapy
(IMRT) have been developed. Side effects of radiotherapy include
toxicity to surrounding structures such as bladder or rectum,
erectile dysfunction, the onset of which can take in the order of a
year to manifest, urethral stricture and urinary incontinence. Pa-
tients undergoing EBRT often receive androgen deprivation therapy
prior to their radiotherapy and for some time afterwards as there is
evidence that this improves outcomes. Brachytherapy is performed
utilizing radioactive sources that are implanted within the prostate
as either seeds or needles. There are long-term concerns regarding
radiotherapy, as one in 70 men will develop secondary malig-
nancies, particularly bladder and rectal tumours.
Radical prostatectomy (Figure 3): radical prostatectomy is
mostly performed via a retropubic approach using either open
(ORP), laparoscopic (LRP) or robot-assisted (RARP) techniques.
For each, a similar surgical procedure is performed and therefore,
similar side effects are seen. The oncological outcomes appear
similar for each, although RARP appears to have a faster return
of continence and lower positive margin rates but is more
expensive. Lymphadenectomy is hardest with LRP. Blood loss
and transfusion rates are lowest with RARP and LRP. A minority
of procedures are performed via a perineal approach, which does
not allow a simultaneous pelvic lymphadenectomy. Patients
undergoing radical prostatectomy typically stay in hospital 1e3
days postoperatively.
Outcomes from prostatectomy are measured both functionally
and oncologically. Functional outcomes include continence and
potency, both of which are measures of good surgical technique.
Post-prostatectomy incontinence occurs in approximately 5e10%
of men in the long term; it is more common in older men than
younger menandtypically improves over the rst year particularly
with the help of pelvic oor exercises. Signicant incontinence
affecting quality of life and requiring several pads or changes of
clothes each day can be treated by implantation of an articial
urinary sphincter or insome centres by insertionof a sling (<2%of
men). Potency post-prostatectomy is related to the age of the pa-
tient and their potency preoperatively, as well as whether the
cavernosal nerves that innervate the erectile tissue and run over
the prostate have been spared. Post-prostatectomy impotence
can be treated initially by a phosphodiesterase-5 inhibitor either
on demand or daily dosing, whichever is more suitable to the pa-
tients needs, vacuum devices and injectables are also commonly
used.
Trials of radical prostatectomy versus observation for localized
prostate cancer have beencontradictory. The SPCG-4 trial, showed
that radical prostatectomy reduced the risk of death from prostate
cancer by 6%at 15 years. The number needed to treat to avert one
death was 15, however in men under 65 years the number needed
to treat was even lower at 7.
8
A further study, the Prostate Cancer
InterventionVersus ObservationTrial (PIVOT),
9
foundthat inmen
diagnosed in the PSAera, radical prostatectomy did not reduce the
mortality from prostate cancer. The former RCT recruited prior to
the onset of screening era frommales in Scandinavia and the latter
in the USA after several years of PSA-based screening. Conse-
quently, cases in PIVOT were more likely to be indolent cancers in
nature (explaining the loss of difference between the arms).
Minimally invasive focal therapies: recently there has been
growing interest in minimally invasive therapies for organ-
conned prostate cancer. These offer a middle ground between
active surveillance and radical treatment for men with low-risk
cancers whom psychologically do not like surveillance. High-
intensity focussed ultrasound (HIFU) appears to be most attrac-
tive currently. HIFU utilizes ultrasonic energy to heat and destroy
targeted tissues (causing necrosis and cavitation). Although
short-term biochemical outcomes appear promising, long-term
Figure 3 Radical prostatectomy specimen.
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follow-up and RCTs are required to evaluate the oncological
safety of HIFU. Cryotherapy is another treatment modality for
organ-conned disease. This uses the localized destruction of
tissue by extreme low temperatures and thawing. Again RCTs
and long-term follow-up are lacking thus far and patients should
be advised of this when discussing it as a treatment option. At the
current time the National Institute for Health and Care Excellence
(NICE) guidelines do not recommend HIFU or cryotherapy for the
treatment of prostate cancer outside of clinically trials due to the
paucity of good-quality trial data and long-term follow-up.
Locally advanced disease
Many men may be detected with or develop (under surveillance)
tumours that invade the prostatic capsule (pT3a) or seminal
vesicles (pT3b). These are termed locally advanced tumours and
may identied by DRE (palpable T3 disease), PSA (>20 ng/ml)
or biopsy ndings (lots of cores involved, long lengths of cancer
in each core, high-grade cancer (Gleason 8e10)). Men with
locally advanced cancers are at higher risk of death from prostate
cancer (than those with pT1-2) and so require treatment if they
have sufcient life expectancy. These tumors are at risk of me-
tastases and so locally advanced cancers need accurate staging
before treatment (pelvic and abdominal MRI, and bone scan) to
rule out metastases. It is generally accepted that multimodal
treatment are needed in many men with locally advanced cancers
for cure or control. Currently, the options vary between radical
surgery followed by adjuvant radiotherapy versus neo-adjuvant
ADT (starting 3 months) before radical radiotherapy. The latter
has been shown to be better than radiotherapy alone in RCTs,
10
and men remain under ADT for 6e36 months depending upon
tumour risk and desire for potency. HIFU and cryotherapy are
again not NICE approved for use in this setting. Anti-androgens
such as bicalutamide can be used as monotherapy in locally
advanced disease in men with co-morbidity or wishing to avoid
radical treatment.
Metastatic disease
Metastatic disease mayinvolve spreadtothe lymphnodes, bones or
(less commonly) other organs (Figures 4 and 5). Androgen depri-
vationtreatment is the mainstayof treatment for metastatic prostate
cancer. Methods of hormonal manipulation include bilateral
orchidectomy, oestrogens, luteinizinghormone-releasing hormone
(LHRH) agonists and synthetic anti-androgens. Bilateral orchid-
ectomy is a small operative procedure that can be performed under
local anaesthetic, but men often nd it unacceptable and therefore
medical hormonal manipulation is most popular. Oestrogens have
fallen out of favour due to the high cardiovascular risks associated
with them. LHRH agonists are the most common form of hormone
treatment in this circumstance and have been in use since 1990.
LHRH agonists occupy the receptors of LHRH in the pituitary,
initially stimulating the release of LH; however the effect is so
potent that there is down-regulation of LHRH receptors and so
subsequently a reduction in LHrelease. Commonly LHRH agonists
are given as injections either monthly or 3-monthly; however there
is a move towards implants that will last for up to a year. Androgen
deprivation therapy is associated with signicant side effects and
has implications for quality of life. Side effects include sexual
dysfunction, fatigue, hot ushes, change in body composition,
cognitive dysfunction and mood disorders. Long-term sequelae
include osteoporosis, anaemia and metabolic syndrome which in-
cludes abdominal obesity and insulin resistance. Androgen depri-
vation therapy is associated with an increase in diabetes mellitus,
Figure 4 Tc-99m bone scan showing widespread bone metastases
particularly in the spine as well as a left hydronephrosis secondary to
bladder outlet obstruction.
Figure 5 Magnetic resonance imaging T2 weighted scan showing wide-
spread bone metastases from metastatic prostate cancer.
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ischaemic heart disease, myocardial infarction, sudden cardiac
death and stroke.
It is postulated that intermittent androgen deprivation may
allow men with locally advanced and metastatic disease to have
improved quality of life and less side effects but with no adverse
impact on overall survival. There is also the theoretical possi-
bility of delaying hormone resistance. Intermittent androgen
deprivation allows the patient to alternate between androgen
blockade and treatment cessation which will allow hormonal
recovery during the periods between treatments. Treatment is
initially continued until PSA reaches a nadir and then dis-
continued. PSA is monitored and then hormonal manipulation
recommenced once the PSA rises to a pre-determined level.
Intermittent androgen deprivation therapy appears to offer non-
inferior survival, fewer side effects, better quality of life and
possible savings to the healthcare system.
There has been interest in the development of LHRH antag-
onists for the treatment of prostate cancer. LHRH antagonists
have several advantages over LHRH agonists, they reduce
testosterone and PSA levels quicker, and there is no initial
stimulation and so no need for anti-androgen treatment to
prevent tumour are at the start of androgen deprivation
therapy.
Non-steroidal androgen receptor antagonists (e.g. bicaluta-
mide) are used as second-line therapy in addition to LHRH ag-
onists (maximal androgen blockade), but there is little survival
advantage in this, approximately 2e3% at 5 years.
11
Not all men will respond to androgen deprivation therapy,
and approximately 15% will not respond to treatment. A large
proportion of men who initially respond will then go on within
2e3 years to have castration-resistant prostate cancer. Para-
doxically castration-resistant prostate cancer often remains
responsive to other hormonal treatments, therefore patients are
often treated with secondary hormonal therapies that deplete
androgen concentrations further or bind/inhibit the androgen
receptor.
Castrate resistant prostate cancer
Castrate resistant prostate cancer (CRPC) is dened as prostate
cancer that has progressed despite castrate levels of testosterone
(less than 50 ng/ml). In metastatic disease often a rising PSA will
predate symptomatic progression of metastases. Docetaxel is
currently rst-line treatment for men with metastatic CRPC
(mCRPC), and has been shown to prolong survival by a few
months. The eld of CRPC is changing rapidly and many new
compounds are available or becoming available.
In chemotherapy na ve patients both abiraterone acetate and
sipuleucel-T have both been shown to improve overall survival.
Abiraterone acetate is a potent and irreversible inhibitor of
CYP17A1. Abiraterone has been used in chemotherapy naive
castration-resistant prostate cancer patients and has been shown
to improve overall survival and radiographic progression free
survival.
12
Sipuleucel-T (Provenge) T is an immunotherapy
comprised of autologous peripheral-blood mononuclear cells;
this vaccine has been shown to improve overall survival by
several months.
Second-line systemic therapy for those patients who have
failed docetaxel chemotherapy includes carbazitaxel, abiraterone
acetate as well as enzalutamide a novel androgen receptor sig-
nalling inhibitor.
Bone-targeted therapies for metastatic prostate cancer
Current bone-targeted therapies broadly fall into two groups. The
rst is anti-resorptive agents, which target the osteoclast, and
include zoledronic acid which is a nitrogen-containing
bisphosphonate, and denosumab which is a receptor activator of
nuclear factor-kappaB ligand (RANKL) inhibitor. Both of these
can both be used to prevent skeletal related events or to treat
bone pain in metastatic disease. The second group is radio-
pharmaceuticals; these include the b particle-emitting samarium-
153 and strontium-89 and also the alpha-emitting radium-223
chloride.
Complications of metastatic disease
Bone metastases can lead to several complications; these include
pain, hypocalcaemia of malignancy, bone marrow inltration,
skeletal related events and spinal cord compression. Metastatic
destruction of bone reduces its load-bearing abilities and pre-
disposes to fracture; the most frequent fractures are rib fractures
and vertebral collapses. Fractures of long bones and epidural
extension of tumour into the spine causing cord compression is
the most disabling. Long bone metastases are best treated pro-
phylactically, that is, before they fracture, with internal xation
followed by radiotherapy, to inhibit further tumour growth and
bone destruction. For the majority of metastatic prostate cancer
patients, external beam radiotherapy provides excellent pallia-
tion of localized metastatic bone pain.
Spinal cord compression can be a devastating complication of
metastatic bone disease. The development of back pain in a pa-
tient with prostate cancer, particularly if they are known to have
advanced disease, should alert their treating physician to inves-
tigate them further, to pre-empt cord compression occurring. The
development of neurological symptoms, especially bladder and
bowel symptoms merits an urgent MRI scan. The key to a good
outcome from the treatment of acute spinal cord compression is
early diagnosis, high-dose corticosteroids, and urgent surgical
decompression or radiotherapy.
Conclusions
Prostate cancer is a common malignancy particularly in older
men. Screening for prostate cancer is at present controversial;
however it is likely that younger men with little co-morbidity are
those that will benet most from PSA screening. Men with organ-
conned prostate cancer have several treatment options available
to them. These include active surveillance for low-risk prostate
cancer, radical prostatectomy and radiotherapy, either external
beam or brachytherapy. Locally advanced prostate cancer can be
treated by radical surgery with subsequent radiotherapy or
radiotherapy with ADT. Locally advanced and metastatic prostate
cancer can both be treated with ADT alone, but due to side effects
and quality of life issues there has been much interest in inter-
mittent ADT. The treatment of metastatic prostate cancer is a fast-
changing eld at the present time. New treatments are becoming
available all the time and there is much more to offer the man
with castrate-resistant prostate cancer than ever before. A
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FURTHER READING
Reynard J, Brewster S, Biers S. Oxford handbook of urology. 3rd ed.
Oxford University Press, 2013.
Wein AJ, Kavoussi LR, Novick AC, Partin AW, Peters CA. CampbelleWash
urology. 10th ed. Saunders, 2011.
RENAL AND UROLOGICAL SURGERY II
SURGERY 31:10 522 2013 Published by Elsevier Ltd.