CancerStats Prostate cancer – UK

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CancerStats
Prostate cancer – UK
September 2008
Introduction
Prostate cancer is the most common cancer in men in the UKa, accounting for nearly a quarter of all new male cancer diagnoses. Although there
has been a huge rise in prostate cancer incidence over the last 30 years, this has not been reflected in the mortality rates. Much of the increase
in incidence is due to the incidental discovery of prostate cancer following transurethral resection of the prostate (TURP) and, more recently, the
use of prostate specific antigen (PSA) testing.
Table One: Number of new cases and rates of prostate cancer, UK by country, 2005
Number of new cases
Crude rate per 100,000
European age-standardised
rate per 100,000 (95% CI)
England
Wales
Scotland
28,886
117.1
2,249
155.9
2,420
98.5
95.2
113.3
(94.1-96.3)
79.6
(108.6-117.9)
N. Ireland
UK
747
89.0
(76.4-82.9)
85.7
34,302
116.7
(79.5-91.8)
94.6
(93.6-95.6)
Incidence
In 2005, there were 34,302 new cases of
prostate cancer diagnosed in the UK, that is,
around 90 men every day or one man every
15 minutes. Table One shows the numbers and
rates of new cases in the UK and its
constituent countries.1
Figure One: Number of new cases and rates of prostate cancer, by age, UK, 2005
8,000
900
7,000
800
700
600
Cases
5,000
Rates
500
4,000
400
3,000
Rate per 100,000
Number of new cases
6,000
300
2,000
200
1,000
100
Incidence rates increase steeply with age and
the highest rates occur in the oldest age
groups. For men aged 55–59 the incidence rate
per 100,000 is 143; ten years later, at age
65–69, the rate more than triples to 489 per
100,000 and by 85+ the rate is more than five
times higher at 783 per 100,000.
85+
80-84
75-79
70-74
65-69
60-64
55-59
50-54
45-49
40-44
35-39
30-34
25-29
20-24
15-19
10-14
5-9
0
0-4
0
Age
Prostate cancer risk is strongly related to age:
very few cases are registered in men under 50
and three-quarters of cases occur in men over
65 years. The largest number of cases is
diagnosed in those aged 70–74 (Figure One).1
Age at diagnosis
Figure Two: Age-standardised* incidence and mortality rates for prostate cancer by world
regions, 2002 estimates
Northern America
Australia/New Zealand
Western Europe
Northern Europe
Caribbean
It is estimated from post-mortem data, that
around half of all men in their fifties have
histological evidence of cancer in the prostate,
which rises to 80% by age 80, but only 1 in 26
men (3.8%) will die from this disease.2, 3 In
other words, men are more likely to die with
prostate cancer than from it – an important
fact when considering population screening of
asymptomatic men.4, 5
Histology
Nearly all prostate cancers are
adenocarcinomas, mainly occurring in the
peripheral zone of the prostate gland.4
South America
Southern Africa
Southern Europe
Central America
World
Deprivation
Deprivation incidence gradients have been
reported for both England & Wales and
Scotland, with higher rates in the least deprived
populations.6-8 These deprivation gradients have
widened during the 1990s due to the greater
relative increase in incidence for men in the
most affluent groups and are likely to be
influenced by accessibility and uptake of PSA
testing.8
Middle Africa
Western Africa
Incidence
Eastern Europe
Mortality
Eastern Africa
Western Asia
South-Eastern Asia
Northern Africa
South Central Asia
Eastern Asia
0
20
40
60
80
Rate per 100,000
© Cancer Research UK 2008
Registered charity number 1089464
100
120
140
*to World Standard Population
a Excluding non-melanoma skin cancer
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Geographic variation
Worldwide, an estimated 670,000 men were
diagnosed with prostate cancer in 2002,
accounting for 1 in 9 of all new cancers in
males.9 Unlike the UK, it is the second most
common cancer in men after lung cancer
worldwide. Recent incidence rates are heavily
influenced by the availability of PSA testing in the
population and incidence varies far more than
mortality. Three-quarters of all new cases are
diagnosed in the developed world with the
highest rates occurring in North America
(specifically the USA) and the lowest rates in
Asian countries (Figure Two).9 One reason for
the extremely high incidence rate in the USA is
the frequent use of PSA testing in that country.10
Within the USA there are also significant
differences between racial groups. Incidence
ratesb for black Americans are more than 50%
higher than for white Americans, while rates for
Asian Americans are 40% lower than for white
Americans.11
An estimated 301,500 cases were diagnosed in
the 25 member countries of the EU (EU25) in
2006.12 The lowest European rates are in
southern and eastern Europe, and the highest
are found in northern and western Europe
(Figure Three).12
page 2 of 10
Figure Three: Estimated age-standardised* incidence and mortality rates for prostate cancer,
selected EU countries, 2006 estimates
Belgium
Sweden
Austria
France
Germany
Italy
UK
EU
Portugal
Netherlands
Hungary
Greece
Denmark
Incidence
Spain
Mortality
Czech Republic
Slovakia
Poland
Bulgaria
Romania
0
50
100
Rate per 100,000
150
200
*to European Standard Population
Figure Four: Age-standardised* incidence and mortality rates for prostate cancer,
Great Britain, 1975–2006
120
Time trends for a longer period (1975–2005) are
shown in Figure Four for Great Britainc, when
the European age-standardised rates almost
trebled from 32 per 100,000 in 1975 to 95 per
100,000 in 2005.1 During the late 1970s and
1980s rates rose consistently, with an acceleration
of the trend in the early 1990s followed by a
brief levelling off in the mid-1990s and another
rising trend in the late 1990s. Incidence trends by
age group show a similar pattern but with a fall in
the 85+ rate, beginning in the mid-1990s and
then steeply since 2001 (Figure Five).1 Between
1975 and 2005 the number of cases in Great
Britain more than quadrupled from 8,042 in
1975 to 33,555 in 2005.15
Rate per 100,000
Incidence
Mortality
80
60
40
20
Year of diagnosis/death
2006
2005
*to European Standard Population
Figure Five: Age-specific incidence rates for prostate cancer, Great Britain, 1975–2005
1,400
1,200
85+
75-84
65-74
55-64
45-54
1,000
800
600
400
200
b In 2001-2005 the age-standardised (to the 2000 US Standard Population)
incidence rate was 249 per 100,000 for black men, 157 per 100,000 for
white men and 93.8 per 100,000 for Asian men11
c Northern Ireland data is not available before 1993
Registered charity number 1089464
1975
1976
1977
1978
1979
1980
1981
1982
1983
1984
1985
1986
1987
1988
1989
1990
1991
1992
1993
1994
1995
1996
1997
1998
1999
2000
2001
2002
2003
2004
2005
0
© Cancer Research UK 2008
2004
2003
2002
2001
2000
1999
1998
1997
1996
1995
1994
1993
1992
1991
1990
1989
1988
1987
1986
1985
1984
1983
1982
1981
1980
1979
1978
1977
1976
0
1975
Trends
Substantial increases in incidence have been
reported in recent years for many countries
around the world, including the UK.14 During
the last ten years in the UK, European agestandardised rates have increased by a third
from 71 per 100,000 in 1996 to 95 per
100,000 in 2005 while the numbers of cases
rose from 23,682 in 1996 to 34,302 in 2005,
an increase of 45%.
100
Rate per 100,000
A recent analysis of prostate cancer incidence
and mortality within the UK and Ireland
showed relatively little geographical variation.
The availability and uptake of PSA testing
across the country may have obscured the
underlying variation in incidence.13
Year of diagnosis
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Figure Six: Age-standardised* rates of transurethral resection of the prostate (TURP) and
crude rates of PSA testing, Scotland, 1981–1996
1,000
12,000
900
TURP
800
PSA
10,000
700
8,000
600
500
6,000
400
4,000
300
200
2,000
PSA testing rate per 100,000
TURP rate per 100,000
An analysis of prostate cancer incidence trends
in Scotland concluded that much of the apparent
increase between 1981–1996 was caused by
increased detection: before 1989 through
increasing rates of TURPd16 and afterwards
through the rising use of PSA testing (Figure
Six).17 Analyses for other countries including the
USA18, 19 and Australia20 have also pointed to
increased detection being a factor. In the USA
widespread PSA testing on asymptomatic men
from around 1986 resulted in dramatic increases
in incidence (an 82% rise between 1986 and
1991)19 and it is estimated that more than half of
US white men aged over 50 have had their PSA
level tested.10 In western Europe the widespread
use of PSA tests began a few years later, in
around 1989–1990, but the level of population
screening is much lower than in the USA.21 In the
UK it is estimated that between 5–6% of men
over 40 have a PSA test each year.22, 23
page 3 of 10
100
0
0
1981 1982 1983 1984 1985 1986 1987 1988 1989 1990 1991 1992 1993 1994 1995 1996
*to
European
Standard
Population
Year
review of the evidence concluded that foods
containing lycopenes and selenium probably
have a protective effect while diets high in
A strong family history of breast cancer may also calcium may increase risk.38
affect a man’s risk of prostate cancer, particularly
if the family members were diagnosed under the Lycopene
Lycopene, found principally in tomatoes and
Risk factors
age of 60. In particular, germline mutations in
tomato-based products, may reduce the risk of
No modifiable risk factor for prostate cancer
the breast cancer susceptibility genes, BRCA1
prostate cancer. Cooked and processed
has been identified and therefore, at present,
and BRCA2, can predispose men to prostate
tomatoes, such as tomato sauce, are a better
there is insufficient evidence on which to base cancer (for more detail see Molecular biology
source of lycopene than fresh tomatoes. A
a prevention strategy. The established risk
and genetics section).
meta-analysis of 21 studies published from
factors are age, family history and ethnicity.
Many other factors have been studied but the
Recently, genome-wide association studies have 1966–2003, showed that men with the highest
intake of cooked tomato products had a 20%
evidence is inconclusive. One reason for this
identified several genetic variants that each
reduced risk of prostate cancer compared to
may be that different factors are involved in the slightly increase prostate cancer risk.29-33
men with the lowest intake.39 Since then, three
development and promotion of aggressive
However, because such genetic variants are
studies including the European Investigation
disease compared to non-aggressive disease,
common in the population, they may
into Cancer and Nutrition (EPIC)f study40-42 have
making epidemiological studies of prostate
contribute to a significant proportion of all
24
cancer particularly complex. Interpretation of prostate cancer cases. Current research in this shown a significant protective effect with higher
intake of lycopene, although three other studies
risk factors has been further complicated in the area is likely to identify further variants in the
showed no association.43-45
PSA era, when identification of many prostate
next few years. Genetic profiling is being used
cancers is dependent on a threshold PSA level, to inform prostate cancer screening and
Selenium
which in turn is affected by other exposures
treatment.
Several studies have shown a protective
such as body mass. This blurs the distinction
association for selenium, reporting a 30–80%
between ‘cases’ and ‘controls’ leading to the
Ethnicity
risk reduction for prostate cancer.46-48 However,
possibility of PSA-detection bias.25
Variation in incidence rates around the world
and within countries, suggests that risk is affected at least three studies showed no association.49-51
Age (see also Incidence section)
by ethnicity. In the UK, black Caribbean and black Further research is needed and the Selenium
and Vitamin E Cancer Prevention Trial (SELECT)
The strongest known risk factor is age, with
African men have approximately two to three
very low risk in men under 50 and rising risk
times the risk of being diagnosed or dying from may provide much needed answers.52
with increasing age thereafter (Figure One).
prostate cancer than white men, while Asian
Calcium and dairy products
The older the man, the higher the risk and this men generallye have a lower risk than the
Some cohort studies have shown a raised risk
ties in with post-mortem results where
national average.34-36 These results echo those
approximately 80% of men by age 80 were
from the USA where black American men have of prostate cancer for men with high intakes of
calcium from diet and/or supplementation53-56
shown to have cancer cells in their prostate.2
higher rates than white American men and
indeed the highest recorded in the world, while but others have not.57-59 Dairy products, as a
source of calcium, have been extensively
Family history (see also Molecular biology and
Asian American men have much lower rates.
genetics section)
However, migration studies show an increase in studied in relation to prostate cancer. Several
cohort studies show a small significant increase
A family history of prostate cancer is one of
risk as men move from low-risk to higher-risk
the strongest known risk factors for this
countries, suggesting that lifestyle factors play an in risk but findings differ by whether it affects
advanced or localised tumours.56-58, 60, 61 The EPIC
disease. It has been estimated that 5–10% of all important role. For example, South Asian men
study showed overall a 32% increased risk for
prostate cancer cases and 30–40% of earlyliving in the UK have a higher risk of prostate
35g/day higher intake of dairy protein and a 7%
onset cases (men diagnosed <55 years) are
cancer than men living in South Asia.37
26, 27
risk increase for an 0.3g/day intake of dairy
caused by inherited susceptibility genes.
calcium. Protein and calcium from non-dairy
Diet
sources were not associated with risk.62
Risk increases two to three times for men with Diet has been extensively researched because
a first-degree relative diagnosed with prostate
of the large variation in prostate cancer
d TURP is a standard surgical procedure for benign prostatic enlargement, a
cancer.28 If the relative is <60 years old at
incidence between different cultures and their
very common non-cancerous condition in older men. Prostate cancer was
an incidental finding in the tissue removed by TURP in around 10% of
diagnosis or more than one relative is affected traditional diets around the world, particularly
men16
(at any age), the individual’s risk is four times
the Asian versus ‘western’ diet. A variety of
e A study in South East England recorded increased risk for Indian and
Pakistani men and a decreased risk for Chinese and Bangladeshi men when
the average. These factors combine so that if
factors have been looked at but much of the
compared to ‘All White’ men34
more than one relative is affected by earlyresearch is at present inconclusive. A recent
f EPIC is a prospective study of diet and health involving over half a million
onset prostate cancer, the risk is increased by
seven-fold.27
people in ten European countries
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Fat and meat
Extensive research into fat intake has been
inconclusive. One difficulty is measurement of
the different types of fat intake including
saturated and unsaturated fat as well as fatty
acids such as α-linolenic acidg, an omega-3
polyunsaturated fatty acid. A recent large
multi-ethnic cohort study found no increase in
prostate cancer for any source of fat and
therefore did not support earlier studies that
showed a raised risk.63 Further studies are
needed, especially as α-linolenic acid may
protect against cardiovascular disease and
therefore its role for prostate cancer needs to
be clarified.64
dayk.75 Findings since these meta-analyses have
been inconsistent.
page 4 of 10
2005 meta-analysis reporting a 40% increased
risk of prostate cancer in men with a history of
gonorrhoea, and a 50% increased risk with
human papilloma virus infection.94 However,
increased detection or recall bias may have
influenced the result. Since then a large cohort
study found no such association.95
A higher risk of fatal prostate cancer in
smokers compared to non-smokers has been
shown in some studies.76-77 However, no clear
trends were shown with number of cigarettes
smoked per day or between current, ex- and
never-smokers. Two large studies concluded
Endogenous hormones
that smoking is not likely to be linked to either It has long been suggested that high circulating
the incidence or mortality of prostate cancer.78, 79 levels of sex hormones are associated with an
increased risk of prostate cancer as most
prostate cancers respond favourably to
Bodyweight and physical activity
androgen-deprivation and castrated men do not
Obesity is a major health problem in the UK
and has been linked to several major cancers.80, 81 develop prostate cancer.96 However, the most
recent worldwide re-analysis of 18 prospective
However, it is not yet proven to be an
studies, including the EPIC study,97 has shown no
important risk factor for prostate cancer. A
Meat intake, particularly red and processed
meath, has been studied in relation to prostate recent meta-analysis reported a small
association between endogenous sex hormones
borderline significant increase in prostate cancer and risk of prostate cancer overall.98
cancer but findings are inconsistent.
risk with increasing body mass index (BMI).82
Fruit and vegetables
Some cohort studies indicate that obese men
Insulin-like growth factor (IGF-1) is an easily
are at greater risk of dying from prostate cancer measurable protein that is involved in normal
Some studies65-67 have shown a lower risk of
83-85
cell proliferation and death. Both a recent
prostate cancer for men consuming high
while others have reported a reduced risk
quantities of cruciferous vegetables but this was of localised prostate cancer in men with a high meta-analysis and a large Swedish study found
not confirmed in the EPIC study which studied
BMI.86, 87 Although the evidence is far from clear that higher concentrations of IGF-1 were
130,000 men and found no association between for prostate cancer, general health advice would associated with an increased risk of prostate
cancer with a clear dose-response
total fruit and vegetable intake or cruciferous
be for men to maintain a healthy BMI.
relationship.99,100 However, other studies
vegetables and risk of prostate cancer.68
Physical inactivityl88 has been linked to several
including EPIC have shown no association.101-103
serious diseases such as diabetes and heart
Vitamin E, green tea and soy
IGF-1 levels may mediate the effects of many
disease as well as some cancers, particularly
environmental exposures as its levels are
The Alpha-Tocopherol, Beta-Carotene Cancer
regulated by other cancer risk factors such as
Prevention (ATBC) Study in smokers showed a colon cancer, but there is no strong link with
bodyweight, diet and physical exercise. The
32% reduction in risk of prostate cancer in men prostate cancer.81
relationship between several components of
receiving daily alpha-tocopherol (the major
the IGF system and prostate cancer is
form of vitamin E in supplements).69 Other
Medications, medical procedures and infections
studies have shown little or no association.
Non Steroidal Anti-inflammatory Drugs (NSAIDs) undergoing further investigation.104, 105
Further research is underway to clarify the
There is some evidence that aspirin use
equivocal results, in the SELECT trial.52
particularly, may reduce the risk of prostate
Diabetes mellitus
cancer.89 Results from other studies have been
The risk of prostate cancer was significantly
lower, by 16% in the most recent meta-analysis,
Green teai has been studied due to its regular mixed.
among men with diabetes mellitus than among
consumption by Japanese and Chinese men
those without this condition but why this is so
Statins
whose prostate cancer risk is low. Green tea
is not clear.106, 107 A number of possible
contains high level of polyphenols which have
In the laboratory, cholesterol-reducing statins
70
71
anti-oxidant effects. One cohort and one
have shown possible chemopreventive
mechanisms are discussed in the latest metaproperties against cancers. However, a
analysis107 and recent research suggests that
case-control study72 showed a reduced risk of
systematic review of observational studies and
prostate cancer with green tea consumption
there may be a genetic link between diabetes
randomised controlled trials found that statinand a dose-response relationship with the
and prostate cancer.108
quantity drunk, although a third study found no use was not associated with short-term cancer
risk but an association with reduced longer-term Molecular biology and genetics
effect.73 More research into the possible
risk cannot yet be ruled out.90 Further research Research into prostate cancer genetics aims to
chemopreventive properties of green tea is
needed.
improve our understanding of men’s risk of
on the effects of statin-use on prostate cancer
disease and the factors that drive cancer
risk or the course of the disease is needed.91
East Asian diets have higher soy content than
progression. This knowledge has the potential
western diets, for example, with the
to improve diagnosis and guide the
Vasectomy
consumption of tofu, soymilk and miso. As the
development and use of targeted treatments.
A 2002 meta-analysis reported a small
incidence of prostate cancer is lower in these
increased risk of prostate cancer following
countries, soy and isoflavonesj have been
vasectomy, with risk ratios increasing with time Prostate cancer often clusters in families and
studied to see if they are protective factors but since vasectomy, from 1.07 in the first 10 years 5–10% of all prostate cancers may have a
to 1.23 after 30 years.92 However, a subsequent substantial inherited component. Searches for
findings are inconsistent.
high-risk prostate cancer loci have identified the
cohort study showed an association only for
Alcohol and smoking
localised tumours, suggesting an increased
g Sources of α-linolenic acid include nuts, seeds, vegetables oils, green leafy
Two meta-analyses of alcohol consumption and likelihood of detection of early prostate cancer vegetables such as spinach and grass-fed meat such as beef
h Including cured meat, sausages, hamburgers and meat-balls
prostate cancer have been carried out. The
in men who have undergone vasectomy.93
i Obtained from the plant Camellia sinensis
largest study found no association74 whilst the
j Isoflavones are found in a number of plant foods but the main source is
other showed only small risk increases, although Infections
the soy bean. The main soy isoflavones are daidzein and genistein
k One unit contains 8 grams of alcohol
dose-related, of 5%, 9% and 19% with
Sexually-transmitted diseases and prostatitis
l Government recommendations are that people undertake 30 minutes of
consumption of 25, 50 and 100 grams per
may increase the risk of prostate cancer with a moderate or vigorous physical exercise five times a week but only 40% of
men and 28% of women achieved this in 200688
© Cancer Research UK 2008
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familial breast cancer gene BRCA2 as an
important susceptibility factor. Carriers of
germline mutations in BRCA2 have at least five
times greater risk of prostate cancer and
frequently develop a more aggressive form of
the disease.109, 110 The current IMPACT study is
evaluating the benefits of PSA screening in this
high-risk population.111 However, BRCA2
mutations account for only 2% of all early-onset
cases (<55years) indicating that further
susceptibility loci exist.109 Mutations in the BRCA1
gene have a smaller effect, increasing a man’s risk
of prostate cancer by less than two-fold.112
Current evidence indicates that prostate cancer
inheritance is complex with numerous lowerpenetrance gene variants contributing to disease
progression. Several studies highlight ELAC2,
MSR1 and RNASEL as candidate genes for
hereditary prostate cancer.113 MSR1 and RNASEL
encode proteins involved in innate immunity,
which fits well with the recent hypothesis that
inflammation plays a key role in prostate
carcinogenesis.114 The International Consortium
for Prostate Cancer Genetics has also identified
a novel susceptibility locus on chromosome 22.115
Genetic variants common in the wider
population may also contribute to sporadic
cases of prostate cancer. For example, single
nucleotide polymorphisms (SNPs) in the
Androgen Receptor (AR) gene, inflammatoryrelated genes and hormone metabolising genes
have all been linked to increased risk of
disease.116, 117 Strong evidence also links
polymorphisms on chromosomes 8 and 17
with prostate cancer and a combination of five
of these SNPs can increase an individual’s risk
by more than five-fold.118 Three large
international studies have identified a further 10
important prostate cancer susceptibility loci
and highlighted candidate genes within these
regions that may contribute to this disease
including MSMB, KLK3 and LMTK2.29, 31, 119
page 5 of 10
Figure Seven: Diagram of the prostate
Bladder
Prostate
gland
Penis
Urethra
Testis
Table Two: Treatment and management options for men with localised disease
Watchful waiting
Active surveillance
Brachytherapy
Prostatectomy
High dose conformal radiotherapy
Cryotherapy
High intensity focused ultrasound
Low-risk men (PSA <
10ng/ml and Gleason
score <6 and T1-T2a)
Intermediate-risk men
(PSA 10-20ng/ml or
Gleason score 7 or T2b-T2c)
◊
◊
◊
◊
◊
◊
◊
X*
X*
†
X*
X*
◊
X
X
*
*†
X*
X*
(adapted with permission from NICE (2008) CG58. Prostate cancer: diagnosis and treatment. London).
Preferred treatment
X Not recommended
◊ Treatment option
X* Not recommended unless as part of a clinical trial comparing use with established interventions
* Offer if there is a realistic prospect of long term disease control
† neo-adjuvant ± adjuvant hormone therapy (for Gleason score >8) is recommended
frequently underlie the onset of androgenindependent disease that fails to respond to
hormone deprivation strategies. Alterations to
other pathways involving PI3K, ERBB2 and BCL2
are also linked to the transition to hormoneindependence.124, 125
Genetic profiling is likely to become more
important in the future providing valuable
prognostic information and guiding the use of
different treatment options. Patients with two
copies of the TMPRSS2-ERG fusion gene have
been linked with worse prognosis.126 Key genes
such as LMTK2 are also being considered as
targets for novel prostate cancer treatments.
In addition to germline faults, mutations in key
oncogenes and tumour suppressor genes have
been detected in prostate cancer cells per se,
including amplification of MYC and loss of
NKX3.1, TP53, CDKN1B and PTEN.120
Chromosomal translocations have also been
found to fuse 5’ regulatory elements of genes
upstream of ETS transcription factors.121, 122
Epigenetic events such as DNA
hypermethylation affect the expression of several
genes in prostate cancer including GSTP1, a gene
involved in carcinogen detoxification.123 This
alteration occurs in nearly all prostate cancers
and may prove useful as a diagnostic marker.
Symptoms
The prostate gland lies at the base of the
bladder surrounding the upper part of the
urethra (Figure Seven).127 Localised prostate
cancer is often asymptomatic but some
symptoms can arise from enlargement of the
prostate gland. The symptoms for localised
prostate cancer may be the same as those for
benign prostatic enlargement (BPE)m, namely
frequency and difficulty in urinating, and
occasionally blood in the urine. If untreated,
bladder obstruction may eventually occur. Men
with more advanced disease may present with
pain from widespread skeletal metastases,
especially back pain.
Much research is now focussing on the faulty
molecular pathways that contribute to prostate
cancer progression. AR signalling in particular,
plays a crucial role at different stages of the
disease. Overexpression and mutation of the
AR gene can alter both the ligand sensitivity
and specificity of the receptor. These changes
Stage and grade
Tumours are usually staged using the TNM
system.4, 128 In brief, T1 and T2 tumours (‘early
stage’) are confined within the prostatic capsule.
T3 tumours have grown through the prostatic
capsule and are known as ‘locally advanced’. T4
tumours are also regarded as locally advanced,
© Cancer Research UK 2008
High-risk men (PSA
>20ng/ml or Gleason
score 8-10 or T3-T4)
Registered charity number 1089464
assuming spread is confined to lymph nodes or
nearby tissues. The most common site of distant
metastasis is the bones. Tumours are graded
according to the histology of the malignant cells.
The most widely used grading system for
prostate cancer is the Gleason system.129 To
assess the Gleason score, biopsies must be
obtained which are given scores. As prostate
cancer may be histologically heterogeneous a
primary (most common pattern) and secondary
score are given and then added together. It is
now recommended that the worst score is
always included even if present in only a small
proportion of the cancer. Gleason score
effectively ranges from 6–10. Tumour size also
has a bearing on prognosis.
Treatment
Treatment options should be fully discussed
with each patient. Many treatments have serious
side-effects and men need access to evidencebased information in order to make informed
decisions, alongside health professionals.130
Localised disease
There is no consensus on best treatment for
early prostate cancer. Treatment decisions may
be based on the risk of disease progression,
categorised into low, intermediate and high
risk131 (Table Two).130
Low risk early tumours can be monitored with
‘watchful waiting’ or ‘active surveillance’.
Watchful waiting is based on the premise that
many patients are elderly with a relatively short
life expectancy. Their prostate cancer is likely to
progress very slowly, may not cause symptoms
and will not cause their death.
m Also called benign prostatic hyperplasia (BPH)
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Figure Eight: Rates of radical prostatectomy and orchidectomy, England, 1991–2004
(Adapted with permission from Hussain S et al. BJU Int 2008;101(5):547–55)
14
12
Radical prostatectomy All ages
Rate per 100,000
Active surveillance is for low-risk men, suitable
for radical treatment should their disease
progress. If it does not, then over-treatment is
avoided. Monitoring consists of PSA testing,
digital rectal examination (DRE) and repeat
biopsy as necessary - the optimum monitoring
protocol has not been identified.132-134 Radical
treatment is an option, if the patient prefers.
page 6 of 10
10
Orchidectomy All ages
8
6
4
2
A randomised trial comparing radical
prostatectomy and watchful waiting management
for men with clinically localised prostate cancer
predominantly not detected by PSA testing,
reported a statistically significant reduction in
overall mortality and prostate-specific mortality at
12 years for men receiving surgery who were
younger than 65 years.136 There have been no
adequate comparative trials between the
different types of prostatectomy, or between
surgical and radiotherapy approaches. A recent
systematic review of treatments for localised
prostate cancer suggests from cohort studies that
there are likely to be, at most, small differences
between the different radical treatment options.137
Clinical trial entry should always be considered to
help answer treatment uncertainties. The UK
Prostate Testing for Cancer and Treatment
(ProtecT) trial completes recruitment in 2008. It
is evaluating treatment effectiveness (‘active
monitoring’ vs radical surgery vs radiotherapy) for
clinically localised prostate cancer in men aged
50–69 years identified through population-based
PSA testing.138 The increasing use of radical
prostatectomy in England is shown in Figure
Eight.139
1992
1991
1993
1994
1996
1995
1998
1997
Year
2000
2002
2001
2003
2004
1,200
(Adapted with permission from Hussain S et al. BJU Int 2008;101(5):547–55)
1,000
LH-RH analogues
Anti-androgens
Oestrogens
800
600
400
2004
2003
2002
2001
2000
1999
1998
1997
1996
1995
1994
1993
1992
1991
1990
1989
1988
1987
1986
1985
1984
1983
1982
1981
1980
1979
1978
1977
0
1976
200
Year
Some men, previously thought to have localised
disease, are found to have involved margins at
radical prostatectomy. Adjuvant radiotherapy has
been shown to reduce the rate of biochemical
and clinical recurrence but follow-up is presently
too short to assess the impact on survival.141 The
widespread usage of super sensitive PSA assays
to detect biochemical recurrence at an early time
point has led to the establishment of the
RADICALS Trial. This will compare immediate
adjuvant radiotherapy with early salvage
radiotherapy following a rise in PSA levels. If the
latter is as effective, approximately half the men
may avoid radiotherapy and its associated
toxicities.142
Treatment developments
Treatment efficacy in prostate cancer is
complicated by side-effects that may profoundly
affect quality of life, such as erectile dysfunction
and urinary incontinence.143, 144 Both are
common following radical treatment. Bowel
toxicity can occur following radiotherapy to the
prostate or pelvic nodes.
For both early and locally advanced disease,
conformal radiotherapy is standard. It delivers
high, effective doses of radiation to the tumour
Locally advanced disease
while minimising damage to the healthy
Radiotherapy is the standard of care for locally
surrounding tissue, thereby reducing side-effects,
advanced disease which approximates to
disease in men who have two or more high risk particularly to the bowel.145 Intensity modulated
factors using the National Cancer Collaborative radiotherapy (IMRT) ‘shapes’ the radiotherapy
dose, as well as the field, and is in research.
Network (NCCN) classification131 as shown in
Table Two. Neo-adjuvant hormone therapy can Recruiting until at least 2011, the CHHiP trial is
currently investigating hypofractionated IMRT
shrink tumours prior to radiotherapy. Postfor both efficacy and side-effect incidence.146, 147
radiotherapy adjuvant hormone therapy is
advocated for men with a Gleason score above Brachytherapy using radioactive prostatic
implants is an alternative to external beam
7. An international trial investigating whether
radiation for localised prostate cancer: main
hormone therapy alone can produce similar
side-effects are impotence and urinary
results to radiotherapy (MRC PRO7140)
symptoms. Brachytherapy is approved by NICE
completed recruitment in 2005.
© Cancer Research UK 2008
1999
Figure Nine: Hormone treatment for prostate cancer, UK, 1975–2004
1975
Radical treatment options for curing localised
disease include prostatectomy or radiotherapy.
Erectile dysfunction and urinary incontinence are
issues for both approaches but more likely with
radical prostatectomy compared to external
beam radiotherapy.135 For intermediate and high
risk disease, neo-adjuvant and/or adjuvant
hormone therapy is an additional option.
0
Number of prescriptions per 100,000
There is no standard approach for intermediate
risk tumours. Radical treatment is generally
preferred, with active surveillance a viable
alternative. High risk tumours are usually
treated radically. Watchful waiting is acceptable
in some circumstances, with fully informed
patient consent.
Registered charity number 1089464
as a monotherapy148 or as a booster dose,
alongside external beam radiotherapy.149
Surgical developments include laparoscopic
(keyhole) surgery and intra-operative nerve
sparing surgery (IONS). The latter aims to
preserve erectile function where possible.
Laparoscopic surgery may or may not be
carried out with the assistance of a robotic
device (robotic-assisted laparoscopic
prostatectomy). Both approaches result in less
blood loss during surgery than during open
surgery150 but meta-analyses indicate that
urinary incontinence and erectile dysfunction
rates are similar to that of open surgery.151, 152
Side-effect profiles between treatments are not
clear. Brachytherapy may provide better sexual
function than either external beam
radiotherapy or surgery but can cause more
urinary problems.153-155 Radiotherapy generally
produces more bowel toxicity than surgery.154, 155
Long term quality of life may be better overall
with surgery than with either brachytherapy or
external radiotherapy although to some extent
it evens out over time.156
Metastatic disease
In the UK, approximately 20–30% of men with
primary prostate cancer present with incurable
metastatic disease.157, 158 Hormone treatment can
give good short-term disease control by lowering
androgen levels, principally testosterone. Options
for androgen withdrawal are surgical castration
(bilateral orchidectomy)n or drug therapy with
luteinising hormone-releasing hormone (LH-RH)
analogueso. These show similar efficacy and siden In 1941 Higgins and colleagues discovered the beneficial effects of
castration on prostate cancer and won a Nobel prize for this work in 1966
o These affect the levels of luteinising hormone produced by the pituitary
gland, which leads to a reduction in testosterone produced in the testes.
They are also called gonadotrophin hormone-releasing analogues
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The effect on survival of intermittent androgen
withdrawal (as opposed to continuous therapy)
is being investigated. Short periods of treatment
are followed by periods of monitoring, with
treatment restarting following PSA progression
or should symptoms occur. This can preserve
potency during periods off treatment.
Figure Ten: One-, five- and ten-year age-standardised relative survival for prostate cancer,
men aged 15-99 diagnosed in England and Wales, 1971–2001
100
80
% survival
effect profiles.130 Side-effects include impotence,
hot flushes, osteoporosis, gynaecomastia,
tiredness and metabolic alterations.159 Androgen
deprivation achieves an overall median survival
time of approximately two and a half years and
around 80% of patients have symptomatic
relief.160 Hormonal treatment trends over time
are shown in Figure Nine.139 The fall in
orchidectomy rates can be seen in Figure Eight.
page 7 of 10
One year
Five years
Ten years #
60
40
20
* period
analysis
**
0
1971-1975
1976-1980
1981-1985
1986-1990
1991-1995
Year of diagnosis
1996-1999
2000-2001*
** data not
available
# not agestandardised
Figure Eleven: Five-year age-adjusted relative survival, selected countries in Europe 1990–99
and the US 1996–2003
US White
US All races
US Black
A third hormonal therapy option is antiandrogen treatmentp. This is not as effective in
controlling metastatic cancer, but is less likely to
affect sexual function. The most troublesome
side-effects are gynaecomastia and breast pain. A
single radiotherapy fraction to the breasts or the
anti-oestrogen tamoxifen is a useful preventative
measure. Combining anti-androgens with
androgen deprivation (medical or surgical) is
known as maximum androgen blockade or
MAB. This may give a modest survival advantage
but increases morbidity.161-163 Additional hormonal
treatments include low dose corticosteroids or
oestrogen (stilboestrol).
Austria
Switzerland
Germany
Netherlands
Finland
Iceland
Italy
France
Sweden
Spain
Norway
England
Wales
1996–2003
Scotland
Northern Ireland
1995–99
Poland
1990–94
Slovenia
Czech Republic
Metastatic prostate cancer will nearly always
become refractory to hormone therapy. The
main treatment option is then chemotherapy
with docetaxel and steroids.130 This is not
recommended for men with a Karnofskyq
performance status below 60%.164
Denmark
0
20
40
60
80
100
% survival
Figure Twelve: Five-year relative survival for prostate cancer patients, by age, England and Wales,
1999–2003
100
Future treatments
Various biological therapies are in trials, including
cancer vaccines and monoclonal antibodies.
Other research is investigating treatment
combinations such as chemotherapy,
bisphosphonates and strontium 89, or hormone
therapy with or without chemotherapy,
bisphosphonates and Cox-2 inhibitor. Recently
the CYP17 inhibitor, abiraterone acetate, which
ablates androgen and oestrogen synthesis from
all tissue sources has shown significant activity in
castrate resistant disease and is entering phase III
trials.169 For localised disease, though both are
approved by NICE, high-intensity focused
ultrasound (HIFU) and cryotherapy are not
recommended outside clinical trials. Research
continues into their use as primary therapy or
© Cancer Research UK 2008
% survivall
80
Bone pain is the biggest problem with castrate
resistant metastatic disease. Radiotherapy and
analgesics should be tried first for palliation.130
Radiotherapy provides effective pain relief while
surgery may be necessary for pathological
fractures.165 Bisphosphonates may be used if
these treatments fail.130 The precise role of
bisphosphonates in treating advanced prostate
cancer is under investigation.166-168
60
40
20
0
15–49
50–59
60–69
Age at diagnosis
salvage following prior radiotherapy. NICE assert
that evidence is sufficient regarding safety but
lacking in long term efficacy and effect on quality
of life.170-172
Survival
Survival rates for prostate cancer have been
improving for more than 30 years. However,
interpretation of these trends is difficult as the
case-mix on which they are based is likely to
have changed over time with earlier diagnosis
following the advent of TURP and PSA testing.
The detection of a greater proportion of latent,
earlier, slow-growing tumours in more recent
time periods will have the effect of raising
survival rates due to lead-time bias, that is, the
difference in time between screen detection
and clinical detection in the absence of
screening.173 Lead-time bias is estimated to be
Registered charity number 1089464
70–79
80–89
between 5–12 years, varying with a man’s age
at screeningr.23, 174 There may also have been
genuine improvements in survival due to more
effective treatment, both for early, aggressive
prostate cancers and for advanced cases.175
The five-year relative survival rate for men
diagnosed with prostate cancer in England and
Wales in 2000–2001 was 71%, compared with
only 31% for men diagnosed in 1971–1975
(Figure Ten).176, 177 The one and 10-year rates
have also risen dramatically. Similar increases
have occurred in Scotland: five-year relative
p These block the binding of testosterone and dihydrotestosterone (DHT)
in the prostate cancer cells and therefore block the action of androgens
produced by both the testes and the adrenal glands
q The Karnofsky scale measures physical ability and scores normal health as
100%. A person with a performance status of 60% would require
occasional help with physical needs
r Data from the European Randomized Study of Prostate Cancer (ERSPC)
estimated for a single screening test, mean lead times of 12 years at age 55
and six years for a man aged 75174
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Table Three: Number of deaths and mortality rates for prostate cancer, UK by country, 2006
Number of deaths
Crude rate per 100,000
European age-standardised
rate per 100,000 (95% CI)
England
Wales
Scotland
8,506
34.3
546
37.7
779
31.9
24.9
25.0
(24.4-25.5)
24.3
(22.9-27.1)
N. Ireland
UK
207
24.6
(22.6-26.0)
22.0
10,038
34.0
(19.0-25.0)
24.8
(24.3-25.3)
Figure Thirteen: Number of deaths and mortality rates for prostate cancer, by age, UK, 2006
3,000
800
700
2,500
2,000
Deaths
500
Rate per 100,000
600
Number of deaths
survival rates increased from 47% for patients
diagnosed in 1980–1984 to 80% for patients
diagnosed in 2000–2004.178 The increase in
survival rates is particularly pronounced in the
1990s when PSA testing became more
prevalent.179 The same problems of
interpretation apply to international
comparisons of survival rates (Figure
Eleven).180,181 The 99% five-year survival rate
recorded for white American men is likely to
reflect the stage distribution of registrations in
that country due to PSA testing.182
page 8 of 10
© Cancer Research UK 2008
Registered charity number 1089464
85+
80-84
75-79
70-74
65-69
60-64
55-59
50-54
45-49
40-44
35-39
30-34
25-29
20-24
15-19
5-9
10-14
0-4
Rates
Survival from prostate cancer is strongly related
1,500
400
to the stage of the disease at diagnosis. For
300
disease which is confined to the prostate, five1,000
year relative survival is 90% or more, but if
200
500
disease is metastatic at presentation five-year
100
relative survival is lower at around 30%.s183 For
0
0
most cancers survival rates decrease with age
of patient, but five-year relative survival rates
Age at death
for men diagnosed with prostate cancer in their
60s are higher than rates for either younger or 2. Lack of specificity. Conditions other than
External Quality Assessment Service (UK
older men (Figure Twelve).183, 184
NEQAS) are used.
prostate cancer, such as BPE, prostatitis and
lower urinary infections, can give rise to
PSA testing, the Prostate Cancer Risk
Mortality
elevated levels of PSA. About two-thirds of
Management Programme and informed
In the UK, prostate cancer is the secondt most
men with an elevated PSA level (measured
consent
as >4ng/ml) will not have prostate cancer
common cause of cancer death in men after
Prostate cancer affects many men and the
but will suffer the anxiety, discomfort and risk lung cancer.1 In 2006 there were 10,038 deaths
disease is incurable when diagnosed at a late
of follow-up investigations.3, 4
from prostate cancer in the UK, accounting for
stage. An accurate method of detecting early,
12% of all male cancer deaths.194-196 The number
treatable disease is therefore highly desirable.
of deaths and the mortality rates for prostate
3. The natural history of prostate cancer is
cancer in the UK and its constituent countries
poorly understood. At present it is not
Three tests for prostate cancer are available,
in 2006 are shown in Table Three.1 The
possible to reliably predict which tumours
Digital Rectal Examination (DRE), Prostate
will be aggressive and which will require little majority of deaths (93%) occur in men aged 65
Specific Antigen (PSA) measurement and
or no treatment. A proportion of patients
and over as Figure Thirteen shows.1 In men
transrectal ultrasound (TRUS) biopsy but all
with early, localised disease detected through aged 85 and over, prostate cancer overtakes
have drawbacks.4, 157 Of the three, the PSA test
PSA testing and then biopsy, will receive
lung cancer to become the most common
is the most acceptable but there are problems.
unnecessary treatment, with considerable
cause of cancer death.
PSA is an enzyme produced by the prostate
side-effects.
which can be measured in the blood. It is clear
Geography
that a number of factors, other than the
4. There is a lack of consensus on the best
Mortality rates worldwide (Figure Two) vary
presence/absence of cancer, can affect the
treatment for early stage prostate cancer.
15-fold and although North America ranks first
levels of PSA, such as the age of the man,
in terms of incidence, it is eighth for mortality,
obesity and the presence of benign prostatic
5. There is no evidence that screening reduces with the highest mortality rates being recorded
hypertrophy.185 Research into making the PSA
in the Caribbean. The widespread use of PSA
mortality. Screening trials are underway in
test more accurate is ongoing and includes
testing in the USA results in not only higher
the US, UK and in Europe but it will be
looking at PSA density (takes into account the
some years before the results are known.188-192 incidence but also a much higher proportion of
size/volume of the prostate gland), velocity
early stage cases being diagnosed than in
(how fast it rises over time), doubling time and As a result of these problems, population
countries with lower levels of testing and this
the ratio between two different components of screening is not recommended and instead the naturally leads to higher survival rates overall
PSA, ‘free’ and ‘complexed’.3, 186 Free PSA is
and lower mortality rates relative to incidence.
Department of Health launched the Prostate
associated with benign prostatic conditions and Cancer Risk Management Programme
For instance, 60–70% of the prostate cancers
complexed PSA with cancer so their ratios may (PCRMP) in 2002.186 One of its main aims is to diagnosed in Japanese men have extended
help to interpret total PSA levels, alongside
beyond the prostate versus only 11% in US
provide clear and balanced information about
DRE findings, previous biopsy results, ethnicity,
white men.197 Significant decreases in mortality
the benefits and limitations of PSA testing.3, 186
prostate size and co-morbidities.3
(see Trends below) have been recorded in
Asymptomatic men can then make an
informed decision about whether they wish to some countries since 2002 which will not be
The main reasons why PSA testing is not at
reflected in these rankings (Figure Two).
have a PSA test or not, after discussion with
present suitable for population screening of
their primary care physician. Referral guidelines
asymptomatic men are summarised below.
Trends
recommend that PSA levels take age into
Overall in GB prostate cancer mortality was
account with cut-off values of >3.0ng/ml for
1. Lack of sensitivity. Around 15% of men with
fairly stable during the 1970s but began to
men aged 50-59, >4.0ng/ml for men aged 60a normal (measured as ≤4ng/ml) PSA level
increase in the early 1980s (Figure Four).
69 and >5.0ng/ml for men aged 70+.193 Interwill have prostate cancer.187 In other words,
Mortality peaked in the early 1990s when the
laboratory variability has also been identified
the test will provide them with false
European age-standardised death rate reached
and the PCRMP recommends that only
reassurance.3
laboratories participating in the UK National
s based on patients resident in England 1999–2002
t In 2006 there were 19,600 lung cancer deaths responsible for 24% of all
male cancer deaths
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CancerStats – Prostate cancer – UK
Figure Fourteen: Age-specific mortality rates, prostate cancer, UK, 1971–2006
1,000
800
Rate per 100,000
30 per 100,000 in 1992. Since then there has
been a slight fall in the rates and in 2006 the
European age-standardised rate was 25 per
100,000. This was the first sustained decrease in
annual death rates for thirty years. A decrease
in mortality has also been observed in the USA
since 1991198 and in Europe since 1993.199 A
comparison of mortality rates in the USA and
UK between 1975–2004, reported that
mortality peaked in the early 1990s for both
countries, but the subsequent fall in mortality
until 2004 was much greater in the USA.200
page 9 of 10
85+
75-84
65-74
55-64
45-54
600
400
200
controlled trials can provide definitive answers
about the efficacy of screening.139
Acknowledgements
Cancer Research UK wishes to thank Professors D Dearnaley and R Martin and Dr
R Eeles for their expert advice on this report and Dr S McPhail for providing the
survival by stage analysis. However, the content of this CancerStats report is entirely
the responsibility of Cancer Research UK. Cancer Research UK would also like to
acknowledge the essential work of the cancer registries in the UK (www.ukacr.org/).
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
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© Cancer Research UK 2008
2005
2003
2001
1999
1997
1995
1993
1991
Year of death
Future
In 1999, prostate cancer overtook lung cancer
to become the most common solid tumour in
As yet it is not possible to say what proportion UK men. As a health problem, it will continue
to grow due to the ageing of the male
of the fall in mortality is the result of
improvements in treatment,201 changes in cancer population and the increasing ad hoc use of
registration coding,202 the attribution of death to PSA testing. With many more cases of early
localised cancer being diagnosed, it is
prostate cancer, and the effects of PSA
imperative that a method is developed that
testing.203 Only the ongoing randomised
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1987
1985
1983
1981
1979
1977
1975
1973
1971
0
The UK mortality rates by age group between
1971–2006 are shown in Figure Fourteen.
Rates for men under 84 years reached a peak
in 1992 and have declined consistently since
then. Recent rates for men over 85 had two
peaks: the first in 1996 which was followed by
a decline and then a further increase to 2003,
since when the rates have fallen.
Further information
For a list of other CancerStats reports and PowerPoint
Presentations, all freely downloadable, visit our Publications
website http://publications.cancerresearchuk.org
choose ‘Browse by type’ and then select from the list. Or email
[email protected] for more information and help.
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Registered charity number 1089464
differentiates between cases which need radical
treatment and those that do not.204 Otherwise
large numbers of men may receive unnecessary
and possibly debilitating treatment and place a
significant burden on the NHS. Research into
the underlying molecular biology of the disease
has thrown up a number of possibilities and
these biological markers may also prove useful
in monitoring treatment. As this report has
outlined, all aspects of this important disease
are under scrutiny, from prevention to new
methods of detection and treatment.
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