Prostate Cancer Risk Management Programme
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Prostate Cancer
Risk Management Programme
information for primary care
PSA testing in asymptomatic men
Deborah C Burford 1
Michael Kirby 2
Joan Austoker 1
1
Cancer Research UK
Primary Care Education Research Group
2
Faculty of Health and Human Sciences
University of Hertfordshire(63) The Royal College of Radiologists’ Clinical Stanford JL, Stephenson RA, Penson DF, et al. Physician 2005; 51:977–982.
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(64) Anderson J. Surgery for early prostate cancer. (76) Guay A, Seftel AD. Sexual foreplay (87) Malcolm JB, Derweesh IH, Kincade MC,
In: Kirk D, ed. International Handbook of Prostate incontinence in men with erectile dysfunction DiBlasio CJ, Lamar KD, Wake RW, et al.
Cancer. Euromed Communications Ltd, 1999, after radical prostatectomy: a clinical Osteoporosis and fractures after androgen
pp. 99–111. observation. Int J Impot Res 2008; 20:199–201. deprivation initiation for prostate cancer. Can J
(65) Schroder FH, Hugosson J, Roobol MJ, Tammela (77) Koper PC, Heemsbergen WD, Hoogeman Urol 2007; 14:3551–3559.
TL, Ciatto S, Nelen V, et al. Screening and MS, Jansen PP, Hart GA, Wijnmaalen AJ, et al. (88) Shahinian VB, Kuo YF, Freeman JL, Goodwin JS.
prostate-cancer mortality in a randomized Impact of volume and location of irradiated Risk of fracture after androgen deprivation
European study. N Engl J Med 2009; 360:1320– rectum wall on rectal blood loss after for prostate cancer. N Engl J Med 2005;
1328. radiotherapy of prostate cancer. Int J Radiat 352:154–164.
(66) Andriole GL, Grubb RL, III, Buys SS, Chia D, Oncol Biol Phys 2004; 58:1072–1082.
Church TR, Fouad MN, et al. Mortality results (78) Fulmer BR, Bissonette EA, Petroni GR,
from a randomized prostate-cancer screening Theodorescu D. Prospective assessment
trial. N Engl J Med 2009; 360:1310–1319. of voiding and sexual function after
(67) Barry MJ. Screening for prostate cancer – the treatment for localized prostate carcinoma:
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external beam radiotherapy. Cancer 2001;
(68) European Association of Urology. EAU
91:2046–2055.
position statement on screening for prostate
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Authors
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Dr Deborah C Burford1 125
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cancer: an update. Eur Urol 2008; 53:37–44.
Professor Michael Kirby2 179:141–145.
(70) Berger AP, Gozzi C, Steiner H, Frauscher F,
Dr Joan Austoker1 (80) Gelblum DY, Potters L, Ashley R, Waldbaum
Varkarakis J, Rogatsch H, et al. Complication
R, Wang XH, Leibel S. Urinary morbidity
1
Cancer Research UK Primary Care Education Research Group rate of transrectal ultrasound guided prostate
following ultrasound-guided transperineal
Cancer Epidemiology Unit biopsy: a comparison among 3 protocols with
prostate seed implantation. Int J Radiat Oncol
6, 10 and 15 cores. J Urol 2004; 171:1478–
University of Oxford Biol Phys 1999; 45:59–67.
1480.
Tel: 01865 289677 (81) Crook J, McLean M, Catton C,Yeung I,
(71) Raaijmakers R, Kirkels WJ, Roobol MJ,
Website: http://pcerg.ceu.ox.ac.uk/ Tsihlias J, Pintilie M. Factors influencing risk
Wildhagen MF, Schrder FH. Complication
of acute urinary retention after TRUS-guided
2
Visiting Professor rates and risk factors of 5802 transrectal
permanent prostate seed implantation. Int J
Faculty of Health and Human Sciences ultrasound-guided sextant biopsies of the
Radiat Oncol Biol Phys 2002; 52:453–460.
prostate within a population-based screening
University of Hertfordshire (82) Khaksar SJ, Laing RW, Henderson A,
program. Urology 2002; 60:826–830.
Sooriakumaran P, Lovell D, Langley SE.
(72) Rosario DJ, Lane JA, Metcalfe C, Goodwin
Biochemical (prostate-specific antigen)
2nd edition, July 2009 L, Doble A, Avery KN, et al. The Prostate
relapse-free survival and toxicity after 125I
Biopsy Effects (ProBE) study – interim
low-dose-rate prostate brachytherapy. BJU Int
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Urology 2006; 68:1057–1060. (85) Katz A. What happened? Sexual consequences
Online: www.orderline.dh.gov.uk e-mail: dh@prolog.uk.com Tel: 0300 123 1002 Fax: 01623 724 524 Textphone: 0300 123 1003
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21Preface
The purpose of this booklet is to supply primary care teams with an easy reference to assist them in
providing asymptomatic men with information on the benefits, limitations and implications of having a
PSA test for prostate cancer.
Development of the original booklet, published in 2002, was informed by consultation with over 100
GPs and primary care cancer leads, as well as advice from an expert multidisciplinary group set up by
the Department of Health to advise on all aspects of the Prostate Cancer Risk Management Programme
(PCRMP). The pack has subsequently been evaluated; references can be found in the evidence document
available at http://www.cancerscreening.nhs.uk/prostate/index.html.
In 2007, the PCRMP commissioned a review of this booklet, its summary sheet and the accompanying
patient information leaflet. This second edition, published in 2009, incorporates information from recent
research developments and the recommendations of the National Institute for Health and Clinical
Excellence (NICE) in the Prostate cancer: diagnosis and treatment guidelines, published in February 2008.
This booklet was reviewed by GPs and members of the PCRMP Scientific Reference Group prior to
publication.
It is anticipated that this pack will be reviewed in 3 years’ time, unless major significant breakthroughs
are made within that time frame.
1Acknowledgements
The authors would like to acknowledge the multidisciplinary Scientific Reference Group and particularly
thank those who sent in detailed comments. We would also like to thank Professor Jenny Donovan,
Professor Stephen Langley FRCS(Urol), Mrs Jane Toms, Dr Chris Parker FRCR, Mr John Neate and Mr
Mike Birtwistle who have contributed and the GPs who reviewed the materials prior to publication.
Members of the PCRMP Scientific Reference Group
Dr Anne Mackie (Chair) Mr David Gillatt Dr Athene Lane Mrs Janet Rimmer
UK National Screening Consultant Urologist Senior Research Fellow and Coordinator, NHS Cancer
Committee Coordinator of the ProtecT Screening Programmes
Ms Sonia Hall Study
Dr Joan Austoker Practice Nurse Association Mr Derek Rosario
Cancer Research UK Primary Dr Jane Melia Senior Clinical Lecturer
Professor Freddie Hamdy
Care Education Research Cancer Screening Evaluation and Honorary Consultant
Nuffield Professor of Surgery
Group Unit Urological Surgeon
and Professor of Urology
Mr Peter Baker Dr Anthony Milford Ward Mr Peter White
Dr Patricia Harnden
Men’s Health Forum Consultant Immunologist UK NEQAS for
Consultant Histopathologist Immunochemistry and
Dr Deborah Burford Dr Sue Moss
Mrs Anna Jewell Immunology
Cancer Research UK Primary Cancer Screening Evaluation
The Prostate Cancer Charity
Care Education Research Unit Mr Richard Winder
Group Mr Patrick Keane Deputy Director, NHS Cancer
Dr Uday Patel
Consultant Urologist Screening Programmes
Dr Richard Clements Consultant Radiologist
Consultant Radiologist Dr James Kingsland Professor Julietta Patnick
GP and Department of Health
Mr Tim Elliott Director, NHS Cancer
Advisor
Department of Health Screening Programmes
Professor Michael Kirby
Professor Chris Foster Professor Chris Price
GP and University of
Professor of Cellular and Consultant Clinical Biochemist
Hertfordshire
Molecular Pathology
2Contents
1 Introduction 5
2 Prostate cancer background information 6
2.1 Incidence and mortality 6
2.2 Natural history of prostate cancer 7
2.3 Risk factors for prostate cancer 7
2.4 Clinical features 8
2.4.1 Localised prostate cancer 8
2.4.2 Locally advanced prostate cancer 8
2.4.3 Metastatic prostate cancer 8
2.5 Lower urinary tract symptoms and prostate cancer 8
3 Assessment of prostate cancers 9
3.1 The PSA test 9
3.1.1 Test benefits 9
3.1.2 Test limitations 9
3.1.3 Test practicalities 10
3.1.4 Referral guidance 10
3.2 Digital rectal examination of the prostate 11
3.3 Transrectal ultrasound 11
3.4 TRUS-guided prostate biopsy and Gleason score 11
3.4.1 Biopsy benefits 12
3.4.2 Biopsy limitations 12
3.5 Imaging techniques 12
3.6 The future of prostate cancer detection 12
34 Management of prostate cancer 13
4.1 Management options for localised prostate cancer 13
4.1.1 Watchful waiting 13
4.1.2 Active surveillance and active monitoring 13
4.1.3 Radical prostatectomy (open, laparoscopic and robotic) 14
4.1.4 Radiotherapy (external beam and brachytherapy) 14
4.1.5 High-intensity focused ultrasound and cryotherapy 14
4.1.6 Adjuvant therapy 14
4.2 Locally advanced and metastatic prostate cancer 14
4.3 Monitoring effectiveness of treatment with PSA 14
5 Population screening for prostate cancer 15
6 Conclusions 16
7 Resources for further information on prostate cancer 17
8 Appendices 18
Appendix 1: Complications of TRUS biopsy 18
Appendix 2: Complications of radical prostatectomy 18
Appendix 3: Complications of radiotherapy 18
Appendix 4: Complications of adjuvant therapy 18
9 References 19
41 Introduction
Prostate cancer is now the second most in 2002 [2,3]. One of the main aims of
common cause of cancer deaths in men in the programme is to ensure that men
the UK [1]. There has been considerable who are concerned about the risk of
media focus on the disease, along with prostate cancer receive clear and balanced
calls for the introduction of a national information about the advantages and
prostate cancer screening programme. disadvantages of the PSA test, biopsy and
The prostate-specific antigen (PSA) test is treatments for prostate cancer. This will
currently the best available and can lead to enable men to make informed decisions
the diagnosis of localised prostate cancer about whether or not to have a PSA test.
for which potentially curative treatment Many men have inaccurate or incomplete
can be offered. However, there are a knowledge about the PSA test, gained
number of uncertainties surrounding the either from the media or through friends
PSA test and the diagnosis and treatment and relatives. There may be advantages to
of prostate cancer. Currently, there is no a man knowing his PSA level and in finding
evidence that the benefits of a PSA-based cancer at an ‘early’ stage; however, there
screening programme would outweigh the may also be disadvantages to being tested.
harms. The patient’s personal preferences should
be an important factor in the decision.
The Prostate Cancer Risk The following factors will vary between
Management Programme and individuals and affect their decision about
informed choice whether or not to have a PSA test:
The Prostate Cancer Risk Management ■■ fear of cancer;
Programme aims to help the primary ■■ the consequences of the diagnosis of
care team give clear and balanced disease which is unlikely to become
information to men who request details symptomatic (e.g. anxiety);
about testing for prostate cancer. ■■ the potential impact of treatment
complications on quality of life; and
Any man over the age of 50 who ■■ the importance placed upon the
asks for a PSA test after careful current lack of scientific proof [4].
consideration of the implications
should be given one. This booklet provides background
information about the diagnosis and
treatment of prostate cancer and outlines
In response to growing public concern the issues surrounding the use of the PSA
about the risks of prostate cancer, the test. This booklet is part of an information
government launched the Prostate pack, which also contains a summary card
Cancer Risk Management Programme and patient information sheets [5].
52 Prostate cancer background information
2.1 Incidence and mortality Figure 1
Number of new cases of prostate cancer in the UK, 2005.
Prostate cancer is the most common
8000
cancer and the second most common
cause of cancer-related deaths in men in 7000
the UK. In 2005, a total of 34,302 men
were diagnosed with prostate cancer, 6000
Number of cases
and, in 2006, 10,038 men died from the 5000
disease [1]. The most common cause of
cancer-related deaths is lung cancer, which 4000
was diagnosed in 22,259 men in 2005 and
3000
which claimed the lives of 19,600 men in
2006 [1]. 2000
Prostate cancer is largely a disease of 1000
older men, and diagnosis is less common
below the age of 50 (Figure 1). The average
0–4
5–9
10–14
15–19
20–24
25–29
30–34
35–39
40–44
45–49
50–54
55–59
60–64
65–69
70–74
75–79
80–84
85+
age at diagnosis is 70–74 years and the
average age at mortality is 80–84 years.
The numbers of deaths by age in 2006 are Age group
shown in Figure 2.
Ninety-three per cent of prostate cancer Figure 2
deaths occur in the 65 and over age Number of deaths from prostate cancer in the UK, 2006.
group. By the age of 80, approximately
3000
80% of men will have some cancer cells
in their prostate (Table 1) [6]. However,
in contrast, around 1 in 26 men (3.8%) in 2500
England and Wales will die from prostate
Number of deaths
cancer [7]. By comparison, 1 in 2 men will 2000
die from cardiovascular disease and 1 in 53
from colon cancer [7]. 1500
The number of prostate cancer cases has 1000
risen steadily since 1975 [1]. Part of the
increase is a result of an ageing population.
500
However, improved ascertainment by
cancer registries, improved diagnostic
accuracy and additional methods of
0–4
5–9
10–14
15–19
20–24
25–29
30–34
35–39
40–44
45–49
50–54
55–59
60–64
65–69
70–74
75–79
80–84
85+
detecting prostate cancer have also
contributed to the increase in age-specific
incidence. Initially, this came from the use Age group
6of transurethral resection of the prostate Table 1
(TURP) as therapy for benign disease, with Presence of prostate cancer determined at autopsy
mandatory histological examination of Age 20–29 30–39 40–49 50–59 60–69 70–79
chips removed during TURP. Subsequently,
there has been a widespread increase in Percentage of men in
the use of the PSA test and ultrasound- whom prostate cancer 8 28 39 53 66 80
guided biopsies in men with raised PSA was detected at autopsy
levels. These tests have led to the diagnosis
of many cancers, some of which would not
have presented clinically within the man’s 2.3 Risk factors for prostate for 43% of cases by age 55 [13] and
lifetime [8]. cancer research is currently under way to identify
prostate cancer predisposition markers
As with other cancers, prostate cancer There is often increased anxiety [14]. A link between prostate cancer and
can cause premature death in the UK and amongst men with risk factors, a family history of breast cancer has been
reduce life expectancy. Early detection particularly those with a family history established, believed to be due to the
and treatment may reduce the impact of of prostate cancer. If these men BRCA1 and BRCA2 genes [15,16].
this cancer. A study of differing mortality present in primary care, it is important
rates in the USA and the UK has noted that they receive the best available The relative risk to a patient increases
that a striking decline in prostate cancer information and support to assist them with increasing numbers of first-degree
mortality in the USA coincided with the in the decision of whether or not to relatives diagnosed (Table 2). The father-
increasing use of PSA screening. However, have a PSA test. to-son relative risk is increased 2.5-fold
the authors noted that the differences whilst the relative risk between brothers is
may be attributable to different treatment increased 3.4-fold [17].
approaches between the two countries The causes of prostate cancer are not
or differing recording of cause of death as known. A recent review of 18 studies At present, there are no definitive
well as any effect of screening [9]. showed that sex hormones do not alter guidelines for prostate cancer screening in
the risk of prostate cancer [10]. The risk high-risk families in the UK because of the
2.2 Natural history of prostate factors for incidence (listed below) may be uncertainties around the effectiveness of
cancer different from the risk factors for mortality testing and treatment.
(e.g. family history) [11].
The natural history of prostate cancer Ethnicity
is not fully understood. Prostate cancer The strongest risk factor is age (see Table
is not a single disease entity but more a 1), but many other factors also play a part: Black men (irrespective of black-African
spectrum of diseases, ranging from slow- or black-Caribbean origin) have a 3-fold
growing tumours, which may not cause Family history higher risk of developing prostate cancer
any symptoms or shorten life, to very than white men [18] whilst Asian and
aggressive tumours (see section 3.4 for Prostate cancer may cluster in families, and Oriental men have the lowest incidence
staging procedures). Some tumours can approximately 5–10% of cases are thought [19,20]. South Asian men living in England
change from being low risk to high risk. to have a substantial inherited component have a lower incidence of prostate cancer
Many men with slow-growing tumours die [12]. It has been estimated that a strong than their white counterparts (0.8:1) [21].
with their cancer rather than of it. predisposing gene could be responsible
7Table 2 difficult to collect as metastatic disease can
Effect of family history on the relative risk of prostate cancer present very late after diagnosis. Although
Number of first-degree the majority of men with metastatic
Increase in relative risk prostate cancer die from the disease, it
relatives diagnosed
does respond well to hormonal therapy,
2.5-fold, increasing to 4.3-fold if the relative
1 which often keeps it controlled for several
was under 60 years of age at diagnosis
years. The 5-year survival rate of men
2 3.5-fold
who present with metastatic disease is
approximately 30% [28].
Diet unusual for these early cancers to cause 2.5 Lower urinary tract
any symptoms, but they may be palpable by symptoms and prostate
Much of the research investigating a digital rectal examination (DRE). cancer
link between diet and prostate cancer
is, at present, inconclusive [1]. Studies Localised cancers range from just a few Lower urinary tract symptoms (LUTS)
have suggested that lycopenes [22,23] cells to more extensive disease that is are common in older men. It is important
and possibly selenium [24] may have considered ‘clinically important’. to realise that early prostate cancer itself
a protective effect. The evidence for will not usually produce symptoms and
red meat is equivocal [1]. However, a 2.4.2 Locally advanced prostate that LUTS (frequency, urgency, hesitancy,
diet high in protein or calcium from cancer terminal dribbling and/or overactive
dairy products may increase the risk of bladder) are usually related to the
developing prostate cancer [25]. For a These cancers have extended outside the presence of BPE rather than prostate
more comprehensive list of dietary risk prostatic capsule and are also frequently cancer [29]. Between 70% and 80%
factors, please see the Cancer Research asymptomatic. of prostate tumours originate in the
UK Prostate CancerStats sheets which peripheral zone of the gland distant from
accompany this booklet [1]. Obesity has 2.4.3 Metastatic prostate cancer the urethra [30]. As a consequence, by the
also been linked to prostate cancer, with time prostate cancer itself causes LUTS,
risk of high-grade disease increasing with Metastases may be the first sign of it may have reached an advanced and
body mass index (BMI) [26]. prostate cancer, which frequently incurable stage.
metastasises to the bones, causing pain.
2.4 Clinical features Appearance on x-ray is usually as a Due to the high coincidence of BPE and
sclerotic lesion. It has been estimated prostate cancer in the older age group,
2.4.1 Localised prostate cancer that, in 1992, 34% of men diagnosed with some men will have a benign pathology and
prostate cancer in the Thames Valley a co-existing early prostate cancer [31].
Localised prostate cancer (confined within presented with metastatic disease [8] and When a man seeks advice about LUTS this
the capsule) is usually asymptomatic. in 1999 the UK figure was approximately can lead to investigations which diagnose
Prostate cancers, unlike benign prostatic 22% [27]. However, information about what is a coincidental prostate cancer.
enlargement (BPE), tend to develop in staging is not always available with
the outer part of the prostate gland. It is incidence reports and these data are also
83 Assessment of prostate cancers
There are currently several ways of chance of a prostate cancer diagnosis. The 3.1.1 Test benefits
determining the presence and/or extent of PSA test provides the opportunity; where
prostate cancers: clinically relevant prostate cancer does ■■ The PSA test may lead to the
exist, it will be diagnosed at a stage when detection of cancer before symptoms
■■ the prostate-specific antigen (PSA) treatment options and outcome may be develop.
test; improved. However, the PSA test may ■■ The PSA test may lead to the
■■ digital rectal examination (DRE); lead to investigations which can diagnose detection of cancer at an early stage
■■ transrectal ultrasound (TRUS); clinically insignificant cancers which would when the cancer could be cured or
■■ TRUS-guided prostate biopsy and not have become evident in a man’s treatment could extend life.
histology; and lifetime. ■■ Repeat PSA tests may provide
■■ imaging techniques (magnetic valuable information, aiding in a
resonance imaging [MRI], The most commonly used PSA test prostate cancer diagnosis.
computerised tomography [CT] scan, measures the total amount of prostate-
x-ray, bone scan). specific antigen (both free and protein 3.1.2 Test limitations
bound) in the blood. An alternative recent
3.1 The PSA test test calculates the ratio of free:total PSA ■■ The PSA test is not diagnostic: those
to give an indication of whether prostate with an elevated PSA level may
cancer is present; free PSA is associated require further investigation, possibly
The PSA test should not be added to with benign conditions and bound PSA a TRUS-guided prostate biopsy (see
a list of investigations without a careful with malignancy, so a low ratio (< 25%) section 3.4) and histology to confirm
explanation of why the test is being may be indicative of cancer [33]. A lower the presence of prostate cancer.
performed and its implications. significant ratio than 25% may be quoted ■■ PSA is not tumour specific in
by the local laboratory based on their the prostate [36]. Therefore,
specific assay method [34]. other conditions, such as benign
Prostate-specific antigen (PSA) is a enlargement of the prostate,
glycoprotein responsible for liquefying The PSA test is currently the best method prostatitis and lower urinary tract
semen and allowing sperm to swim of identifying an increased risk of localised infections, can also cause an elevated
freely. It is expressed in both benign and prostate cancer. However, since PSA is PSA. About two-thirds of men
malignant processes involving epithelial an enzyme also found in men without with an elevated PSA1 do not have
cells of the prostate. Due to an alteration prostate cancer, and PSA values tend to prostate cancer detectable at biopsy
in the architecture of the prostate in rise with age due to BPE, the difficulty [37,38], but this will vary from centre
conditions such as prostatitis and BPE in using this marker comes in defining to centre.
as well as prostate cancer, PSA leaks the ‘normal’ range and knowing when ■■ The PSA test result may not
out, leading to increased levels in the referral and biopsy are appropriate. Recent be elevated and provide false
bloodstream. research has indicated that PSA levels reassurance. One study has shown
are diluted in obese men [35]; however, that approximately 15% of all men
The incidence of prostate cancer varies there is currently no specific guidance on with a ‘normal’ PSA level may have
up to 4-fold between different European how obesity should affect PSA values for prostate cancer, and 2% will have
countries, being higher in those countries referral, so the PCRMP recommends that
where PSA testing is more common [32]. the values given (see Table 3) should be
Men who have a PSA test increase their used for all men, regardless of their weight. 1
This publication classed an
abnormal PSA level as > 4 ng/ml.
9high-grade cancer,2 although it is not Prior to performing a PSA test, the 3.1.4 Referral guidance
known how many of these would conditions listed in the box above should
have become clinically evident in a be met in order to ensure that, where
man’s lifetime [39]. This is due to possible, a raised PSA result is the result of The serum PSA level alone should not
the poor sensitivity and specificity prostate cancer, not a confounding physical automatically lead to a prostate biopsy.
of the PSA test [38]. A one-off test condition [40].
is therefore not reliable enough to Other factors that should be
provide reassurance. Evidence indicates that PSA is stable in considered in conjunction with the PSA
■■ The PSA test may lead to the whole blood for up to 16 hours at room level are prostate size, DRE findings,
identification of prostate cancers temperature. When taking blood you age, ethnicity, co-morbidities, history of
which might not have become should ensure that the specimen will any previous negative biopsy and any
clinically evident in the man’s lifetime. reach the laboratory and be separated previous PSA history.
■■ A single PSA test will not distinguish within this time frame. The quality of PSA
between aggressive tumours which testing can vary between laboratories, The patient should be involved in any
are at an early stage but will develop depending on the type of PSA test decision about referral to another
quickly and those which are not, but employed. To reduce the effects of this healthcare provider.
further tests may provide valuable variation, samples should be sent only to
information. laboratories which employ a method for
PSA assay which is equimolar (measures The Prostate Cancer Risk Management
3.1.3 Test practicalities free and complexed PSA equally) and has Programme recognises that, currently,
calibration traceable to the World Health there is a wide range of referral practice
Organization international standard [41]. around the country. Further work is being
Before having a PSA test men should Such laboratories should also participate done to consider the evidence in this area,
not have: in the UK National External Quality with the aim of standardising the test itself
Assessment Service (UK NEQAS) for PSA and the referral values used.
■■ an active urinary infection (PSA testing. In addition, samples from each
may remain raised for many individual patient should always be sent to The Prostate Cancer Risk Management
months); the same laboratory. Programme recommends that age-related
■■ ejaculated in the previous 48 referral values are used as detailed in Table
hours; 3. The PCRMP will be piloting a recent
■■ exercised vigorously in the finding from the ProtecT study, which
previous 48 hours; showed that two PSA tests performed 7
■■ had a prostate biopsy in the
previous 6 weeks; or Table 3
■■ had a DRE within the previous Age-related referral values for total PSA levels recommended by the Prostate Cancer Risk
week. Management Programme [43]
Age PSA referral value (ng/ml)
50–59 ≥ 3.0
60–69 ≥ 4.0
2
This publication classed an 70 and over > 5.0
abnormal PSA level as ≥ 4 ng/ml.
10weeks apart allowed more accurate risk 3.2 Digital rectal examination of 3.4 TRUS-guided prostate biopsy
prediction and may assist in decision- the prostate and Gleason score
making as to whether or not to proceed
with referral [42].
DRE is a useful diagnostic test for men Approximately two-thirds of men
with lower urinary tract symptoms. undergoing TRUS biopsy because of
Although age-related referral values
an elevated PSA level are found not to
have traditionally been used, it is now
DRE is not recommended as a have cancer.
also recognised that PSA levels are a
continuum, as demonstrated by the screening test in asymptomatic men.
The best management for those with
Prostate Cancer Prevention Trial [38].
a persistently elevated PSA level but
Whereas a very high PSA reading is
negative biopsies is unclear. These men
strongly suggestive of cancer, the situation The digital rectal examination (DRE) is a
may face prolonged periods of follow-
is less clear when the PSA is mildly useful diagnostic test for men with lower
up and may experience considerable
elevated, because of the contribution of urinary tract symptoms or symptoms
anxiety.
BPE. Specialist advice should be sought on suggestive of metastatic disease. It allows
abnormal results. assessment of the prostate for signs of
prostate cancer (a hard gland, sometimes
There are additional factors which should with palpable nodules) or benign
be considered in conjunction with the enlargement (smooth, firm, enlarged gland). A TRUS biopsy involves taking 10 to 12
PSA level: prostate size, DRE findings, However, a gland which feels normal does cores of prostatic tissue through the
age, ethnicity, co-morbidities, history of not exclude a tumour. Cancer of the rectum under ultrasound guidance [52]. A
a previous negative biopsy and the man’s prostate may produce changes detected on series of biopsies are taken in a systematic
own view [44]. a DRE, but these are not specific and many manner and additional biopsies may be
early prostate cancers will not be detected taken if a lesion is seen. If a tumour is
The following are associated with high- by DRE [51]. detected, histological examination reveals
grade cancer: how well differentiated the tumour is.
3.3 Transrectal ultrasound Tumour differentiation is graded by a
■■ smaller prostate volume (as Gleason score, by analysing the most
determined by TRUS) [45–47]; Transrectal ultrasound (TRUS) can be used common and second most common
■■ abnormal DRE findings (if the to examine the prostate and determine tumour patterns. Each tumour pattern is
prostate gland is enlarged, tender, its size accurately but its main value is in assigned a grade (1 to 5) and these grades
nodular, hard or immobile due to enabling precise needle placement in the are combined to produce the Gleason
adhesion to surrounding tissue) prostate during systematic prostate biopsy. score (2 to 10). The lower the score, the
[45,48,49]; It is not sufficiently reliable to exclude more well differentiated the tumour, the
■■ increasing age [45,49,50]; and prostate cancer and should not be used to less likely the tumour is to progress and
■■ black-African and black-Caribbean screen asymptomatic men. the better the prognosis. Tumours can be
ethnicity [45,49]. classified into three categories on the basis
of their Gleason score: low grade (≤ 6),
Previous negative prostate biopsy results intermediate grade (= 7) and high grade (8
are associated with a reduced risk of to 10).
finding high-grade cancer.
11At the recommended PSA referral values, (see Appendix 1 for full details). indolent and aggressive cancers. Studies
the following should also be taken into ■■ Up to 20% of tumours are missed at are currently under way to investigate
account: co-morbidities, ethnicity, family biopsy (false negatives) [53], although aspects of PSA levels, such as proportions
history and abnormal DRE findings. Biopsy the number of tumours missed at of free and complexed PSA, PSA density,
may be carried out prior to treatment, biopsy decreases with the number of PSA velocity and PSA doubling time
unless there is a high clinical suspicion cores taken. (reviewed in [55]). The proportion of free
of prostate cancer because of a high ■■ Diagnosis of prostate cancer which PSA is higher in benign conditions and the
PSA level and evidence of multiple bone is not clinically significant may have a proportion of complexed PSA is higher
metastases (positive isotope bone scan or significant impact on the patient. The in malignant conditions, so a low free to
sclerotic metastases on plain radiographs) patient may experience increased complexed PSA value can be indicative of
[44]. psychological burden and problems prostate cancer. High PSA levels from a
gaining (more costly) insurance cover small prostate volume (prostate density;
As with other medical procedures, the [54]. PSA level divided by the TRUS estimated
biopsy procedure can cause significant ■■ Management of men with a negative prostate volume) may raise the suspicion
anxiety. Most men describe the biopsy biopsy but a persistently elevated of prostate cancer. PSA levels tend to
as an embarrassing, uncomfortable PSA level is very difficult. Prolonged increase with the progression of prostate
experience, and some describe it as painful periods of follow-up, with the cancer; calculating the rate of increase in
(although this should be alleviated by use possibility of re-biopsy, may cause PSA and the time taken for a PSA level
of local anaesthetic) [52]. considerable anxiety. to double can be useful diagnostic tools,
although the best method of calculation,
3.4.1 Biopsy benefits 3.5 Imaging techniques ideal number of time measurements
and optimum time intervals between
■■ A biopsy can find cancer before Imaging techniques such as magnetic measurements are unknown at present
symptoms develop. resonance imaging (MRI), computerised [56].
■■ A biopsy can identify cancerous tomography (CT) scans and radioisotope
tissue and identify the grade of bone scans can be used to assess the Research is also under way to find
tumour. extent of cancer and whether it has, alternatives to the PSA test, such as
■■ A negative biopsy result can relieve or how far it may have, spread. No prostate cancer 3 (PCA3) [57], human
anxiety about prostate cancer, imaging test is sufficiently reliable to kallikrein 2 (HK2) [58] and early prostate
although a second biopsy may be exclude prostate cancer or to screen cancer antigen 2 (EPCA-2) [59]. In
necessary if recommended by the asymptomatic men. addition, genetic markers such as 2+Edel,
multidisciplinary team, particularly if which can potentially distinguish between
the PSA level remains elevated. 3.6 The future of prostate cancer aggressive and non-aggressive cancers, are
■■ The diagnosing capability of the detection being investigated [60].
biopsy procedure increases with the
number of cores taken. The PSA test is the best currently available
for prostate cancer, but there are concerns
3.4.2 Biopsy limitations about its accuracy. There has been much
debate about how it can be improved
■■ Post-biopsy complications include to provide a more reliable detection
bleeding and infection, but antibiotics procedure for prostate cancer, as well
should be given, so infection is rare as a method of differentiating between
124 Management of prostate cancer
The management of localised prostate ■■ cryotherapy; and Before choosing a treatment regime, men
cancer is central to the controversy ■■ adjuvant therapy. should be appropriately counselled about
surrounding screening. Men considering a the important quality of life differences
PSA test should understand that: There is continuing debate regarding between the options. Research to find
the appropriate identification of patients the optimal treatment regime is ongoing
■■ early detection and treatment of for the different treatment options. and a treatment decision aid will soon be
prostate cancer may be beneficial; Comparisons of efficacy between available [62].
■■ at present, there remains uncertainty treatment options are difficult because
about how to identify those men of differences in case mix, staging and 4.1.1 Watchful waiting
at greatest risk of prostate cancer treatment techniques but, generally,
and likely to benefit from further surgery is more likely to cause urinary During watchful waiting the patient is
investigations and treatment; and sexual dysfunction and radiotherapy followed up regularly in primary care.
■■ there is, at present, no strong is more likely to cause bowel and rectal The approach is non-invasive and avoids
evidence to indicate which treatment injury [61]. Randomised controlled trials unpleasant side-effects. Watchful waiting
option is most suitable for which such as the ProtecT study (http://www.epi. is offered to men who, on the grounds of
man; and bris.ac.uk/protect/index.htm) are under their age or co-morbidity or on the basis
■■ active treatments have significant way. This is a large UK trial comparing of having slowly progressing tumours, are
side-effects, although improvements radical prostatectomy, radical radiotherapy likely to die from other causes and will
to treatment regimes and their side- and active monitoring. The study recruited not suffer significant morbidity from their
effects are being made. men between 2001 and 2008 and the prostate cancer. These men will be offered
primary outcome is 10-year survival, palliative treatment only if and when
4.1 Management options for with the initial results expected in 2015. symptoms of prostate cancer develop. Such
localised prostate cancer Additional UK-based treatment trials treatment will not be curative, but will aim
(http://www.cancerhelp.org.uk/trials/trials/ to slow the cancer growth sufficiently to
To date, there are no data from default.asp for more details) are currently prevent the man dying from it.
randomised controlled trials giving recruiting patients.
clear evidence about the optimum 4.1.2 Active surveillance and active
treatment for localised prostate cancer. Men with localised low-risk prostate monitoring
cancer (as defined by Gleason grading,
PSA level and T-stage) who are considered During active surveillance or monitoring
There are several different management suitable for radical treatment should the patient is followed up regularly by an
options: also be offered active surveillance after oncologist or urologist. Active surveillance
appropriate counselling. Full NICE or monitoring is offered to men who are
■■ watchful waiting; guidance on treatment options is available generally younger and fitter and who wish
■■ active surveillance or active at http://www.nice.org.uk/guidance/index. to avoid the possibility of unnecessary
monitoring; jsp?action=byID&o=11924. treatment of indolent cancers. The
■■ radical prostatectomy (open, downside is that disease may spread locally
laparoscopic or robotic); Men and their partners should be and advanced disease, which may be more
■■ radiotherapy (external beam advised that infertility arising from sexual difficult to treat, may develop. The aim is
radiotherapy [EBRT] or dysfunction may be a significant side-effect to monitor those with stable disease and
brachytherapy); of radical treatment. to identify where radical treatment may
■■ high-intensity focused ultrasound
(HIFU);
13be appropriate for those whose cancer for men with less than 10 years’ life radiotherapy for apparently localised
progresses. Men on active monitoring will expectancy. disease [64]. Hormone therapies
be monitored by serial PSA tests. Men (luteinising hormone-releasing hormone
on active surveillance will be monitored Brachytherapy may be given by two very [LHRH] analogues or anti-androgens)
by serial PSA tests and repeat prostate different techniques. Low dose rate (LDR) attempt to suppress growth of the
biopsies. Radical treatment with curative brachytherapy involves the permanent cancer by reducing circulating androgen
intent is offered if there are signs of implantation of tiny radioactive seeds into levels. They can be used as adjuvant
disease progression. the prostate to deliver a high radiation treatments to those outlined above and
dose into the gland. High dose rate (HDR) are also widely used in the control of
4.1.3 Radical prostatectomy (open, brachytherapy requires fine catheters to metastatic disease. Side-effects include
laparoscopic and robotic) be inserted into the prostate, through sexual dysfunction, loss of libido, breast
which a radioactive source is temporarily swelling, hot flushes and osteoporosis (see
The aim of radical prostatectomy is to passed. Although the isotope used has a Appendix 4 for more details). Men on the
remove the entire prostate gland and higher dose rate, the overall dose is lower watchful waiting regimen who develop
to cure the disease; however, complete than that given by LDR brachytherapy symptoms of progressive disease are
tumour clearance is not always achieved so it is usually given in conjunction with usually managed with hormone therapy.
and approximately 20% of men go on to EBRT. This latter technique is much more
develop biochemical or clinical recurrence recent, with limited clinical data, and is 4.2 Locally advanced and
of the disease [63]. Recurrence does not, usually reserved for patients with high- metastatic prostate cancer
however, necessarily equate with death risk disease. Possible side-effects include
from prostate cancer. Complications urinary symptoms and sexual dysfunction. Clinically advanced localised cancer
of surgery include operative mortality, cannot normally be eradicated by surgery
sexual dysfunction and urinary problems 4.1.5 High-intensity focused alone. The rate of progression of the
(see Appendix 2 for more details). This ultrasound and cryotherapy disease varies considerably. Patients with
treatment is uncommon in men over 70 locally advanced disease mainly receive
years of age [44]. High-intensity focused ultrasound (HIFU) radiotherapy or hormone therapy.
and cryotherapy are newer radical Some men live for many years with few
4.1.4 Radiotherapy (external beam therapies for the treatment of localised symptoms, whilst others develop extensive
and brachytherapy) prostate cancer undergoing assessment disease quite rapidly.
through clinical trials. At present, there
Radiotherapy aims to cure the disease. is insufficient knowledge about the 4.3 Monitoring effectiveness of
See Appendix 3 for more details on benefit and harm of these therapies for treatment with PSA
complication rates for external beam their routine use. HIFU aims to cure the
radiotherapy (EBRT) and brachytherapy. disease by heating the prostate gland using PSA levels are used to monitor disease
ultrasound waves. Cryotherapy aims to activity in those with established prostate
EBRT involves an external source of cure the disease by freezing the prostate cancer, giving an indication of response
radiation targeted at the tumour. Short- gland. to treatments. It may also give an early
term side-effects relate mainly to bowel indication of the progression of a cancer
and bladder problems from the radiation. 4.1.6 Adjuvant therapy either after treatment or as part of an
Longer-term complications include sexual active surveillance or monitoring protocol.
dysfunction and urinary problems. This Adjuvant hormone therapy is being
treatment is not usually recommended used increasingly in conjunction with
145 Population screening for prostate cancer
To date there are no UK data from statistically significant reduction in the because of our poor understanding of
randomised controlled trials to show rate of death from prostate cancer by the natural history of different types of
the benefit to harm ratio of using the 20% in men aged 55 to 69 years. However, prostate cancer and an optimal treatment
PSA test for prostate cancer screening. this was associated with a high risk of regime [69].
However, there is evidence from overdiagnosis and therefore overtreatment
Europe to show that the PSA test (1410 men would need to be screened There are significant gaps in our
can save lives from prostate cancer, and 48 additional cases of prostate cancer knowledge about the PSA test, prostate
but it is unknown how many cases would need to be treated to prevent one cancer and treatment options. The
would be diagnosed and subsequently death). After studying the ERSPC data, potentially harmful effects of prostate
overtreated. the European Association of Urology screening are particularly significant.
concluded that current published data are Whilst some early cancers would be
insufficient to recommend the adoption of detected and lives saved, the introduction
There have been calls for a national population screening for prostate cancer of a PSA-based screening programme at
screening programme for prostate cancer, as a public health policy due to the large this stage would undoubtedly lead to some
just as there are for breast and cervical overtreatment effect [68]. After 7 to 10 men with indolent disease unnecessarily
cancers. Three trials are currently under years of follow-up, the PLCO concluded experiencing the side-effects of radical
way in the UK, Europe and the USA. The that the rate of death from prostate treatment, including sexual dysfunction,
UK-based Prostate testing for cancer and cancer was very low in men aged 55 to urinary problems and, in extreme cases,
Treatment (ProtecT) (http://www.epi. 74 years and did not differ significantly death.
bris.ac.uk/protect/index.htm) study was between the screening and control groups.
open for recruitment until December Both studies revealed levels of screening For these reasons, the National Screening
2008, with follow-up due to continue for that had taken place before the trials began Committee has recommended that a
a further 10 years. The ProtecT study and screening outside the study by men prostate cancer screening programme
includes a randomised controlled trial in the control arm of the PLCO may have should not be introduced in the UK at
looking at the potential impact of prostate led to a reduction in size of the difference this time. Instead, the Prostate Cancer Risk
cancer screening. Recruitment has also in prostate cancer mortality between Management Programme was introduced
ended for the European Randomised the screening and control arms. Neither so that men who ask about a PSA test can
Study of Screening for Prostate Cancer of these studies used data from a UK make an informed choice, based on good
(ERSPC) (http://www.erspc.org/) and the population or UK-comparable screening quality information, about the advantages
American Prostate, Lung, Colorectal and protocols, nor have the impacts on men’s and disadvantages of having the test. To aid
Ovarian (PLCO) cancer screening trial symptoms and quality of life or costs been men in making a decision which is right for
(http://prevention.cancer.gov/programs- published for either study, so care must be them, a decision aid was developed and
resources/groups/ed/programs/plco/ exercised in applying these results to any is available at http://www.prosdex.com/
about). Further information from these decisions about a screening programme in index_content.htm.
trials will be available in 2015, 2010 and this country.
2014 respectively, but results from the
ERSPC [65] and interim findings from When considering population screening
the PLCO [66] have resulted in more programmes, the benefits and harms
controversy around PSA-based prostate should be assessed, and the benefits should
cancer screening [67]. After a median always outweigh the harms. For prostate
follow-up of 9 years, the ERSPC concluded cancer the benefits of a population
that PSA-based screening resulted in a screening programme are not yet known
156 Conclusions
Prostate cancer is a significant health of a population screening programme men who request a PSA test receive
problem, mainly affecting older men. would reduce mortality in the UK balanced information about the pros and
There are problems surrounding the without significant numbers of men being cons to assist them in making an informed
early diagnosis and treatment options overtreated. Due to the uncertainties shared decision about being tested.
for the disease, and to date there is no surrounding PSA testing and treatments
evidence to say whether the introduction for prostate cancer, it is imperative that
167 Resources for further information on prostate cancer
Organisation Website address Telephone number
Prostate Cancer Risk Management Programme http://www.cancerscreening.nhs.uk/prostate/index.html
NHS Direct http://www.nhsdirect.nhs.uk/ 0845 4647
NHS Choices http://www.nhs.uk/Pages/homepage.aspx
Health Talk Online http://healthtalkonline.org/
UK Prostate Link http://www.prostate-link.org.uk/
Cancer Research UK http://www.cancerresearchuk.org/ 0808 800 4040
Cancerbackup http://www.cancerbackup.org.uk/home 0808 800 1234
The Prostate Cancer Charity http://www.prostate-cancer.org.uk/ 0800 074 8383
Prostate UK http://www.prostateuk.org 020 8877 5840
Prostate Cancer Support Federation http://www.prostatecancerfederation.org.uk 0845 601 0766
178 Appendices
Appendix 1: Complications of Incontinence is a significant problem for Appendix 4: Complications of
TRUS biopsy some patients after radical prostatectomy. adjuvant therapy
It is difficult to quantify and there are wide
Two large studies of 5,957 and 5,802 variations in the definitions and assessment Reports of erectile dysfunction range
prostate biopsies showed that minor of incontinence between studies. It has from 50% to 100% [84], and 54% of men
complications were relatively common been reported that 15.3% of men are report a loss of libido after 1 year [85].
(haematospermia, 36.3–50.4%; haematuria, incontinent 5 years after surgery [77]. Up to 80% of men report experiencing
14.5–22.6%; rectal bleeding which subsided hot flushes [86]. Reports of gynaecomastia
without intervention, 1.3–2.3%) whilst Nineteen per cent of men report bowel (breast swelling) range from 13% to 70%,
major complications were relatively urgency and 10% of men report painful depending on the therapy drug used
rare (prostatitis, 0.9%; fever, 0.8–3.5%; haemorrhoids 5 years after surgery [78]. [84]. Twenty-three per cent of patients
epididymitis, 0.07–0.7%; rectal bleeding for developed osteoporosis within 66 months
longer than 2 days, 0.6%; urinary retention, Appendix 3: Complications of [87], and this reduction in bone mineral
0.2–0.4%) [70,71]. Re-admission to hospital radiotherapy density has been linked to a 7% increased
as a result of prostate biopsy was required risk of bone fractures [88].
in 0.4% of cases [71]. External beam radiotherapy
In a recent UK-based analysis of 750 men Urinary problems are reported by 4.1% of
(within the ProtecT study) who underwent men, 29% report bowel urgency and 20%
TRUS-guided biopsy, reported side- report painful haemorrhoids at 5 years
effects included haematospermia (83.6%), post-operatively [75]. Levels of erectile
haematuria (64.9%) and rectal bleeding dysfunction decrease from 63.5% 2 years
(33.1%) [72]. post-operatively to 50.3% 5 years post-
operatively [75]. Approximately 33% of
Appendix 2: Complications of men experience moderate episodes of
radical prostatectomy rectal bleeding 3 years after treatment
[77].
Two large studies of 4,165 and 11,010 men
undergoing radical prostatectomy show Brachytherapy
that the surgical risk of mortality within
30 days is less than 0.5%, but that the risk Between 1% and 2% of men report
increases with age [73,74]. urinary problems 1 year after treatment
[78,79]. Reports of urinary retention in
Several factors have been shown to the literature range from 2.2% to 13%
influence post-operative sexual function [80,81]. A UK-based study has reported
(e.g. age, clinical and pathological stage and a 7% retention rate [82]. Potency was
surgical technique). Erectile dysfunction maintained in 83% of patients 2 years after
has been reported by up to 82.1% of men brachytherapy, with only 17% reporting
at 2 years and 79.3% of men 5 years post- erectile dysfunction [83].
operatively [75] and climacturia (leakage
of urine at climax) in 38% 9 months after
surgery [76].
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