COMMON CANCERS

Prostate cancer Key points

Nick Waldron C There is no UK screening programme for prostate cancer
Simon Chowdhury
C Treatment for localized and locally advanced disease is indi-
vidualized but generally of curative intent; options include
surgery, radiotherapy (sometimes with hormonal therapy) and
Abstract
brachytherapy
Prostate cancer is a major health problem. In the UK, it is the most
common male cancer and the second most common cause of male
C Metastatic disease, although incurable, has a high median
cancer death. Its strongest predeterminant is increasing age. Virtually
overall survival compared with other solid tumours. These
all cancers are adenocarcinomas, the grade being indicated by the
patients can be suitable for aggressive treatments for non-
Gleason score. There are often no presenting symptoms. Investiga-
oncological problems
tions such as serum prostate specific antigen, digital rectal examina-
tion, biopsy and, increasingly, magnetic resonance imaging (MRI) are
C Metastatic disease has an increasing number of effective
required for diagnosis. Local staging consists of MRI, with computed
treatments in both the castrate-sensitive and castrate-
tomography (CT), bone scanning and, increasingly, positron emission
resistant phases
tomography-CT for detecting metastases. Management depends on
disease stage, the patient’s fitness and their wishes regarding treat-
ment. Active surveillance is increasingly used for low-volume and
low-grade cancers. For localized prostate cancer, radical prostatec-
tomy and radical radiotherapy offer high cure rates; for example sur- In the UK, around 30 new cases of prostate cancer are diag-
vival at 10 years can be as high as 90% for a well-differentiated, nosed every day. The incidence is increasing; this is thought to
localized prostate cancer. Hormonal therapy, which lowers or blocks result from greater disease awareness and increased detection
testosterone, is used in locally advanced and metastatic disease; it because of the prostate specific antigen (PSA) serum test. Pros-
slows but does not cure metastatic disease. Cytotoxic chemotherapy tate cancer accounted for 11,631 deaths in the UK in 2016, and
is increasingly used for castrate-refractory prostate cancer and has 7% of male cancer deaths.
been shown to significantly improve overall survival in hormone-
naive patients with metastatic prostate cancer.
Keywords Chemotherapy; gleason score; hormonal therapy; MRCP; Risk factors
prostate cancer; prostate specific antigen; prostatectomy; Age e incidence rises with increasing age. In the UK between
radiotherapy 2014 and 2016, there were around four new cases per year in
men aged 40e45, compared with 10,242 in those aged 65e69.1
Ethnicity e the highest incidences are found in African
eAmerican men and the lowest in Chinese men.
Familial e several studies have shown a prevalence of
Epidemiology prostate cancer within certain families. This hereditary form of
Prostate cancer is the second most common cancer in men prostate cancer starts 6e7 years before the sporadic type. Mul-
worldwide, and the fifth leading cause of cancer mortality in tiple genes have been implicated.
male patients. There is great variation in its incidence rate Genetic e mutations in BRCA1 and more frequently BRCA2
worldwide. The incidence is highest in Oceania, North America are associated with some prostate cancers. BRCA2 mutations are
and Europe (85e112 cases per 100,000), and lowest in South and associated with higher grade cancers, rapid progression and
Eastern Asia and North America (4e11 cases per 100,000). poorer overall survival. Other associated genes include
HOXB13.
Modifiable risk factors e there are no accepted preventable
risk factors with a ‘sufficient’ or ’concerning’ level of evidence
linked to prostate cancer development, but the World Cancer
Nick Waldron MRCP is a Medical Oncology Registrar at Auckland City Research Fund has concluded that there is ‘probable’ evidence
Hospital, Auckland, New Zealand, and previously worked as a Fellow linking increased body fatness and increased adult height.
in the Genitourinary Oncology Department at Guy’s Hospital,
London, UK. Competing interests: none declared.
Simon Chowdhury MRCP is a Consultant Medical Oncologist
Pathology
Specializing in the Treatment of Prostate Cancer at Guy’s Hospital, Over 95% of prostate cancers are adenocarcinomas; less com-
London, UK. Competing interests: Simon Chowdhury has served in a
mon types include sarcomas and neuroendocrine tumours. Most
consulting or advisory role and/or on speakers bureaus for Clovis
(90%) adenocarcinomas are acinar, with ductal carcinomas less
Oncology, Astellas Pharma, Beigene, Janssen, Pfizer, and Sanofi;
received honoraria from GlaxoSmithKline and Novartis; and received common. About 70% of cancers are found in the peripheral zone,
research funding from Clovis Oncology, Johnson & Johnson, and 20% in the transition zone and 10% in the central zone. Prostate
Sanofi. Travel support from Beigene. cancer is often multifocal.

MEDICINE 48:2 119 Ó 2019 Published by Elsevier Ltd.

COMMON CANCERS

Clinical features Risk stratification and staging investigations

At this stage, if cancer is confirmed, the above investigations are
In very early disease, there are often no symptoms, cases being
reviewed in the multidisciplinary meeting to establish a risk
identified from a raised PSA value. Patients can present with
category that will guide the investigations required for further
urinary symptoms such as hesitancy, nocturia and retention.
staging. NICE and EAU guidelines suggest stratifying into low,
Systemic symptoms such as fatigue, weight loss and bone pain
intermediate or high risk based on PSA concentration, Gleason
can indicate metastatic disease. Once there is a clinical suspicion
score and clinical stage (which can be obtained at this point from
of prostate cancer, the following tests are likely to be used to
either DRE or MRI):
achieve a definitive diagnosis.
For low-risk patients e many patients undergo MRI
Prostate specific antigen scanning at this point if it was not performed before
This glycoprotein is produced only by cells of the prostate gland. biopsy.
It is raised in prostate cancer, benign prostatic hyperplasia and For intermediate-risk patients e EAU guidance recom-
prostatitis, and more transiently after prostate biopsy and in mends considering computed tomography (CT) scans of
acute urinary retention. PSA is thus a sensitive but non-specific the abdomen and pelvis, and isotope bone scans to screen
test for prostate cancer. Because of its ability to detect prostate for metastatic disease.
cancer before symptoms develop and at an early stage, it has For high-risk patients e CT and bone scanning are
been extensively studied as a potential screening test for prostate mandated.
cancer (see Screening, below, for controversies and current
recommendations). Positron emission tomography (PET): two tracers, choline
and radio-labelled prostate-specific membrane antigen (PSMA),
Digital rectal examination (DRE) can be used in PET imaging for prostate cancer. There is
This essential part of the urological examination enables the size increasing evidence that PET scanning provides more accurate
of the prostate gland to be assessed and nodules or lumps to be detection of metastatic disease than CT and bone scanning. Ac-
detected. It also enables clinical staging. cess is still limited to patients with equivocal findings or those
relapsing after radical therapy.
Ultrasound-guided biopsy
Tissue diagnosis is obtained by transrectal or transperineal Management
ultrasound-guided biopsy, which can cause sepsis, urinary
This depends on whether the prostate cancer is localized
retention or severe rectal bleeding. However, only around 70%
(confined to the prostate gland), locally advanced (larger tu-
of ultrasound-guided biopsies show cancer, and of these, only
mours or invading nearby structures), or metastatic.
40% are likely to have a clinically significant cancer. The other
30% of detected cancers, once known about, would be moni- Localized prostate cancer
tored and potentially treated, at unnecessary cost to both the There are three treatment strategies for localized prostate cancer.
person and healthcare system. The chosen treatment will depend on patient choice, co-
morbidities and risk category.
Magnetic resonance imaging (MRI)
Prostate MRI has emerged as a potential alternative first-line
For low-risk localized prostate cancer: regardless of the treat-
investigation for patients with a high enough risk of clinically
ment chosen, patients have a 10-year prostate cancer survival
meaningful prostate cancer. Studies have shown that prebiopsy
rate of around 98%.
MRI scans, if negative, give clinicians enough confidence to
Active surveillance e this has curative intent and aims to
avoid nearly 30% of biopsies. In addition, patients with a posi-
prevent unnecessary treatment. It involves regular DRE and PSA
tive MRI result who go on to biopsy (which can then be MRI-
measurement, and in some centres repeated MRI and/or DRE.
guided) are more likely to have clinically significant cancer
Active treatment should be considered if there is evidence of
(38% versus 26% for those undergoing standard ultrasound-
progression. The ProtecT trial has shown that, compared with
guided biopsy without a preceding MRI scan). As a result,
surgery and radiotherapy, patients undergoing active surveil-
recent updates to both National Institute for Health and Care
lance are more likely to develop signs of disease progression and
Excellence (NICE)2 and European Association of Urologists
metastatic disease than those treated with immediate radical
(EAU) guidelines3 recommend offering MRI as the first-line
therapy (8% versus 3%). However, there is no difference in
investigation to those with clinically suspected prostate cancer.
prostate cancer survival at 10 years.
Histopathology Radical prostatectomy e this is complete surgical removal of
Prostate cancer is graded using the Gleason system, which is the prostate gland. Patients are more likely at 6 months to suffer
based on the microscopic appearance of the prostate’s glandular minor urinary problems (71%) and erectile dysfunction (66%)
architecture. A grade between 1 and 5 is given first to the most than with active surveillance or radiotherapy.
dominant pattern, and then to the second most common pattern. External-beam radiotherapy (EBRT) e advances have led
The two grades are added together to give the Gleason score, to improved accuracy and fewer adverse effects, but long-
which ranges from 2 to 10. This gives an indication of prognosis term proctitis, rectal bleeding, incontinence and haematuria
and tumour progression, with higher scores associated with more occur in about 10% of patients. Studies have demonstrated a
aggressive disease. small increase in risk of colorectal cancer after EBRT for

MEDICINE 48:2 120 Ó 2019 Published by Elsevier Ltd.

COMMON CANCERS

prostate cancer, mainly observed after 5e10 years, and pa- Castrate-refractory prostate cancer: this stage of the disease is
tients should be counselled on this. the lethal phase, and up until relatively recently there was a
Brachytherapy e radioactive seeds are deployed directly into paucity of effective treatments. However, a number of effective
the prostate. It can be an alternative to radiotherapy in selected therapies have become available over the last few years. Response
individuals. rates are high but only transient. Patients often sequence through
Watchful waiting e this is another option for those patients the different treatments below, and there is currently no definitive
felt to have a life expectancy of <10 years because of co- evidence to guide the order in which they are used.
morbidities. Treatment, usually with androgen deprivation Second-generation hormonal therapies e more detail can be
therapy (see below), is held in reserve unless symptoms develop found in Hormonal therapy for cancer on pages 103e107 of this
related to progressive cancer. issue.
Abiraterone lowers testosterone further by blocking the
For intermediate-risk localized prostate cancer: the prostate CYP17 enzyme involved in testosterone biosynthesis.
cancer-specific mortality rate for intermediate-risk localized Abiraterone has been shown in large Phase III clinical trials
prostate cancer at 10 years is around 13% in patients not treated to significantly improve overall survival in metastatic
radically. Surgery and radiotherapy are likely to be more bene- CRPC. There is also now evidence that it also delays dis-
ficial than active surveillance in this group than in low-risk dis- ease progression and improves survival in castrate-
ease, but all are reasonable options and should be discussed. sensitive disease, although it has not yet been approved
by NICE in that setting.
For high-risk localized prostate cancer: treatment consider- Enzalutamide is a novel antiandrogen that has higher af-
ations are as for locally advanced prostate cancer (see below). finity for the androgen receptor than pre-existing anti-
androgens, resulting in greater efficacy. It has shown a
Locally advanced prostate cancer significant survival advantage for men with metastatic
Most of these patients who do not have significant co-morbidities CRPC.
should be treated with radical intent. Selected patients can be These agents are usually the first treatment for castrate-
managed surgically. Most are offered radiotherapy with hor- resistant disease. Once there is disease progression on one of
monal treatment (usually for 2e3 years), with a 10-year overall these agents, it is highly unlikely the other will work.
survival of 58%. In the Systemic Therapy in Advancing or Met-
astatic Prostate Cancer: Evaluation of Drug Efficacy (STAMPEDE) Cytotoxic chemotherapy e docetaxel has been shown to
trial, patients with high risk locally advanced prostate cancer improve overall survival, as has cabazitaxel.
with a Gleason score >8, PSA >40 ng/ml or a clinical stage of T3
or T4 were shown to benefit from docetaxel chemotherapy before Bone-directed therapies e radium-223 has been shown to be
radiotherapy. beneficial for CRPC patients with only bone metastases (with or
without small nodal metastases), but is not effective for men with
Metastatic prostate cancer visceral disease.
This is defined as prostate cancer that has spread either to lymph
nodes outside the pelvis or to other organs. It is best thought of Palliative radiotherapy e this is used for local symptom control,
as a disease with two phases: hormone/castration-sensitive and such as pain from bone metastases or local urinary symptoms
castrate-refractory prostate cancer (CRPC). The median overall from progressive prostate disease.
survival for metastatic prostate cancer is around 5e6 years. The
most common sites for metastatic disease are bone (around Entry into clinical trials e this should be considered for suitable
80%), extrapelvic lymph nodes (11%), liver and lung (around patients. Genomic testing of tumours is driving the development
10% each). of personalized therapies based on each person’s cancer biology.
One promising area is using poly(ADP-ribose) polymerase
Castration-sensitive prostate cancer: the dominant biological (PARP) inhibitors for cancers with deleterious mutations in ho-
pathway for prostate cancers is via the androgen receptor. The mologous recombinant DNA repair genes (e.g. BRCA1, BRCA2,
mainstay of systemic treatment in this phase aims to lower an- ATM). Improved radioisotope treatments such as PSMA lute-
drogens/testosterone to castrate levels using medical or surgical tium-177 also show promise.
castration, as discussed in detail in Hormonal therapy for cancer
on pages 103e107 of this issue. Screening
Chemotherapy e the practice-changing STAMPEDE trial
found that adding docetaxel chemotherapy to standard PSA has been studied as a test for prostate cancer screening. The
androgen deprivation therapy improved median overall sur- European Randomized Study of Screening for Prostate Cancer
vival in patients with newly diagnosed metastatic prostate (ERSPC)5 randomized 162,243 asymptomatic men aged 50e74
cancer. An improvement in median overall survival of 22 years to either a screening group (n ¼ 72,890) with routine PSA
months (65 months versus 43 months) was observed. All measurement every 4 years or a non-screening group. Analysis at
men with newly diagnosed metastatic disease should be 9 years of follow-up showed that:
considered for docetaxel chemotherapy as part of their initial 75% of patients with a positive PSA result in the screening
treatment.4 group had a negative biopsy result

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COMMON CANCERS

the cumulative incidence of prostate cancer was 8.2% in KEY REFERENCES

the screening group versus 4.8% in the non-screening 1 Cancer Research UK. Prostate cancer statistics, https://www.
group cancerresearchuk.org/health-professional/cancer-statistics/
at 13 years of follow-up, the relative risk of prostate cancer statistics-by-cancer-type/prostate-cancer/incidence#heading-One
mortality was reduced by 21% in the screening group, but (accessed 10 October 2019).
781 men would need to be screened and 27 treated for each 2 European Association of Urologists. Prostate cancer, https://
prevented death uroweb.org/guideline/prostate-cancer (accessed 16 June 2019).
models estimate that around 40% of the screen-detected 3 James ND, Sydes MR, Mason MD, et al. Docetaxel and/or zole-
cancers, many of which were treated with unavoidable dronic acid for hormone-naïve prostate cancer: first overall survival
adverse effects, would never have gone on to cause clini- results from STAMPEDE (NCT00268476). J Clin Oncol 2015;
cally meaningful disease. 33(suppl): 5001.
The UK National Screening Committee does not recommend 4 National Institute for Health and Care Excellence. Prostate cancer:
the use of PSA as a population screening tool. It does, however, diagnosis and management. London: National Collaborating
suggest use of PSA screening in well-informed patients with a Centre for Cancer, May 2019.
higher baseline risk of prostate cancer. This remains an area of 5 Schroder FH, Hugosson J, Roobol MJ, et al. Screening and
controversy. A prostate-cancer mortality in a randomized European study. N Engl
J Med 2009; 360: 1320e8.

TEST YOURSELF
To test your knowledge based on the article you have just read, please complete the questions below. The answers can be found at the
end of the issue or online here.

Question 1 He was given 3 litres of 0.9% Sodium chloride intravenously.

A 64-year-old man presented with nocturia. He was normally fit
and well, was taking no regular medications, and was working What is the next most appropriate action?
full time as an accountant. A Commence an anti-androgen followed after 14 days by a
On clinical examination, there was an enlarged, nodular prostate. luteinizing hormone-releasing hormone analogue
B Arrange a bone biopsy
Investigation C Arrange a prostate biopsy
Prostate specific antigen (PSA) 6 ng/ml (<4) D Arrange an urgent MRI whole spine
E Start on a syringe driver for the pain and refer to palliative
care, adopting an entirely symptomatic approach to this
What is the next most appropriate investigation?
gentleman’s management.
A MR scan of the prostate
B Ultrasound-guided prostate biopsy
C Repeat of the PSA test Question 3
D No action required A 54-year old man with a recent diagnosis of metastatic prostate
E CT scan of the abdomen and pelvis cancer (multiple bone metastases) presented for review. He had
been on luteinizing hormone releasing hormone (LHRH) agonists
for 8 weeks, with an improvement in prostate specific antigen
Question 2
(PSA) results from 84.1 ng/ml to 15.0 ng/ml (<4). Before diag-
A 73-year-old man presented with a 1-week history of confusion,
nosis, he had been fit and well and taking no regular medication.
lethargy and abdominal pains. In the 3 months before admission,
He was continuing to work full time.
he had been requiring significantly more analgesia for lower back
and left hip pain. He had no other past medical history.
What is the most appropriate management plan?
Clinical examination showed multiple areas of focal tenderness
A Continue the LHRH antagonist, and check the PSA every 12
in the pelvis but no focal neurological signs.
weeks
B Discuss the addition of chemotherapy with cabazitaxel
Investigations
C Discuss starting radium treatment
Adjusted calcium 3.3 mmol/litre (2.1e2.6)
D Discuss the addition of chemotherapy with docetaxel
Prostate specific antigen 284.4 ng/ml (<4)
E Discontinue the LHRH antagonist and monitor PSA every
Nuclear medicine bone scan showed evidence of multiple
12 weeks
sclerotic bone metastases in the lumbar spine and pelvis

MEDICINE 48:2 122 Ó 2019 Published by Elsevier Ltd.