Cancer of the prostate glandThomas Swallow

Simon Chowdhury

Roger S Kirby

AbstractProstate cancer constitutes a major health problem. It is estimated that the

lifetime risk of western men having prostate cancer is about 30%, with the

risk of dying from the cancer being 3%. Increasing age is the strongest pre-

y fat

consumed seems to be a risk factor for the development of

COMMON CANCERSSimon Chowdhury MRCP is a Consultant Medical Oncologist specializing

in the treatment of prostate cancer at Guys Hospital, London, UK.

Conflicts of interest: none declared.

Roger S Kirby FRCS(Urol) is a Honorary Professor of Urology at

St Georges Hospital, and University College London, London, UK.

Conflicts of interest: none declared.determinant for the development of prostate cancer. Virtually all cancers are

adenocarcinomas, the grade being indicated by the Gleason score. Often,

there are no presenting symptoms. Investigations such as serum

prostate-specific antigen (PSA), digital rectal examination and biopsies

via a transrectal ultrasound probe are required for diagnosis. Staging, if

required, consists of magnetic resonance imaging or computed tomog-

raphy for locally advanced disease and/or a bone scan for detection of

bony metastases. Management depends largely on the stage of the

disease. For localized prostate cancer, radical prostatectomy can offer

a cure. Adverse consequences include erectile dysfunction and inconti-

nence. Prostate cancer is also radiosensitive and treatment can be given

as external-beam radiotherapy or in the form of brachytherapy. Hormonal

therapy, such as luteinizing hormone-releasing hormone analogues and

anti-androgens, is used in locally advanced and metastatic disease.

Hormones do not cure but slow the progression of the cancer. Follow-up

consists of PSA surveillance and other therapeutic options can be consid-

ered if the PSA starts to rise. Cytotoxic chemotherapy is increasingly

being used for hormone-escaped prostate cancer. The survival rate at 10

years may be as high as 90% for a well-differentiated, localized prostate

cancer.

Keywords brachytherapy; Gleason score; hormonal therapy; prostate

cancer; prostatectomy; PSA; radiotherapy

Prostate cancer is becoming an increasingly significant interna-

tional health problem; it may soon overtake lung cancer as the

leading cause of cancer-related mortality in men in developed

countries. For a western male, the lifetime risk of:

developing microscopic prostate cancer is 30% developing clinical disease is 10% death from the disease is 3%.

Thomas Swallow MRCS is a Clinical Research Fellow in Urology at

St Georges Hospital, London, UK. Conflicts of interest: none declared.MEDICINE 40:1 10prostate cancer. The diet is rich in dairy products and red meat in

areas with a high incidence (e.g. USA). Studies have indicated

that vitamins E and D, as well as the trace element selenium, may

protect against prostate cancer.

Testosterone and its main metabolite, dihydrotestosterone, are

the principal hormones regulating the growth and function of the

prostate gland. Cancer of the prostate is rarely found in castrated

men. Conversely, relatively high concentrations of circulating

testosterone have been found in African-American men, possibly

explaining their higher incidence of prostate cancer compared to

Caucasian men.

Other risk factors have been suggested, including vasectomy,

environmental (e.g. exposure to cadmium) and viral factors.Diet appears to have a significant influence on the risk

prevention of prostate cancer. The amount of dietarEpidemiology

Prostate cancer is diagnosed in about 30,000 and 200,000men each

year in the UK and USA, respectively. These figures have risen

steadily over the last 20 years. This statistic should be interpreted

with caution because of increased detection due to the prostate-

specific antigen (PSA) serum test (though an increase in clini-

cally significant cancer appears to have occurred). Prostate cancer

kills more than 9,000 men in the UK each year.

There is significant variation in the incidence of clinical

prostate cancer worldwide. It is relatively high in northern

Europe and North America, intermediate in southern Europe and

South America, and low in the Far East and Asia. The highest

incidences are found in African-American men and the lowest in

Chinese men.

Aetiology and risk factors

A direct cause of prostate cancer has not been discovered, but

several risk factors have been identified.

Familial: several studies have shown the prevalence of prostate

cancer within certain families. This familial or hereditary form of

cancer is characterized by either:

three successive generations being affected with thedisease

a clustering of three or more men with the disease ina nuclear family

two men with early-onset prostate cancer (i.e. age

The likelihood of local extension outside the prostate capsule,

COMMON CANCERSinvasion into the seminal vesicle, and nodal and distant metas-

tases increases with increasing PSA, tumour volume and Gleason

score. Invasion into the seminal vesicle is associated with nodal

and distant spread. The obturator lymph node chain is the most

common site for lymphatic spread. Metastatic spread usually

involves non-regional lymphatics and the axial skeleton.

Diagnosis

Early low-grade prostate cancer is usually asymptomatic. Locally

advanced or metastatic disease is usually the cause if men

present with symptoms. Local growth can cause obstructive or

irritative urinary symptoms. Metastatic spread can present as

bone pain and even compression of the spinal cord. The main

investigations to diagnose prostate cancer are discussed below.

PSA: most cancers are discovered by routine measurement of

PSA in serum. A screening programme for prostate cancer andProstate cancer is graded using the Gleason grading system, which

is based on the microscopic appearance of the glandular architec-

ture of the prostate. The system is in two parts: a grade between

1 and 5 is given to themost dominant pattern; then a gradebetween

1 and 5 is given to the second commonest pattern. The two are

added together to give the Gleason score. Thus, a Gleason score

ranges from 2 to 10 and is usually fully annotated (e.g. 3 4 7).The grade indicates the degree of glandular differentiation: grade 1

indicates a well-differentiated tumour, whereas grade 5 is a poorly

differentiated tumour. The Gleason score gives an indication of

prognosis and tumour progression.

The staging of prostate cancer is assessed using a number of

diagnostic tools, including digital rectal examination, bone

scintigraphy and MRI. Not all are essential in every case; the

decision is guided by the concentration of PSA in serum, Gleason

score and the clinical stage. Imaging is often unnecessary in

patients who are at low risk of metastases using these

parameters.

Tumour progressionGrading and stagingProstatic intraepithelial neoplasia (PIN) is the precursor of

prostate cancer. Cells show similar characteristics to those of

prostate cancer cells, but the basal cell layer is present. PIN is

often found adjacent to areas of prostate cancer, and its identi-

fication in biopsy specimens in the absence of cancer warrants

further investigation for concurrent invasive carcinoma.Pathology

Over 95% of prostate cancers are adenocarcinomas; the

remainder are neuroendocrine tumours or sarcomas. Character-

istic prostate adenocarcinoma cells have hyperchromatic,

enlarged nuclei with prominent nucleoli and abundant cyto-

plasm. The basal cell layer is absent in prostate cancer, but

present in normal glands and the glands of benign prostatic

hyperplasia. Prostate cancer is often multifocal. About 70% are

found in the peripheral zone, 20% originate in the transition

zone, and 10% are within the central zone.MEDICINE 40:1 11the routine measurement of PSA is not present in the UK. The

advantages would be:

an initial increase in incidence rates as more cancers aredetected, followed by a fall as they are treated

detection of the disease at earlier stages and decrease inmortality from advanced disease

an increase in relative survival rate as compared to othercauses of death

detection of disease at a younger age and at lowerconcentrations of PSA.

The disadvantages include the:

number of false-positives e the PSA test lacks specificity,and the concentration may be high due to other causes

(e.g. infection (prostatitis), benign prostatic hyperplasia

(BPH), acute urinary retention, vigorous digital rectal

examination)

number of false-negatives e the PSA test lacks sensitivity,and the concentration may be within the typical normal

range even in the presence of cancer

potential identification and subsequent treatment of clini-cally irrelevant disease.

The upper limit of normal PSA is usually 4 ng/ml, but this value

will include some patients with BPH and some with prostate

cancer. The PSA increases with age, so the value must be adjusted

for age. Further refinements of the PSA have been employed.

The speed of rise of PSA concentration (PSA velocity)during the year before the diagnosis of cancer is strongly

associated with the risk of death from prostate cancer.

The ratio of free:total concentration of PSA can indicatewhether a rise is due to BPH or cancer. A value of less than

18% suggests cancer and biopsy is indicated.

The digital rectal examination is an essential part of the urolog-

ical examination, enabling the size of the prostate gland to be

assessed, and nodules or lumps to be detected. The digital rectal

examination alone can determine the need for further investiga-

tion. The cancer can be staged by assessing whether the tumour

extends to the seminal vesicles or invades adjacent structures.

Transrectal ultrasound and biopsy are indicated if cancer is

suspected because of a raised PSA and the findings of the digital

rectal examination. This procedure is done under local anaes-

thesia and biopsies of the prostate are taken via a transrectal

ultrasound probe. Ultrasound-guided biopsy:

provides more accurate staging than the digital rectalexamination

allows lesions to be identified enables the volume of the prostate gland to be measured.

Biopsies are taken with a Tru-Cut needle and 6e12 cores are

removed. This process samples a small percentage of the prostate

gland, but the urologist or radiologist can focus on taking samples

from lesions that feel or look suspicious on ultrasound. Occa-

sionally, despite a high PSA, the biopsies are negative for cancer,

or PIN is found. Most urologists recommend repeat biopsies or

even saturation biopsies (20 biopsies are taken) if suspicion

remains high. In general, transrectal ultrasound and biopsies have

a low morbidity. Infection is seen in less than 5% (provided anti-

biotic prophylaxis is used) and less than 2% have significant

bleeding. Anticoagulants should be stopped before biopsy. 2011 Published by Elsevier Ltd.

the entire prostate gland, which reduces the risk of disease

tate gland. The urethra is then anastomosed to the base of the

fewer adverse effects, but proctitis, rectal bleeding and haema-

turia can occur. There is also a 1e3% risk of incontinence. In

carefully selected patients, external-beam radiotherapy offers

a 15-year overall survival, similar to that seen after radical

prostatectomy. Radiotherapy may be combined with hormonal

therapy and two trials have shown improved overall survival in

high-grade and locally advanced disease with the use of pro-

longed androgen deprivation therapy (see below) following

radiotherapy. The cancer cannot usually be treated by surgery if

recurrence occurs. One study has revealed a doubling of inci-

dence of rectal carcinoma in patients treated with external-beam

radiotherapy, so post-treatment rectal bleeding should be

investigated.

Brachytherapy is the deployment of radioactive seeds directly

into the prostate gland. It can be done as a two-stage (two visits

to hospital; to be measured and then implanted with the seeds)

or a one-stage procedure. Brachytherapy can be combined with

external-beam radiotherapy in patients considered at high risk of

recurrence. Brachytherapy is most suitable for patients with

smaller, lower-risk cancers and for men with small or medium-

sized prostate glands. Long-term tumour control from mature

series appears to be equivalent to prostatectomy and external-

beam radiotherapy. Without careful case selection, the predom-

inant complication is the occurrence of obstructive urinary

symptoms, including the need for prolonged catheterization.

Sexual function is thought to be better preserved after brachy-

therapy compared to surgery and radiotherapy.

COMMON CANCERSbladder. The obturator lymph nodes are sampled. A catheter is

left for 2 weeks while the urethra and bladder heal. A recent

randomized controlled clinical trial showed a significant

improvement in mean survival in patients treated by radical

prostatectomy compared to those managed by watchful waiting,

and a 50% reduction in the development of metastases.

Erectile dysfunctionmay result in up to 50%of patients, but can

be greatly improved with phosphodiesterase-5 inhibitors. Stress

incontinence is seen in 2e3% and almost invariably improves

with pelvic floor exercises, physiotherapy and/or anticholinergics.

Careful histopathological examination of the whole tumour

specimen can identify patients at higher risk of recurrence, which

can be reduced by postoperative radiotherapy.

External-beam radiotherapy: radiation therapy provides

a definitive treatment approach for localized and locallyrecurrence. The procedure is commonly done through a hori-

zontal or vertical incision on the lower abdomen. Laparoscopic

and robot-assisted laparoscopic removal of the prostate are

becoming more common. Particular care is taken to preserve the

delicate nerves on either side of the prostate; this reduces the risk

of impotency. The seminal vesicles are removed with the pros-Radical prostatectomy (Figure 1) has the advantage of removingoccur if the cancer progresses.Other investigations

MRI or CT of the pelvic area is indicated if biopsies are positive

for adenocarcinoma. This gives anatomical information about

the local extension of the cancer and lymph node involvement,

which is important if a radical prostatectomy is considered.

Whole-body bone scintigraphy is carried out if the PSA is

over 10 ng/ml. This gives information on bony metastases that

may influence management.

New molecular studies are available that may negate the need

for prostate biopsies. A specific urine sample assay can detect

PCA3, a gene that is overexpressed in prostate cancer tissue. A

prostate massage is done so that prostate cells are shed; these are

then caught via a urine sample for analysis.

Differential diagnosis

Induration of the prostate, apparent on digital rectal examination,

is also associated with prostatitis, previous transurethral resection

of the prostate, needle biopsy or prostatic calculi. The main

differential diagnoses are BPH, prostatic calculi and prostatitis.

Management

Localized prostate cancer

Watchful waiting/active surveillance may be the most appro-

priate course for men aged over 70 years and/or those with

significant co-morbidity, particularly if the cancer is low volume

and the Gleason score is low. Careful follow-up with regular

digital rectal examination and monitoring of PSA is important.

Counselling and implementation of active treatment shouldMEDICINE 40:1 12advanced disease. Pelvic lymph nodes can be included in the

treatment field. Advances in radiotherapy have led to the radia-

tion beam being focused on the prostate gland. This has led to

Watchful waiting

Number at risk

347Radicalprostatectomy

348

343

341

332

326

284

279

210

198 104

118

Incidence of death from prostate cancer: watchful waitingversus radical prostatectomy

00

40

30

10

20

2 4 6

Years of follow-up

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8 10

Radical prostatectomy

Watchful waiting

Source: Bill-Axelson A, Holmberg L, Ruutu M et al. Scandinavian ProstateCancer Group Study No. 4. Radical prostatectomy versus watchful waiting inearly prostate cancer. New Engl J Med 2005; 352: 197784. Reproduced withpermission.

Figure 1 2011 Published by Elsevier Ltd.

Locally advanced prostate cancer

Hormonal therapy

Analogues of luteinizing hormone-releasing hormone

(LHRHa) are usually given as a depot injection every 3 months.

They act by over-stimulating LHRH receptors in the pituitary gland

and, via negative feedback, stop the release of luteinizing hormone

from the pituitary gland. The concentration of circulating testos-

terone is reduced to a castration level. These agents reduce the size

of the cancer and slow progression, but do not eradicate the

disease. Themain adverse effects of androgen deprivation therapy

(ADT) are hot flushes, sweats, and reduced libido. Patients may

also notice reduced muscle mass, reduced strength and weight

gain. A proportion of patients suffer reduced bone mineral density

and there is known to be an increased risk of non-traumatic frac-

LHRHa and anti-androgens in combination confer complete

testosterone blockade. It is not clear whether this combination

therapy significantly increases the time to progression or overall

survival. Combination therapy is probably best suited to

younger, relatively fit men with advanced prostate cancer

because it may result in a longer period before disease

progression.

Follow-up: most patients have regular measurement of PSA.

After radical prostatectomy, the PSA should remain at zero if all

the cancer has been removed. In locally advanced and metastatic

disease treated with hormones, it should fall to very low levels

initially.

COMMON CANCERSLHRHa: the response to this treatment in metastatic cancer is

about 80%, and benefits last for 18e36 months. A large rise in

circulating testosterone may be seen when the injection is first

given, causing bone pain and even spinal cord stenosis; anti-

androgens are given to protect against this tumour flare.

Newer LHRH antagonists (e.g. degarelix) do not cause a surge

and may have a role in emergency situations e such as newly

diagnosed cancer presenting with cord compression.months.tures, somen at risk of osteoporosis should be carefullymonitored

or treated with bisphosphonates where necessary.

Anti-androgens block the action of testosterone on the pros-

tate gland. Adverse effects include breast enlargement and

soreness. They can also cause mild stomach upset and damage

the liver. They do not have such a profound effect as LHRHa on

potency and libido. Anti-androgens slow the progression of, but

do not cure prostate cancer.

Metastatic prostate cancer

About 70% of men with metastatic prostate cancer die from their

cancer within 5 years. Progression can be delayed for several

years by the treatments discussed below.

Bilateral orchidectomy is the surgical removal of both testicles

so that testosterone is no longer produced. Prosthetic testes can

be inserted for a better cosmetic appearance. A subcapsular

orchidectomy (only the cells of the testes are removed and the

capsule is left) can be done. The main adverse effects are hot

flushes, loss of libido and impotence. About 80% of men respond

to this treatment, which slows disease progression for about 18MEDICINE 40:1 13and practice. London: Taylor and Francis, 2005.Castrate-refractory prostate cancer

Prostate cancer eventually becomes insensitive to hormone

ablation and the PSA begins to rise (castrate-refractory prostate

cancer). This rise is often accompanied by clinical symptoms,

particularly bone pain. Whole-body bone scintigraphy must be

repeated to see if the cancer has spread. This is an area that is

changing rapidly and therapeutic options that have been shown

to benefit the patient include:

modifying existing hormonal therapy (e.g. abiraterone) cytotoxic chemotherapy (e.g. docetaxel) bone-directed therapies (e.g. bisphosphonates, monoclonal

antibodies to RANK-ligand, radioisotopes)

palliative radiotherapy.Most of these treatments have shown a small benefit in the late

stages of disease and it is hoped that, by using them earlier in the

treatment of locally advanced and metastatic disease, they will

have a greater effect.

Prognosis

The natural history of prostate cancer is highly dependent on

stage, grade, co-morbidity and age. The survival rate at 10 years

for a well-differentiated, localized prostate cancer may be as high

as 90%; for a poorly differentiated tumour it drops to 60% or

less. Prostate cancer is one of the few solid cancers that is readily

curable, if it is detected early. A

FURTHER READING

Kirby RS, Partin A, Feneley M, Parsons K, eds. Prostate cancer: principles 2011 Published by Elsevier Ltd.

Cancer of the prostate gland Epidemiology Aetiology and risk factors

Pathology Grading and staging Tumour progression

Diagnosis Other investigations Differential diagnosis Management Localized prostate cancer Locally advanced prostate cancer Metastatic prostate cancer Castrate-refractory prostate cancer

Prognosis Further reading