Prostate Cancer

Mr R PuriBSc, MBBS, MS, D Urol,

FRCS(Urol)Consultant Urologist

Bradford Royal Infirmary

Relationship of the prostate to the urogenital tract

Testis

Penis

Urethra

Bladder

Ejaculatoryduct

Seminal vesicle

Prostate

What does the prostate do?

• The coagulum formed by the ejaculated semen liquefies within 20 minutes as a result of prostate proteolytic enzymes

Best known is Prostate Specific Antigen

PSA

What does the prostate do?

• Contributes to the seminal plasma– 60% seminal vesicles– 20% prostate

• Prostate add– PSA – Zinc– Phospholipids– Spermine

Age-adjusted incidence and mortality rates in the UK and the USA

Oliver et al 2000

1970

1972

1974

1976

1978

1980

1982

1984

1986

1988

1990

1992

1994

1996

05

101520253035

Year

Mor

talit

y ra

te p

er 1

00,0

00 m

ales

Inci

denc

e ra

te p

er 1

00,0

00 m

ales

1970

1972

1974

1976

1978

1980

1982

1984

1986

1988

1990

1992

1994

1996

020406080

100120140160180200

Year

England and Wales USA Yorkshire (England)

Prostate CancerFacts

• Commonest cancer in men after middle age• Second only to lung cancer as cause of death in

men• Histological prostate cancer in 30% of

population• Lifetime risk of developing clinical prostate

cancer is 10%• Risk of death from prostate cancer is 3%

NYCRIS Data 1998Bradford HA pop. 483285

• Incidence - Europe• Mortality - Europe

• Incidence - NYCRIS• Mortality - NYCRIS

- 65.1/100,000- 25.2/100,000

- 76.4- 30.5

Bradford HA pop. 483285Extent of problem

• New cases per year - 183

• Deaths due to Ca P - 73

Only 94 out of the 183 will be offered potentially curative treatment

Detection of Prostate Cancer

• Digital Rectal examination• PSA testing• Trans rectal ultrasound and biopsy

PSA production and action

T, testosteroneDHT, dihydrotestosterone5-R, 5-reductase

Epithelial cellNucleus

PSA secretedinto gland lumen and blood stream

PSA(neutral serine protease)

Translation

mRNA

Testosterone

DHT5

-R

Transcription

http://www.uronet.org/visual/mar97/image4.gif

PSA values

• Age specific40 - 49 2.5 ng/ml (ug/L)50 - 59 3.560 – 69 4.070 – 79 6.5

• ERSPC - any value above 3 is abnormal• Recent US guidelines - any value above 2.5 is

abnormal

PSA values-2

• PSA 2.5 – 4 12% CaP4 - 10 36% CaP > 10 50% CaP

• Free / Total PSA• Complexed PSA• PSA density• PSA velocity

PresentationLocalised Disease

Local Disease• Asymptomatic• Raised PSA• LUTS

– Obstructive– Irritative

• UTI

Locally Advanced• Haematuria• Impotence• Suprapubic and

perineal pain• Haemospermia• Anuria• Renal failure

PresentationMetastatic Disease

• Low back pain• Spinal cord compression• Bone pain• Anaemia• Weight loss

Presentation

Why wait for symptoms ?Or

Should we screen for prostate cancer ?

Does screening decrease prostate cancer death?

Bartsch et al 2000Gohagan et al 1994

Labrie et al 1999Schröder et al 1999

Study location and dates

Canada 1986-1996

Austria 1993-1998

Europe 1998- (ERSPC trial)

USA 1993- (PLCO trial)

No. patients

46,732

21,079

113,194

74,000

Effect of screeningon mortality

69%**

42%*

Data availableafter 2005

Data availableafter 2005

*p<0.05**p<0.01

Benefits of PSA/DRE Screening: European Experience

County Tyrol, AustriaPopulation 630,000Free PSA testing available 24hrs a day since 1993• Decrease in mortality due to CaP by

32%,42% ,33% in 1997,98 &99• Stage migration - Organ confined cancers

increased from 28% in 93 to 82% in 98

Early Detection of Prostate CancerAre There Any Benefits?

• In non screened populations only 30% of CaP detected is organ confined

• Only 22% of patients with PSA >10 have organ confined disease

• Only 30% of patients with T3 disease are free of PSA recurrence 5 years after Radical Prostatectomy

Early Detection of Prostate CancerAre There Any Benefits?

• In screened population 71-97% of the detected cancers were organ confined at staging

• 70% of these cancers are organ confined after radical prostatectomy

• 10 year PSA non progression rate is 80%• Disease specific survival rate at 15 years is 84-

97%

Screening for prostate cancer:conclusions

• Ongoing debate: would increased detection decrease disease-specific mortality?

• Screening costs need to be balanced against higher costs of treating patients with advanced disease

• Costs could be considerably reduced by increased sensitivity of screening assay

Diagnosis:transrectal ultrasound (TRUS)

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Biopsy technique

Histological grading:Gleason system

Kirby 1999

Gleasongrade

1 2 3 4 5

Why the Debate About Treating Prostate Cancer?

Prostate cancer is unique amongst solid tumours in that it exists in two form

• Pussy cat

• Tiger

Why the Debate About Treating Prostate Cancer?

Latent Cancer (Pussy Cats)• Prevalence 20-48%, increases with age 60 -70% of men over 80 years have latent

carcinoma prostate

• Well to moderately differentiated, localised, CaP in older men is often not clinically significant

Why the Debate About Treating Prostate Cancer? The Tigers• A patient below 65yrs diagnosed to have a

CaP has a75% chance of developing metastasis and 52% chance of dying from CaP if he lives 15 years

• Screening does not detect latent cancer• Majority of cancers detected on screening are

localised cancers• Localised CaP is curable

Treatment for prostate cancer

High-grade PINMetastatic

diseaseHormone

insensitive

Radical prostatectomy Radiotherapy

‘Watchful waiting’ Radiotherapy

Hormonal therapy‘Watchful waiting’

Hormonal therapy

D1.5 D2 D2.5 D3TxN0M0 T3-4

Locallyadvanced

Localisedprostatecancer

Treatment options: Chemotherapy

Time (years)

PIN, prostatic intraepithelial neoplasia

Clinical staging TNM 1997

T1a

T1b

T1c

T1a/b

T1c

T2a

T2b

T3a

T3b

T3c

T4

Clinical staging (4)Nx = loco-regional lymph nodes

cannot be evaluatedN0 = no lymph node involvementN1-N3 = regional lymph metastasis

N1 = solitary <2 cm N2 = solitary >2 cm and <5 cm N3 = >5 cm

D3 refractory tohormonal therapy

D1-D1.5

D2-D2.5

D3S hormone sensitive D3I hormone insensitive

No TNM equivalent

N+

M+Mx = no metastasis can be

evaluatedM0 = no distant metastasisM1 = distant metastasis present a = lymph nodes other than regional nodes b = skeletal c = other sites

The use of nomograms for predicting disease recurrence

• Preoperative PSA level• Preoperative

Gleason score• TNM clinical stage

Preoperative and postoperative nomograms

Kattan et al 1998Kattan et al 1999Partin et al 1997

Partin’s NormogramsT1c (inpalpable)

Gleason sum score 7 PSA <4

OC 63%

PSA 4-10OC 49%

PSA 10 – 20OC 35%

T2aOC 22%

TreatmentLocalised Prostate Cancer

• Radical Prostatectomy– Retropubic– Perineal– Laproscopic– Robotic

• Radiotherapy– External beam – CT guided Conformal– Brachytherapy

• Experimental– Cryotherapy

Radical Prostatectomy

Disadvantages of Radical Prostatectomy

• Mortality 0.5%• Incontinence rate 10%• Impotence >50%• ? Effect on survival

Majority of patients would be happy to go through the procedure again inspite of the side effects

Radiotherapy

External Beam RT Brachtherapy

•Standard

•Conformal CT guided planning

•Iodine

•Palladium

*TRUS planning

*MRI planning

Adjuvant Hormone Treatment

Neoadjuvant Hormone Treatment

BrachytherapyTransperineal seed implant

Belldegrun et al 2000

Brachytherapy vs radical prostatectomy:7-year progression-free survival

Brachytherapy

79%

79%

Radical prostatectomy

84%

98%

No. patients

299

198

Ramos et al 1999

Polascik et al 1998Ragde et al 1997

Radiotherapy plus hormonal therapy for locally advanced prostate cancer

NeoadjuvantPilepich et al 1995RTOG 86-10Shearer et al 1992

AdjuvantBolla et al 1997, 1999EORTC 22863 Pilepich et al 1997Lawton et al 1999RTOG 85-31Granfors et al 1998

Significant improvement in progression-free survivalSignificant reduction in tumour volume (downsizing)

Significant improvement in overall survival & disease-free survivalSignificant improvement in overall 5-year survival (for poor prognosis patients)

Significant improvement in progression-free survival & overall survival

Management of locally advanced/ metastatic prostate

cancer• LHRH agonists

• Orchiectomy

• Antiandrogen monotherapy

• Maximal androgen blockade

Early treatment of locally advanced disease/metastatic/poorly differentiated

cancer

Treatment of T3NXM0MRC study Feb 1997 BJU• Deferred treatment resulted in

• Higher incidence of local progression• Higher incidence of painful metastasis• Higher incidence of ureteric obstruction• Twice the number of serious complications• Disadvantage in terms of survival

Prostate cancer is hormone-dependent

LHRH, luteinising hormone-releasing hormoneLH, luteinising hormoneACTH, adrenocorticotrophin

Testosterone

LHRH

Pituitary

Cortisol Adrenalandrogens

Prostate

Testes

Prolactin

Adrenal

HypothalamusLH

ACTHOestrogen

LHRH Agonists

ZoladexProstap

Mechanism of action of ‘Zoladex’ (goserelin)

P LH

PLH

PLH

1. Normal LH release 2. Hypersecretion of LH

3. Hyposecretion of LH

Furr and Hutchinson 1992

Administration of ‘Zoladex’ (goserelin)

Antiandrogens: chemical structures

‘Casodex’ (bicalutamide)

Hydroxyflutamide

Nilutamide (RU 23908)

NH

OH

C

O

C

CH3

CH2 SO2 F

CF3

CN

NO2

CF3

NHCOCOH

CH3

CH3

Cyproterone acetate

C = O CH3

CH2CH3

CH3

CIO

OAcO

NO2

CF3

NC

CH3

CH3O

C

NH

C

Mechanism of action of Flutamide &‘Casodex’ (bicalutamide)

LHRHHypothalamus

Pituitary gland

LH

ACTH

Adrenal gland

Testis

Circulating testosterone

Androgens

Othertarget tissues

DHT

‘Casodex’(bicalutamide)

Prostate cell

Androgenreceptor

-ve feedback control

Nucleus

DHT

X

Overall survival in M0 patients: median 6.3 years’ follow-up

% patients surviving

0

20

40

60

80

100

Time (days)0 200 400 600 800 1000 1200 1400 1600 1800 2000 2200 2400 2600

HR 1.05; 95% CI 0.81, 1.31; p=0.70 Iversen et al 2000

‘Casodex’ (bicalutamide) 150 mg Castration

2800

Hormone insensitive prostate cancer:Options

• Antiandrogen withdrawal

• Second-line hormonal therapy

• Chemotherapy

Role of androgen ablation in hormone sensitive/insensitive prostate cancer

• Not all of the cancer will be unresponsive and discontinuation of androgen suppression could allow tumour regrowth

• Continued androgen suppression may provide survival benefits in hormone-refractory prostate cancer

• Androgen ablation should be continued indefinitely based on minimal risk versus potential benefits

The role of antiandrogens in hormone ‘insensitive’ prostate cancer

• Progressing prostate cancer may respond to switching the antiandrogen therapy

– ‘Casodex’ (bicalutamide) is effective in some patients previously treated with flutamide

– flutamide is effective in some patients in whom first-line hormonal therapy has been highly effective

• There are treatment options if patients progress on antiandrogens

Stilboesterol

Honvan

Chemotherapy

In patients with hormone-refractory prostate cancer

• prednisone• mitoxantrone• docetaxel• estramustine

• ZD1389

ZD1839: mechanism of actionPotent and selective inhibitor of the epidermal growth

factor receptor (EGFR)

ProliferationX

Membrane Cancer cell

ZD1839

EGF TGF

ApoptosisXMetastasisXAngiogenesisX Nucleus

KinaseX

HOLISTIC APPROACH

It is the recognition that the patient must be educated so that he can, understand how to live, and sometimes die with his disease,but without anxiety.

Case 1

• 62 year civil servant presents with nocturnal voiding frequency of times for last 6 months

Case 2

• 72 years old farmer presents with haemospermia. PSA 17 clinically T2b neoplastic prostate

Case 3

• 79 years old with acute retention