Prostate Cancer

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Prostate Cancer

• Mr R Puri
• BSc, MBBS, MS, D Urol, FRCS(Urol)
• Consultant Urologist
• Bradford Royal Infirmary

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Relationship of the prostate to the urogenital
tract
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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

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What does the prostate do?

• Contributes to the seminal plasma
• 60 seminal vesicles
• 20 prostate
• Prostate add
• PSA
• Zinc
• Phospholipids
• Spermine

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Age-adjusted incidence and mortality rates in the
UK and the USA
Oliver et al 2000
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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
  

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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

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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

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Detection of Prostate Cancer

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

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PSA production and action
Epithelial cell
Nucleus
PSA secretedinto gland lumen and blood stream
DHT
PSA(neutral serine protease)
Testosterone
5a-R
Translation
Transcription
mRNA
T, testosterone DHT, dihydrotestosterone 5a-R,
5a-reductase
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PSA values

• Age specific
• 40 - 49 2.5 ng/ml (ug/L)
• 50 - 59 3.5
• 60 69 4.0
• 70 79 6.5
• ERSPC - any value above 3 is abnormal
• Recent US guidelines - any value above 2.5 is
  abnormal

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PSA values-2

• PSA 2.5 4 12 CaP
• 4 - 10 36 CaP
• gt 10 50 CaP
• Free / Total PSA
• Complexed PSA
• PSA density
• PSA velocity

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PresentationLocalised Disease

• Local Disease
• Asymptomatic
• Raised PSA
• LUTS
• Obstructive
• Irritative
• UTI

• Locally Advanced
• Haematuria
• Impotence
• Suprapubic and perineal pain
• Haemospermia
• Anuria
• Renal failure

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PresentationMetastatic Disease

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

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Presentation

• Why wait for symptoms ?
• Or
• Should we screen for prostate cancer ?

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Does screening decrease prostate cancer death?
Bartsch et al 2000Gohagan et al 1994 Labrie et
al 1999 Schröder et al 1999
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Benefits of PSA/DRE Screening European
Experience

• County Tyrol, Austria
• Population 630,000
• Free 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

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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 gt10 have organ
  confined disease
• Only 30 of patients with T3 disease are free of
  PSA recurrence 5 years after Radical
  Prostatectomy

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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

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Screening for prostate cancerconclusions

• 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

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Diagnosistransrectal ultrasound (TRUS)
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Biopsy technique
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Histological gradingGleason system
Kirby 1999
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Why the Debate About Treating Prostate Cancer?

• Prostate cancer is unique amongst solid tumours
  in that it exists in two form
• Pussy cat
• Tiger

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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

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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

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Treatment for prostate cancer
Localisedprostatecancer
Metastatic disease
Hormone insensitive
Locallyadvanced
High-grade PIN
D1.5
D2
D2.5
D3
TxN0M0
T3-4
Time (years)
Treatment options
Radical prostatectomy Radiotherapy Watchful
waiting
Hormonal therapy
Chemotherapy
Radiotherapy Hormonal therapy Watchful waiting
PIN, prostatic intraepithelial neoplasia
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Clinical staging TNM 1997
T1a/b T1c T2a T2b
T3a T3b T3c T4
T1a
T1b
T1c
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Clinical staging (4)
N
Nx loco-regional lymph nodes cannot be
evaluatedN0 no lymph node involvementN1-N3
regional lymph metastasis N1 solitary lt2 cm N2
solitary gt2 cm and lt5 cm N3 gt5 cm
D1-D1.5
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
D2-D2.5
D3S hormone sensitive D3I hormone insensitive
No TNM equivalent
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The use of nomograms for predicting disease
recurrence

• Preoperative PSA level
• Preoperative Gleason score
• TNM clinical stage

Preoperative and postoperative nomograms
Kattan et al 1998 Kattan et al 1999 Partin et al
1997
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Partins NormogramsT1c (inpalpable) Gleason sum
score 7

• PSA lt4
• OC 63
• PSA 4-10
• OC 49

• PSA 10 20
• OC 35
• T2a
• OC 22

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TreatmentLocalised Prostate Cancer

• Radical Prostatectomy
• Retropubic
• Perineal
• Laproscopic
• Robotic
• Radiotherapy
• External beam CT guided Conformal
• Brachytherapy
• Experimental
• Cryotherapy

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Radical Prostatectomy
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Disadvantages of Radical Prostatectomy

• Mortality 0.5
• Incontinence rate 10
• Impotence gt50
• ? Effect on survival
• Majority of patients would be happy to go through
  the procedure again inspite of the side effects

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Radiotherapy
Brachtherapy
External Beam RT

• Standard
• Conformal CT guided planning

• Iodine
• Palladium

TRUS planning MRI planning
Adjuvant Hormone Treatment Neoadjuvant Hormone
Treatment
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BrachytherapyTransperineal seed implant
Belldegrun et al 2000
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Brachytherapy vs radical prostatectomy7-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
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Radiotherapy plus hormonal therapy for locally
advanced prostate cancer
Neoadjuvant Pilepich et al 1995RTOG
86-10 Shearer et al 1992 Adjuvant Bolla et al
1997, 1999EORTC 22863 Pilepich et al
1997Lawton et al 1999RTOG 85-31 Granfors et al
1998
Significant improvement in progression-free
survival Significant reduction in tumour volume
(downsizing) Significant improvement in overall
survival disease-free survival Significant
improvement in overall 5-year survival (for poor
prognosis patients) Significant improvement in
progression-free survival overall survival
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Management of locally advanced/ metastatic
prostate cancer

• LHRH agonists
• Orchiectomy
• Antiandrogen monotherapy
• Maximal androgen blockade

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Early treatment of locally advanced
disease/metastatic/poorly differentiated cancer

• Treatment of T3NXM0
• MRC 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

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Prostate cancer is hormone-dependent
Testosterone
Testes
Pituitary
Hypothalamus
Prostate
Oestrogen
LH
Prolactin
LHRH
ACTH
Adrenal
Cortisol
Adrenalandrogens
LHRH, luteinising hormone-releasing hormone LH,
luteinising hormoneACTH, adrenocorticotrophin
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LHRH Agonists

• Zoladex
• Prostap

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Mechanism of action of Zoladex (goserelin)
Furr and Hutchinson 1992
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Administration of Zoladex (goserelin)
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Antiandrogens chemical structures
CH3
NHCOCOH
NO2
CH3
CF3
Hydroxyflutamide
Casodex (bicalutamide)
CH3
C O
CH3
CH3
CH2
O
CI
Nilutamide (RU 23908)
Cyproterone acetate
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Mechanism of action of Flutamide Casodex
(bicalutamide)
Androgens
ACTH
Prostate cell
Adrenal gland
Nucleus
DHT
LHRH
X
Hypothalamus
Other target tissues
Pituitary gland
Casodex (bicalutamide)
DHT
Androgen receptor
Testis
LH
Circulating testosterone
-ve feedback control
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Overall survival in M0 patients median 6.3
years follow-up
patients surviving
100
80
60
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Casodex (bicalutamide) 150 mg
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Castration
0
0
200
400
600
800
1000
1200
1400
1600
1800
2000
2200
2400
2600
2800
Time (days)
Iversen et al 2000
HR 1.05 95 CI 0.81, 1.31 p0.70
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Hormone insensitive prostate cancerOptions

• Antiandrogen withdrawal
• Second-line hormonal therapy
• Chemotherapy

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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

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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

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Chemotherapy

• In patients with hormone-refractory prostate
  cancer
• prednisone
• mitoxantrone
• docetaxel
• estramustine
• ZD1389

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ZD1839 mechanism of actionPotent and selective
inhibitor of the epidermal growth factor receptor
(EGFR)
EGF
TGFa
Membrane
Cancer cell
X
Kinase
Nucleus
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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.

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Case 1

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

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Case 2

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

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Case 3

• 79 years old with acute retention