Transcript Treatment of Prostate Cancer

Prostate Cancer
Mr R Puri
BSc, MBBS, MS, D Urol,
FRCS(Urol)
Consultant Urologist
Bradford Royal Infirmary
Relationship of the prostate
to the urogenital tract
Bladder
Urethra
Penis
Testis
Seminal
vesicle
Ejaculatory
duct
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
200
180
160
140
120
100
80
60
40
20
0
Year
USA
1970
1972
1974
1976
1978
1980
1982
1984
1986
1988
1990
1992
1994
1996
England and Wales
Mortality rate per 100,000 males
1970
1972
1974
1976
1978
1980
1982
1984
1986
1988
1990
1992
1994
1996
Incidence rate per 100,000 males
Age-adjusted incidence and mortality rates in
the UK and the USA
Yorkshire (England)
35
30
25
20
15
10
5
0
Year
Oliver et al 2000
Prostate Cancer
Facts
• 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 1998
Bradford HA pop. 483285
• Incidence - Europe
• Mortality - Europe
-
65.1/100,000
25.2/100,000
• Incidence - NYCRIS
• Mortality - NYCRIS
-
76.4
30.5
Bradford HA pop. 483285
Extent 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
Epithelial cell
Nucleus
Testosterone
5a-R
PSA
(neutral serine protease)
PSA secreted
into gland
lumen and
blood stream
Translation
Transcription
mRNA
T, testosterone
DHT, dihydrotestosterone
5a-R, 5a-reductase
http://www.uronet.org/visual/mar97/image4.gif
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
PSA values-2
•
PSA
2.5 – 4
4 - 10
> 10
•
•
•
•
Free / Total PSA
Complexed PSA
PSA density
PSA velocity
12% CaP
36% CaP
50% CaP
Presentation
Localised Disease
•
•
•
•
Local Disease
Asymptomatic
Raised PSA
LUTS
– Obstructive
– Irritative
UTI
•
•
•
•
•
•
Locally Advanced
Haematuria
Impotence
Suprapubic and
perineal pain
Haemospermia
Anuria
Renal failure
Presentation
Metastatic 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?
Study location
and dates
No. patients
Effect of screening
on mortality
Canada 1986-1996
46,732
 69%**
Austria 1993-1998
21,079
 42%*
Europe 1998(ERSPC trial)
113,194
Data available
after 2005
USA 1993(PLCO trial)
74,000
Data available
after 2005
*p<0.05
**p<0.01
Bartsch et al 2000
Gohagan et al 1994
Labrie et al 1999
Schröder et al 1999
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
Early Detection of Prostate Cancer
Are 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 Cancer
Are 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
Gleason
grade
1
2
3
4
5
Kirby 1999
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 PIN
Localised
prostate Locally
cancer advanced
TxN0M0
T3-4
Metastatic Hormone
disease insensitive
D1.5
D2
D2.5 D3
Time (years)
Treatment options:
Radical prostatectomy
Radiotherapy
‘Watchful waiting’
Hormonal therapy
Radiotherapy
Hormonal therapy
‘Watchful waiting’
PIN, prostatic intraepithelial neoplasia
Chemotherapy
Clinical staging TNM 1997
T1a/b
T3a
T1c T1a
T3b
T2a
T1b
T3c
T1c
T2b
T4
Clinical staging (4)
N+
Nx = loco-regional lymph nodes
cannot be evaluated
N0 = no lymph node involvement
N1-N3 = regional lymph metastasis
M+
Mx = no metastasis can be
evaluated
M0 = no distant metastasis
M1 = distant metastasis present
a = lymph nodes other than
regional nodes
b = skeletal
c = other sites
D1-D1.5
D2-D2.5
D3 refractory to
hormonal therapy
D3S hormone sensitive
D3I hormone insensitive
N1 = solitary <2 cm
N2 = solitary >2 cm and <5 cm
N3 = >5 cm
No TNM equivalent
The use of nomograms for
predicting disease recurrence
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•
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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
Partin’s Normograms
T1c (inpalpable)
Gleason sum score 7
PSA <4
OC 63%
PSA 4-10
OC 49%
PSA 10 – 20
OC 35%
T2a
OC
22%
Treatment
Localised 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
•Iodine
•Conformal CT
guided planning
•Palladium
*TRUS planning
*MRI planning
Adjuvant Hormone Treatment
Neoadjuvant Hormone Treatment
Brachytherapy
Transperineal seed implant
Belldegrun et al 2000
Brachytherapy vs radical prostatectomy:
7-year progression-free survival
Brachytherapy
Radical
prostatectomy
No.
patients
Ramos et al 1999
79%
84%
299
Polascik et al 1998
Ragde et al 1997
79%
98%
198
Radiotherapy plus hormonal therapy
for locally advanced prostate cancer
Neoadjuvant
Pilepich et al 1995
RTOG 86-10
Significant improvement in progressionfree survival
Shearer et al 1992
Significant reduction in tumour volume
(downsizing)
Adjuvant
Bolla et al 1997, 1999
EORTC 22863
Significant improvement in overall survival
& disease-free survival
Pilepich et al 1997
Lawton et al 1999
RTOG 85-31
Significant improvement in overall 5-year
survival (for poor prognosis patients)
Granfors et al 1998
Significant improvement in progressionfree 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 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
Prostate cancer is hormone-dependent
Testosterone
Hypothalamus
Pituitary
LHRH
Testes
Prostate
Prolactin
Adrenal
Cortisol
LHRH, luteinising hormone-releasing hormone
LH, luteinising hormone
ACTH, adrenocorticotrophin
Adrenal
androgens
LHRH Agonists
Zoladex
Prostap
Mechanism of action of ‘Zoladex’
(goserelin)
2. Hypersecretion
of LH
1. Normal LH release
P
LH
P
LH
3. Hyposecretion
of LH
P
LH
Furr and Hutchinson 1992
Administration of ‘Zoladex’ (goserelin)
Antiandrogens: chemical structures
NH
O
OH
C
C
CH3
CH2 SO2
F
NHCOCOH
NO2
CH3
CH3
CF3
CF3
Hydroxyflutamide
CN
‘Casodex’ (bicalutamide)
CH3
CH3
O
C
NH
C
C
CH2
CH3
C=O
OAc
N
NO2
CF3
O
CH3
Nilutamide (RU 23908)
CH3
O
CI
Cyproterone acetate
Mechanism of action of
Flutamide &‘Casodex’ (bicalutamide)
Androgens
ACTH
Prostate cell
Adrenal gland
Nucleus
DHT
LHRH
Hypothalamus
Pituitary gland
X
Other
target tissues
DHT Androgen
receptor
Testis
LH
-ve feedback control
Circulating testosterone
‘Casodex’
(bicalutamide)
Overall survival in M0 patients:
median 6.3 years’ follow-up
% patients 100
surviving
80
60
40
20
‘Casodex’ (bicalutamide) 150 mg
Castration
0
Time (days)
HR 1.05; 95% CI 0.81, 1.31; p=0.70
Iversen et al 2000
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
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•
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prednisone
mitoxantrone
docetaxel
estramustine
• ZD1389
ZD1839: mechanism of action
Potent and selective inhibitor of the epidermal growth
factor receptor (EGFR)
Cancer cell
X
Kinase
Proliferation
X
Apoptosis
X
Angiogenesis
X
Metastasis
X
Membrane
Nucleus
ZD1839
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