Benign

Prostatic Hyperplasia




96-6-11
Understanding the prostate
Walnut-shaped gland that forms part of the
male reproductive system
Surrounds the urethra - the tube that
carries urine from the bladder out of the
body
n
n
Secretes semen which
carries sperm
During orgasm, prostate
muscles contract and
propel ejaculate out of
the penis
Understanding the prostate
n
n
The size of prostate enlarged microscopically since the
age of 40.Half of all men over the age of 60 will develop
an enlarged prostate
By the time men reach their 70s and 80s, 80% will
experience urinary symptoms
But only 25% of men aged 80 will be receiving BPH
treatment

BPH
n
n
Peripheral zone
Transition zone
Urethra
What is Benign Prostatic
Hyperplasia?

Peripheral zone
Transition zone
Urethra
What causes BPH?
BPH is part of the natural
aging process, like getting
gray hair or wearing glasses
BPH cannot be prevented
BPH can be treated
n
n
n
Blaivas JG. Urol Clin North Am 1985;12:21524
Whats LUTS?
Voiding (obstructive)
symptoms
Hesitancy
Weak stream
Straining to pass urine
Prolonged micturition
Feeling of incomplete
bladder emptying
Urinary retention
Storage (irritative or
filling) symptoms
Urgency
Frequency
Nocturia
Urge incontinence
LUTS is not specific to BPH not everyone with
LUTS has BPH and not everyone with BPH has LUTS
Diagnosis of BPH
Symptom assessment
the International Prostate Symptom Score (IPSS) is recommended as it is used
worldwide
IPSS

is based on a survey and questionnaire developed by the American Urological
Association (AUA). It contains:
seven questions about the severity of symptoms; total score 07 (mild), 819 (moderate),
2035 (severe)
eighth standalone question on QoL
Digital rectal examination(DRE)
inaccurate for size but can detect shape and consistency
PV determination- ultrasonography
Urodynamic analysis
Q
max
>15mL/second is usual in asymptomatic men from 25 to more than 60 years
of age
Measurement of prostate-specific antigen (PSA)
high correlation between PSA and PV, specifically TZV

men with larger prostates have higher PSA levels
1
PSA is a predictor of disease progression and screening tool for CaP
as PSA values tend to increase with increasing PV and increasing age, PSA may
be used as a prognostic marker for BPH
Interfere with sexual life
0
1
2

3
4
5
6
7
8
9
5059 years 6069 years 7079 years
IPSS = 0
IPSS 17
IPSS 819
IPSS 2035
8.5
7.6
6.6
4.9
5.7 5.7
4.6
3.7
4.0
3.5
2.6
1.7
n=12,815
Rosen et al. Eur Urol 2003 n=12815
Sexual Activity Decreases with
Age and LUTS: MSAM-7 Survey
When should BPH be treated?
BPH needs to be treated ONLY IF:
Symptoms are severe enough to bother
the patient and affect his quality of life
Complications related to BPH
n
n
Choosing the right treatment
Consider risks, benefits
and effectiveness of each
treatment
Consider the outcome and
lifestyle needs
n
n
Watchful waiting
Medication
Surgical approaches
nMinimal invasive
nTURP
nInvasive open procedures

Treatment options
n
n
n
watchful waiting
For mild symptoms. follow up1 to 2 times
yearly
Offer suggestions that help
reduce symptoms
Avoid caffeine and alcohol
Avoid decongestants and antihistamines

n
n
n
n
Medication
First line of defense against
bothersome urinary symptoms

Two major types:
blockers - relax the smooth
muscle of prostate and provide a
larger urethral opening
(Hytrin,Doxaben, Harnalidge)

5 reductase inhibitor -
Shrink the prostate
gland (Proscar, Avodart)
n
n
n
n
Benefits
Convenient
No loss of work
time
Minimal risk
Disadvantages
Drug Interactions
Must be taken every day
Manages the problem
instead of fixing it
Medication
n
n
n
n
n
n

Possible side effects of

Impotence
Dizziness
Headaches
Fatigue
Loss of sexual drive

medication

n
n
n
n
n
-Adrenergic Blockers: Rationale
Prostate smooth muscle tone is mediated via

1
-adrenergic receptor
Blockage of the receptor leads to improvement
of flow rate and LUTS
1

Central -receptors and the effect of agents on
these receptors likely play an additional role
Density of adrenergic receptors changes with
prostate size and age
Three
1
-adrenergic receptor subtypes
have been identified (A, B, D)
Schwinn DA. BJU Int. 2000;86(suppl 2):11-22.
Distribution of
1
-Adrenergic Receptors
Localization of
1
-Adrenergic
Receptors (
1
-ARs)

-Blockers
Nonselective
Phenoxybenzamine
Short-acting selective
1
-blocker
Prazosin, Alfuzosin
Long-acting selective
1
-blockers
Terazosin
Doxazosin
Long-acting selective
1A
-subtype
Tamsulosin
Alfuzosin-SR

1
-Adrenergic Blockers: Summary
All currently available
1
-blockers induce fast
improvement in LUTS and flow rate parameters
with similar efficacy
They are all well tolerated; however, the adverse
event spectrum differs between the agents
Terazosin and doxazosin induce more dizziness, fatigue,
and asthenia
Tamsulosin induces more ejaculatory disturbances
None of the
1
-blockers alter urodynamic
parameters, prostate volume or serum PSA
None have been shown to alter the natural history of
the disease or prevent AUR / Surgery
5-Reductase Inhibitor: Rationale
Prostatic differentiation & growth depend on androgenic
stimulation
Testosterone is converted to dihydrotestosterone (DHT)
within the prostatic stromal & basal cells facilitated by
5-reductase enzyme
5-reductase inhibitor: deprive the prostate of its
testosterone support
5-reductase enzyme:
Type I: skin & liver
Type II: stromal & basal cells of prostate, seminal vesicle,
epididymis

Kirby RS et al. Br J Urol. 1992;70:65-72
Tammela TLJ et al. J Urol. 1993;149:342-344
Regulation of cell growth in the
prostate in BPH


DHT-androgen
receptor complex

Growth
factors

Unbalanced


DHT

T

5AR (1 and 2)


Serum testosterone (T)

Prostate
cell




Increased
Cell growth
Cell death
Serum Dihydrotestosterone
(DHT)
5-reductase inhibition
Mode of action
OH
O
O
OH
H
5 -reductase type 1 and 2
NADPH NADP
Testosterone
Dihydrotestosterone
Avodart (dutasteride) - Dual (type 1&2) 5ARI
Proscar(finasteride) - Only type 2 5ARI
Greater and more consistent suppression
of DHT observed with dutasteride
versus finasteride (n=399)
40
20
0
-20
-40
-60
-80
-100

0
DHT (% change from baseline)
4 8 12 16 20 24 28 32 36 40
Time (weeks)
Placebo
Fin 5.0 mg
Dut 0.5 mg

100% Dut patients
49% Fin patients
>70%
>90%
85.4% Dut patients
2.2% Fin patients
Treatment
withdrawn
Richard V. Clark et al. J Clin Endocrinol Metab 89:2179-2184, 2004
Roehrborn et al (2003)
Comparison of adverse events:
Dutasteride vs. finasteride vs. placebo
(n=399)
0
20
40
60
80
100
Any AE Drug-related
AE
Serious AE Withdrawal
due to AE
Placebo
Dutasteride 0.5 mg
Dutasteride 5.0 mg
Finasteride 5.0 mg
Patients (%)
Richard V. Clark et al. J Clin Endocrinol Metab 89:2179-2184, 2004
Dutasteride 4-year studies
(2-year double-blind and 2-year open-label)
Randomised to double-blind phase
n=4325
Key inclusion criteria:
aged 50 years, diagnosis of BPH, PV 30 cc,
AUA-SI score 12, Q
max
15 mL/sec, PSA 1.5 ng/mL
Placebo
n=2158
Dutasteride
n=2167
Entered open-label phase
on dutasteride n=1152
Entered open-label phase
on dutasteride n=1188
P/D D/D
Roehrborn CG et al Urol 63:709-15,2004
Dutasteride therapy results in reductions
in total prostate volume from 124
months that are sustained to 4 years
1 3 6 12 24 48 Treatment month
-0.6
0.2
-2.1
-1.5
1.4
-21.7
-5.2
-13.8
-19.9
-23.6
-26.0
-27.3
-30
-25
-20
-15
-10
-5
0
5
Mean change (%)
* * *

*

*p<0.001 for differences between treatment groups
p<0.001 for change from Month 24 to Month 48
p=0.07 for change from Month 24 to Month 48
Placebo Dutasteride Open-label dutasteride after placebo
Roehrborn CG et al Urol 63:709-15,2004; Debruyne F et al, Euro Urol 2004;46: 488-495
Dutasteride therapy results in improvements
in urinary flow from 1 month, with
continuing improvements over 4 years
0.0
0.5
1.0
1.5
2.0
2.5
3.0
0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48
Treatment month
P/D (n=1152)
D/D (n=1188)
Mean change
(mL/sec)
2.2
1.9
0.6
2.7

*p<0.001 between treatment groups
p=0.042 between treatment groups
p<0.001 vs. Month 24
p=0.007 vs. Month 24
*
Roehrborn CG et al Urol 63:709-15,2004; Debruyne F et al, Euro Urol 2004;46: 488-495
Acute urinary retention
Kaplan-Meier estimates: time to first event
Treatment month
0

1
2
3
4
5
6
7
P/D
D/D
Double-blind Open-label
6.7%
3.3%
0 6 12 18 24 30 36 42 48
Patients (%)
Roehrborn CG et al Urol 63:709-15,2004; M.Emberton et al. 2004 EAU Abstract
57
%
BPH-related surgery
Kaplan-Meier estimates: time to first event
5.6%
3.3%
Treatment month
0

1
2
3
4
5
6
7
P/D
D/D
Double-blind Open-label
0 6 12 18 24 30 36 42 48
Patients (%)
Roehrborn CG et al Urol 63:709-15,2004; M.Emberton et al. 2004 EAU Abstract
48
%

PSA is reduced in a predictable
manner preserving its prostate cancer
screening utility

-60
-50
-40
-30
-20
-10
0
10
20
0 6 12 18 24 30 36 42 48
Treatment Month
M
e
a
n

(
+
/
-

S
E
)

%

C
h
a
n
g
e
-57.2
Double-blind Open-label
Placebo n=1152
Dutasteride
n=1188
Data on File GlaxoSmithKline
Long-term change in prostate volume
Indirect comparison of dutasteride,
finasteride and a-blockers
-30
-20
-10
0
10
20
30
McConnell et al. (1998); McConnell et al. (2003); Roehrborn et al. (2002); Lowe et al. (2003)
% Change in prostate
volume from baseline
Dutasteride
Finasteride
-blockers
0
1
2
3
4
5
6
7
8
9
McConnell et al. (1998); McConnell et al. (2003); Roehrborn et al. (2002); AUA (2003)
Mean AUA-SI score
reduction from baseline
Finasteride
AUA
1 y
PLESS
4 y
MTOPS
4 y
5 y
OL
Tam
label
13 wk
study 1
Tam
label
13 wk
study 2
Alf
1 y
OL
Tera
AUA
1 y
Dox
AUA
1 y
Dox
4 y
MTOPS
Tam
5 y
OL
-blockers
1 y
DB
2 y
DB
4 y
OL
Dutasteride
Symptom improvement
Indirect comparison of a-blockers,
finasteride and dutasteride

5ARIsa-blockers

5ARIs a-blockers




BPH
:
Combination therapy with
5aRIs and a
1
blockers
Rationale for Combination Therapy
Alpha blockers relax the smooth muscle of bladder neck
and prostatic capsule/adenoma, thereby improving
symptoms and flow rates, relieving obstruction
5 ARIs reduce the action of androgens in the prostate,
inducing apoptosis, atrophy, and, by shrinking the
prostate improve symptoms, relieve obstruction and
prevent AUR & prostate surgery

5ARIs

Arrest disease progression

1-adrenergic
blockers

Rapidly relieve symptoms

?
Medical Therapy of Prostatic
Symptoms (MTOPS)
Change in AUA Symptom Score
at Year 4
Median baseline AUA SS = 17.0
Combination
Median point decrease from baseline
Placebo
Doxazosin
Finasteride
2
4 6
8
10
4.0
6.0
5.0
7.0
(p<0.001)
(p<0.047)
(p<0.001)
Change in Qmax at Year 4
Median baseline Qmax = 10.6
Combination
Placebo
Doxazosin
Finasteride
1 2 3 4 5
1.4
2.5
2.2
3.7
(p<0.001)
(p<0.047)
(p<0.001)
Median point decrease from baseline
Conclusions
Single arm therapy with alpha blocker
Improve symptoms and prevent symptom progression
Does not alter natural history or cross over to invasive therapy
Single arm therapy with 5 ARI
Treats symptoms only when LUTS associated with BPH (ie
enlargement or high PSA)
Alters natural history in pts at risk (large gland, high PSA)
Combination (doxazosin+finasteride) therapy is the most
effective form of treatment for LUTS and BPH
Improve symptoms and flow rate
Prevent AUR and/or surgery
Alter the natural history of the disease
SMART1 was designed to examine
short-term dutasteride and a
1
-blocker
combination therapy, followed by
dutasteride monotherapy
Entry criteria:
IPSS 12
PV 30 cc, estimated by DRE
PSA 1.5 10.0 ng/ml
Symptom Management After
Reducing Therapy: SMART1
Barkin et al (2002)
P
l
a
c
e
b
o

1 week
Single
blind

Combination
dutasteride 0.5mg
+ placebo
(tamsulosin)
Combination
dutasteride 0.5mg
+ tamsulosin 0.4mg
once daily

SMART-1: study design
Placebo
run-in
4 weeks
Single
blind
24 weeks
Single
blind
12 weeks
Double blind
DT24 + D12
DT36
Barkin et al (2002)
Wk 30 Wk 36
SMART-1: primary endpoint question
at week 30 by baseline IPSS
100
80
60
40
20
0
Moderate
(baseline IPSS <20)
(n=220)
DT36 DT24 + D12 DT36 DT24 + D12
Severe
(baseline IPSS 20)
(n=82)
% patients better/same
93%
84%
86%
57.5%
Barkin et al (2002)
Severe pts need longer AB treatment
5 Reductase Inhibitors
Finasteride Dutasteride*
Compared to
Baseline
PROWESS
1
PLESS
2
MTOPS
3
2yrs
4
4yrs
5,6,7

Duration (yr) 2 4 4 2 4
Total Prostate Volume -15.3% -18% -19% -25.7% -27.3%
Symptoms -2.1 -3.3 -5.6 -4.5 -6.5
Urinary Flow Rate 1.5 1.9 3.2 2.2 2.7
Risk of AUR -57% -57% -68% -57%
Continue
Reduction
Risk of BPH Surgery -40% -55% -64% -48%
Continue
Reduction
Note: Not from a comparative trial, all result abstracted from treatment group.
PROWESS=Proscar Worldwide Efficacy and Safety Study; PLESS=Proscar Long-term Efficacy and Safety Study;
MTOPS=Medical Therapy of Prostatic Symptoms
*: Avodart Phase III trial2double blind 24open-label study
References:
1. Marberger MJ. Urol.51:677-86,19982. McConnell JD et al. N Engl J Med 338(9):577-63,19983. McConnell JD et al.
N Engl J Med 349(25):2387-98,20034. Roehrborn CG et al.Urol.60:434-41,20025. T.Tammela et al. 2004 EAU Abstract
6. F.Debruyne et al. 2004 EAU Abstract7.M.Emberton et al. 2004 EAU Abstract
Conclusions
In MTOPS study, finasteride afforded long-term reduction
in risk of AUR on surgery when combined with alpha 1-
blocker doxazosin
5ARI alpha blocker,BPH,
BPH
In SMART-1 study, dutasteride can be used in
combination with tamsulosin to achieve fast symptom
relief that is maintained with alpha 1- blocker is removed
after 6 months
BPH,Avodart alpha
blocker,6alpha blocker
Medical Therapy Algorithm
Prostate large
PSA high
5-Reductase
Inhibitor
Combination Rx
Moderate to
severe
bother
-
Adrenergic
Blocker
Prostate
small
PSA low
No Treatment
Prostate small
PSA low
Prostate large
PSA high
Preventive therapy
5-Reductase Inhibitor
Patient
No or
little
bother
IPSS
7
IPSS
>7
IPSS <19
(Moderate)
Short term
IPSS >19
(Severe)
Long term
Surgical treatment
Treatment Modalities for BPH
Watchful waiting
Medical therapy
Phytotherapy
-adrenergic blockers
5-reductase inhibitors
Combination therapy
Office-based treatment
TUMT
TUNA
WIT
Surgicenter/Hospital-based
treatment
TURP (gold standard)
TUIP
Open surgery (prostatectomy)
TUVP
ILC
VLAP
Prostatic stents
Chatelain C et al. In: Chatelain C et al, eds. Benign Prostatic Hyperplasia. Plymouth, UK: Health
Publication Ltd; 2001;519-534. McConnell JD et al. Benign Prostatic Hyperplasia: Diagnosis and
Treatment. Clinical Practice Guideline, Number 8.
Indication of surgical intervention
Acute urinary retention
Gross hematuria
Frequent UTI
Vesical stone
BPH related hydronephrosis or renal
function deterioration
Obstruction
IPSS8, prostate size, image study, UFR
cystoscopic findings, residual urine
Conventional Surgical Therapy
Transurethral resection of the prostate
(TURP)
Open simple prostatectomy
TURP
Gold Standard of care for BPH
Uses an electrical knife to surgically cut
and remove excess prostate tissue
Effective in relieving symptoms and
restoring urine flow
(transurethral resection of the prostate)
n
n
n
TURP
Gold standard of surgical treatment for
BPH
80~90% obstructive symptom improved
30% irritative symptom improved
Low mortality rate 0.2%
The gold standard- TURP
Benefits
Widely available
Effective
Long lasting

Disadvantages
Greater risk of side
effects and complications
1-4 days hospital stay
1-3 days catheter
4-6 week recovery



n
n
n
n
n
n
n
Complication of TURP
Immediate complication
bleeding
capsular perforation with fluid extravasation
TUR syndrome
Late complication
urethral stricture
bladder neck contracture (BNC)
retrograde ejaculation
impotence (5-10%)
incontinence (0.1%)
Open Simple Prostatectomy
too large prostate -- >100 gm
Combined with bladder diverticulum or
vesical stone surgery
Suprapubic or retropubic method
Minimally invasive therapy
During the last decade, numerous amounts of
minimally invasive therapy modalities have
been developed to challenge the traditional
surgery of TURP
The aim of these therapies is to achieve
results similar to TURP but with minimal
anesthesia, complication, risk and hospital
stay.
Minimally invasive therapy for
BPH
transurethral balloon dilatation of the prostate
(TUBDP)
transurethral incision of the prostate (TUI)
intraprostatic stent
transurethral microwave thermotherapy (TUMT)
transurethral needle ablation of the prostate (TUNA)
transurethral electrovaporization of the prostate
(TUVP)
photoselective vaporization of the prostate (PVP),
Cryotherapy
Transurethral ethanol ablation of the prostate
(TEAP),
Minimally invasive therapy for
BPH
transurethral laser-induced prostatectomy
(TULIP)
visual laser ablation of the prostate (VLAP)
contact laser prostatectomy (CLP)
interstitial laser coagulation of the prostate (ILC)
holmium:YAG laser resection of the prostate
(HoLRP)
holmium:YAG laser enucleation of the prostate
(HoLEP)
high-intensity focused ultrasound (HIFU)
coagulation
botulinum toxin-A injection of the prostate
HoLEP Vs. TURP
IPSS & urodynamic findings: no statistically significant
differences
Operation time:
HoLEP 74 +/- 19.5 vs. TURP 57 +/- 15 mins (p <0.05)
Catheterization time:
31 +/- 13 vs 57.78 +/- 17.5 hours (p <0.001)
Hospital stay:
59 +/- 19.9 vs 85.8 +/- 18.9 hours (p <0.001)
Urge incontinence: more common in the HoLEP group
The overall complication rate was comparable in the 2
groups
Journal of Urology. 172(5, Part 1 of 2):1926-1929, November 2004


TURP vs HIGH POWER (80 W) POTASSIUM TITANYL
PHOSPHATE (KTP) LASER VAPORIZATION
Hemostasis: standardized ablation volume of 16 cm
3

tissue (23.3 vs 2.1 ml per minute, p <0.0001).
Tissue ablation: more rapid in the resection group
(100 vs 20 seconds, p <0.001).
Histological examinations: larger coagulation zones for
the KTP group compared to conventional tissue resection
(0.9 vs 0.6 mm, p <0.01).
80 W KTP laser vaporization: bloodless ablative
procedure, but more time-consuming
Journal of Urology. 171(6, Part 1 of 2):2502-2504, June 2004

Uses a very high powered green laser and
a thin, flexible fiber

Fiber is inserted into
the urethra through a
cystoscope

How does PVP work?
n
n
Quickly and precisely vaporizes and
removes the enlarged prostate tissue
The green laser energy is hemostatic, so
there is almost no bleeding
How does PVP work?
n
n
Enlarged Prostate
Urethra is open
Normal urine flow is
restored
Urethra is obstructed
Urine flow blocked

After GreenLight PVP
n
n
n
n
Summary
Minimally invasive therapies for the treatment of BPH
has the advantages such as less blood loss, less
occurrence of hyponatremia, quicker recovery, and
reduced risk of urethral stricture.
However, it also has the disadvantages such as long-
lasting bladder irritation owing to higher temperature
during therapy and possible longer catheterization
period due to swelling of the prostate.
It is still too early to make a definitive conclusion
concerning the future role of these minimally invasive
therapies for the treatment of BPH.