Benign Prostatic Hyperplasia

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Benign Prostatic Hyperplasia
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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

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Understanding the prostate

• Secretes semen which carries sperm
• During orgasm, prostate muscles contract and
  propel ejaculate out of the penis

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BPH
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• 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

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What is Benign Prostatic Hyperplasia?
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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

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Whats LUTS?

• Voiding (obstructive)
• symptoms
• Hesitancy
• Weak stream
• Straining to pass urine
• Prolonged micturition
• Feeling of incompletebladder emptying
• Urinary retention

• Storage (irritative or
• filling) symptoms
• Urgency
• Frequency
• Nocturia
• Urge incontinence

LUTS is not specific to BPH not everyone
withLUTS has BPH and not everyone with BPH has
LUTS
Blaivas JG. Urol Clin North Am 19851221524
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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
• Qmax gt15mL/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 levels1
• 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

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Interfere with sexual life
Sexual Activity Decreases withAge and LUTS
MSAM-7 Survey
8.5
n12,815
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7.6
8
6.6
7
5.7
5.7
6
4.9
4.6
5
Average sex intercourse/activity/ month
4.0
3.7
3.5
4
2.6
3
1.7
2
1
0
5059 years
6069 years
7079 years
Rosen et al. Eur Urol 2003 n12815
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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

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Choosing the right treatment

• Consider risks, benefits and effectiveness of
  each treatment
• Consider the outcome and lifestyle needs

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Treatment options

• Watchful waiting
• Medication
• Surgical approaches
• Minimal invasive
• TURP
• Invasive open procedures

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watchful waiting

• For mild symptoms. follow up1 to 2 times yearly

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• Offer suggestions that help reduce symptoms
• Avoid caffeine and alcohol
• Avoid decongestants and antihistamines

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Medication

• First line of defense against bothersome urinary
  symptoms
• Two major types
• a blockers - relax the smooth muscle of prostate
  and provide a larger urethral opening
  (Hytrin,Doxaben, Harnalidge)

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5 a reductase inhibitor - Shrink the prostate
gland (Proscar, Avodart)
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Medication

• Benefits
• Convenient
• No loss of work
• time
• Minimal risk

• Disadvantages
• Drug Interactions
• Must be taken every day
• Manages the problem instead of fixing it

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Possible side effects of
medication

• Impotence
• Dizziness
• Headaches
• Fatigue
• Loss of sexual drive

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?-Adrenergic Blockers Rationale

• Prostate smooth muscle tone is mediated via
  ?1-adrenergic receptor
• Blockage of the receptor leads to improvement of
  flow rate and LUTS1
• 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. 200086(suppl 2)11-22.
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Distribution of ?1-Adrenergic Receptors
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Localization of ?1-Adrenergic Receptors (?1-ARs)
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?-Blockers

• Nonselective
• Phenoxybenzamine
• Short-acting selective a1-blocker
• Prazosin, Alfuzosin
• Long-acting selective a1-blockers
• Terazosin
• Doxazosin
• Long-acting selective a1A-subtype
• Tamsulosin
• Alfuzosin-SR

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?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

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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. 19927065-72
Tammela TLJ et al. J Urol. 1993149342-344
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Regulation of cell growth in the prostate in BPH
Serum testosterone (T)
Serum Dihydrotestosterone (DHT)






T

Prostate cell

DHT
5AR (1 and 2)


Growth factors
DHT-androgen receptor complex



Cell death


Unbalanced
Increased Cell growth

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5a-reductase inhibition Mode of action
OH
OH
5 ?-reductase type 1 and 2
O
O
H
NADPH NADP
Dihydrotestosterone
Testosterone
Avodart (dutasteride) - Dual (type 12)
5ARI Proscar(finasteride) - Only type 2 5ARI
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Greater and more consistent suppression of DHT
observed with dutasteride versus finasteride
(n399)
DHT ( change from baseline)
40 20 0 -20 -40 -60 -80 -100
Treatment withdrawn
Placebo Fin 5.0 mg Dut 0.5 mg
100 Dut patients 49 Fin patients
gt70
gt90
85.4 Dut patients 2.2 Fin patients
0
4
8
12
16
20
24
28
32
36
40
Time (weeks)
Richard V. Clark et al. J Clin Endocrinol Metab
892179-2184, 2004
Roehrborn et al (2003)
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Comparison of adverse events Dutasteride vs.
finasteride vs. placebo(n399)
Patients ()
100
Placebo
Dutasteride 0.5 mg
80
Dutasteride 5.0 mg
Finasteride 5.0 mg
60
40
20
0
Any AE
Drug-related AE
Serious AE
Withdrawal due to AE
Richard V. Clark et al. J Clin Endocrinol Metab
892179-2184, 2004
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Dutasteride 4-year studies (2-year double-blind
and 2-year open-label)
Randomised to double-blind phase n4325 Key
inclusion criteria aged ? 50 years, diagnosis
of BPH, PV ? 30 cc,AUA-SI score ? 12, Qmax ? 15
mL/sec, PSA ? 1.5 ng/mL
Placebo n2158
Dutasteride n2167
Entered open-label phase on dutasteride n1152
Entered open-label phase on dutasteride n1188
P/D
D/D
Roehrborn CG et al Urol 63709-15,2004
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Dutasteride therapy results in reductions in
total prostate volume from 124 months that are
sustained to 4 years
Placebo
Dutasteride
Open-label dutasteride after placebo
Mean change ()






5
1.4
0.2
0
-0.6
-1.5
-2.1
-5
-5.2
-10
-15
-13.8
-20
-19.9
-21.7
-25
-23.6
-26.0
-27.3
-30
1
3
6
12
24
48
Treatment month
plt0.001 for differences between treatment
groups plt0.001 for change from Month 24 to Month
48 p0.07 for change from Month 24 to Month 48
Roehrborn CG et al Urol 63709-15,2004 Debruyne
F et al, Euro Urol 200446 488-495
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Dutasteride therapy results in symptom
improvements from 6 months, with continuing
improvements over 4 years (completers)
Change in AUA-SI (units)
Double-blind
Open-label
0
P/D (n1152) D/D (n1188)
-1
-2

-3
-2.7
-4
-5

-5.0
-5.6
-6
-6.5
-7
0
3
6
9
12
15
18
21
24
27
30
33
36
39
42
45
48
Treatment month
plt0.001 between treatment groups plt0.001 for
differences within treatment groups from Month 24
Roehrborn CG et al Urol 63709-15,2004 Debruyne
F et al, Euro Urol 200446 488-495
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Dutasteride therapy results in improvements in
urinary flow from 1 month, with continuing
improvements over 4 years
Mean change (mL/sec)
P/D (n1152) D/D (n1188)


2.7
2.2

1.9
0.6
plt0.001 between treatment groups p0.042
between treatment groups plt0.001 vs. Month 24
p0.007 vs. Month 24
Roehrborn CG et al Urol 63709-15,2004 Debruyne
F et al, Euro Urol 200446 488-495
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Acute urinary retentionKaplan-Meier estimates
time to first event
Patients ()
7
Double-blind
Open-label
6.7
6
P/D D/D
5
4
57
3.3
3
2
1
0
0 6 12 18
24 30 36 42 48
Treatment month
Roehrborn CG et al Urol 63709-15,2004
M.Emberton et al. 2004 EAU Abstract
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BPH-related surgeryKaplan-Meier estimates time
to first event
Patients ()
7
Double-blind
Open-label
6
5.6
P/D D/D
5
4
48
3.3
3
2
1
0
0 6 12 18
24 30 36 42 48
Treatment month
Roehrborn CG et al Urol 63709-15,2004
M.Emberton et al. 2004 EAU Abstract
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PSA is reduced in a predictable manner
preserving its prostate cancer screening utility
Double-blind
Open-label
-57.2
Data on File GlaxoSmithKline
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Long-term change in prostate volumeIndirect
comparison of dutasteride, finasteride and
a-blockers
Change in prostate volume from baseline
Dutasteride Finasteride a-blockers
30
20
10
0
-10
-20
-30
2 yrDB
4 yrOL
PLESS4 yr
MTOPS4 yr
6 yrOL
MTOPS Dox4 yr
McConnell et al. (1998) McConnell et al. (2003)
Roehrborn et al. (2002) Lowe et al. (2003)
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Symptom improvementIndirect comparison of
a-blockers, finasteride and dutasteride
Mean AUA-SI score reduction from baseline
a-blockers
9
8
7
6
5
4
3
2
1
0
Tamlabel13 wkstudy 1
Tamlabel13 wkstudy 2
Alf1 yOL
TeraAUA1 y
DoxAUA1 y
Dox4 yMTOPS
Tam5 yOL
McConnell et al. (1998) McConnell et al. (2003)
Roehrborn et al. (2002) AUA (2003)
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5ARIs?a-blockers ??????
5ARIs
a-blockers ????????? ???????? ?????? ????????
? ????????BPH???????
?????????????
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Combination therapy with 5aRIs and a1 blockers
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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

?1-adrenergicblockers
5ARIs
?
Arrest disease progression
Rapidly relieve symptoms
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Medical Therapy of Prostatic Symptoms (MTOPS)
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Change in AUA Symptom Score at Year 4
Placebo
4.0
Doxazosin
(plt0.001)
6.0
Finasteride
(plt0.047)
5.0
Combination
(plt0.001)
7.0
4
6
10
2
8
Median point decrease from baseline

• Median baseline AUA SS 17.0

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Change in Qmax at Year 4
Placebo
1.4
Doxazosin
2.5
(plt0.001)
Finasteride
2.2
(plt0.047)
Combination
(plt0.001)
3.7
1
2
3
4
5
Median point decrease from baseline

• Median baseline Qmax 10.6

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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 (doxazosinfinasteride) 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

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Symptom Management After Reducing Therapy
SMART1

• SMART1 was designed to examine
• short-term dutasteride and a1-blocker
• combination therapy, followed by
• dutasteride monotherapy
• Entry criteria
• IPSS ? 12
• PV ? 30 cc, estimated by DRE
• PSA 1.5 10.0 ng/ml

Barkin et al (2002)
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SMART-1 study design
DT24 D12DT36
dutasteride 0.5mg placebo (tamsulosin)
Combination dutasteride 0.5mg tamsulosin 0.4mg
once daily
Placebo
Placebo run-in
Combination
4 weeks Single blind
24 weeks Single blind
12 weeks Double blind
1 week Single blind
Wk 30
Wk 36
Barkin et al (2002)
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SMART-1 primary endpoint questionat week 30 by
baseline IPSS
Severe (baseline IPSS ?20) (n82)
Moderate (baseline IPSS lt20) (n220)
93
100 80 60 40 20 0
86
84
57.5
Patients ()
Severe pts need longer AB treatment
DT36 DT24 D12 DT36 DT24 D12
patients better/same
Barkin et al (2002)
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5 a Reductase Inhibitors????
Note Not from a comparative trial, all result
abstracted from treatment group. PROWESSProscar
Worldwide Efficacy and Safety Study
PLESSProscar Long-term Efficacy and Safety
Study MTOPSMedical Therapy of Prostatic
Symptoms Avodart Phase III trial??2??double
blind ????2??4??open-label study
References 1. Marberger MJ. Urol.51677-86,1998?2
. McConnell JD et al. N Engl J Med
338(9)577-63,1998?3. McConnell JD et al. N Engl
J Med 349(25)2387-98,2003?4. Roehrborn CG et
al.Urol.60434-41,2002?5. T.Tammela et al. 2004
EAU Abstract?6. F.Debruyne et al. 2004 EAU
Abstract?7.M.Emberton et al. 2004 EAU Abstract?
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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????,????????6?????alpha blocker

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Medical Therapy Algorithm
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Surgical treatment
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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 2001519-534. McConnell
JD et al. Benign Prostatic Hyperplasia Diagnosis
and Treatment. Clinical Practice Guideline,
Number 8.
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Indication of surgical intervention

• Acute urinary retention
• Gross hematuria
• Frequent UTI
• Vesical stone
• BPH related hydronephrosis or renal function
  deterioration
• Obstruction
• IPSS?8, prostate size, image study, UFR
• cystoscopic findings, residual urine

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Conventional Surgical Therapy

• Transurethral resection of the prostate (TURP)
• Open simple prostatectomy

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TURP
(transurethral resection of the prostate)
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
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TURP

• Gold standard of surgical treatment for BPH
• 8090 obstructive symptom improved
• 30 irritative symptom improved
• Low mortality rate 0.2

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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

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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)

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Open Simple Prostatectomy

• too large prostate -- gt100 gm
• Combined with bladder diverticulum or vesical
  stone surgery
• Suprapubic or retropubic method

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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.

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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),

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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)
• holmiumYAG laser resection of the prostate
  (HoLRP)
• holmiumYAG laser enucleation of the prostate
  (HoLEP)
• high-intensity focused ultrasound (HIFU)
  coagulation
• botulinum toxin-A injection of the prostate

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HoLEP Vs. TURP

• IPSS urodynamic findings no statistically
  significant differences
• Operation time
• HoLEP 74 /- 19.5 vs. TURP 57 /- 15 mins (p
  lt0.05)
• Catheterization time
• 31 /- 13 vs 57.78 /- 17.5 hours (p lt0.001)
• Hospital stay
• 59 /- 19.9 vs 85.8 /- 18.9 hours (p lt0.001)
  
• 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
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TURP vs HIGH POWER (80 W) POTASSIUM TITANYL
PHOSPHATE (KTP) LASER VAPORIZATION

• Hemostasis standardized ablation volume of 16
  cm3 tissue (23.3 vs 2.1 ml per minute, p
  lt0.0001).
• Tissue ablation more rapid in the resection
  group
• (100 vs 20 seconds, p lt0.001).
• Histological examinations larger coagulation
  zones for the KTP group compared to conventional
  tissue resection (0.9 vs 0.6 mm, p lt0.01).
• 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
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How does PVP work?

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

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Fiber is inserted into the urethra through a
cystoscope
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How does PVP work?
Quickly and precisely vaporizes and removes the
enlarged prostate tissue The green laser energy
is hemostatic, so there is almost no bleeding
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After GreenLight PVP
Enlarged Prostate
Urethra is open Normal urine flow is restored

• Urethra is obstructed
• Urine flow blocked

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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.

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Thanks for Your Attention!