EUREP23

21st European Urology Residents

Education Programme

1-6 September 2023, Prague, Czech Republic

www.eurep23.org

Course Book Module 2

Module 2 Prostate cancer and male voiding LUTs

Chair: Prostate cancer

08.30 - 09.30 Screening and early detection and staging Page 2 »
Prof. Sascha Ahyai J. Walz
Medical University Graz
Dept. of Urology 09.30 - 10.30 Treatment for localised disease, part 1:
Auenbruggerplatz 29 Page 33 »
Active surveillance and surgical treatment
8036 Graz, Austria
N. Mottet
Sascha.Ahyai@medunigraz.at

10.30 - 11.00 Coffee break

11.00 - 11.45 Treatment for localised disease, part 2: Page 53 »

Faculty: Radiation and focal therapy
N. Mottet
Prof. Nicolas Mottet
11.45 - 12.30 Treatment for locally advanced prostate
University Hospital Page 66 »
Hopital Nord cancer
42055 Saint-Étienne, France M. Sedelaar
nicolas.mottet@wanadoo.fr
12:30 - 14.00 Lunch

14.00 - 15.00 Treatment for metastatic prostate cancer Page 85 »

M. Sedelaar

Male voiding LUTS

Dr. Michiel Sedelaar
15.00 - 16.00 Treatment for male voiding LUTS
Radboud University Medical Centre Page 106 »
Geert Grooteplein 10
S. Ahyai
6525 GA Nijmegen
The Netherlands 16.00 - 16.30 Coffee break
michiel.sedelaar@radboudumc.nl
16.30 - 17.15 Interactive case debate male voiding LUTS
S. Ahyai

17.15 - 18.00 Interactive case debate prostate cancer

All faculty
Dr. Jochen Walz
Institut Paoli-Calmettes
Dept. of Urology
232 Boulevard de St. Marguerite
13009 Marseille, France
walzj@ipc.unicancer.fr

1
 Screening, Early detection and staging
Jochen Walz
Institut Paoli-Calmettes Cancer Centre, Marseille/France

Conflict of Interest Disclosure

I have the following potential conflict(s) of interest to report:

• 3D-Biopsy AAA/Novartis
• ANNA / C-TRUS Astellas
• Astra-Zeneca Bayer
• Blue Earth Diagnostics Exact Imaging
• Intuitive Ipsen
• Janssen Lightpoint medical
• Takeda Telix

Screening and early detection

2
• „The PSA test is used to detect prostate cancer. However, the
test is unsafe and healthy men are treated by mistake. … „
Spiegel Online, 07.10.2012

“In a controversial finding…, a government task force

published its final recommendations against regular prostate
cancer screening, concluding that the harms of the simple
blood test far outweigh any potential benefit.“
New York Times, 21.05.2012

Epidemiology

Marima et al., Int J Mol Sci 2022

3
 Epidemiology

Mortality/
Incidence Mortality
Incidence

Lung /
117910 68820 58%
bronchus

Colon /
80690 28400 35%
rectum

Prostate 268490 34500 13%

Siegel et al., CaCanJ Clin 2022

Main critisism

• No benefit of screening and treatment of prostate

cancer?

• Effect too low to justify screening?

ERSPC
• Prostate cancer specifc mortality, 16
years of follow-up :

• 21% relative risk reduction

• 27% after correction for
non compliance

Hugosson et al., EurUrol 2019

4
 PLCO
• Prostate cancer specific
mortality, 15 years follow-up:

• No significant difference in mortality

Pinsky et al.; Cancer 2017 PSA screening

control

PLCO
Limitations PLCO 2010
1. 45% PSA-test before study inclusion
2. 52% PSA-test in control arm
3. Only 40% with elevated PSA did undergo biopsy in screenig arm

Schroeder et al.; EurUrol 2010; 58:46-52

►oppertunistic screning vs. organized screening

In 2016:
Limitations PLCO
1. 66% PSA-test before study inclusion in control arm
2. 90% PSA-test in control arm
3. More PSA testing in the control groupe relative to intervention arm
Shoag and Jim, NEJM 2016

5
 Effect too low? Comparision to other entities:
Reduction in mortality
• Prostate-Ca ERSPC
• 27% relative risk reduction
Schroeder et al. NEJM 366;11 2012

• Breast-Ca Metaanalysis:
• 15-22% relative risk reduction
Nelson et al; Ann Intern Med 2009; 151

• Colon-Ca PLCO:
• 26% relative risk reduction
Schoen et al; NEJM 366; 2012

Effect too low?

NNI and NND
To avoid one death after 11 years :
• Number needed to invite: 979
• Number needed to detect: 35
Schroeder et al. NEJM 366; 2012
To avoid one death after 13 years:
• Number needed to invite: 781
• Number needed to detect: 27
Schroeder et al. The Lancet 2014
To avoid one death after 16 years:
• Number needed to invite: 570
• Number needed to detect: 18
Hugosson et al., EurUrol 2019
► Suggesting
• Overdetection
• Overtreatment

Effect too low?

NNI and NND in comparison
To avoid one death:
Prostate-Ca:
• Number needed to invite: 570
• Number needed to detect: 27
Hugosson et al. EurUrol 2019
Breast-Ca:
• Number needed to invite: 377-1904
• Number needed to detect: ??
Nelson et al; Ann Intern Med 2009; 151
Colon-Ca:
• Number needed to invite: 871
• Number needed to detect: ??
Schoen et al; NEJM 366; 2012

6
 Effect of PSA based early detection
PSA available
PSA available

Siegel et al., CaCanJ Clin 2022

Conclusion
• PSA screening has a benefit

Major problem of:

• Overdetection
• Overtreatment

►Patient selection for screening is key

U.S. Preventive Services Task Force (USPSTF) 2012

• “The USPSTF recommends against PSA-based screening for prostate
cancer (grade D recommendation). This recommendation applies to men
in the general U.S. population, regardless of age.“
Moyer et al., Ann Intern Med 2012; 157

7
 U.S. Preventive Services Task Force (USPSTF)
currently up-dated in 2017

Who to detect?
Life expectancy is key in patient selection:

► Life expectancy >10 years

• Early detection up to the age of 75

EAU-ESTRO-EANM-ESUR-SIOG- prostate cancer guidelines 2023

How to test with PSA?

EAU-ESTRO-EANM-ESUR-SIOG- prostate cancer guidelines 2023

8
Early PSA >1.6ng/ml ≥2.4 ng/ml

0.68ng/ml 0.85ng/ml

Vickers et al. BMJ 2013

Imaging and when to biopsy?

When to do biospy?

EAU-ESTRO-EANM-ESUR-SIOG- prostate cancer guidelines 2023

9
 Risk calculator
Nomogram Rotterdam PCa risk calcultor

Chun et al., EurUrol 2006 https://www.prostatecancer-riskcalculator.com

Prostate Cancer Imaging

EAU guidelines:

EAU-EANM-ESTRO-SIOG Guidelines Prostate Cancer 2023

EAU-EANM-ESTRO-SIOG Guidelines Prostate Cancer 2022

MRI-first
• n= 251 patients
Biopsy naïve man

Multiparameric MRI

Systematic biopsy (12 cores) + 2 cores on US-lesion

MRI targeted biopsy max 2 lesions/3 cores

Significant Prostate cancer (GG >2) detection rate

Rouvriere et al., Lancet Oncol 2018

10
MRI-first
52 Detection rate (%) Biopsy avoided (%)
60
41
50 20 18
30 32
40
22
30 10
20 9 any cancer 0
10 5 8 significant cancer 0
insginficant cancer
0 systematic
csPCa only by MRI negative

Significant cancer = 3+4

Rouvriere et al., Lancet Oncol 2018

4M-Study
• n= 626 patients

Biopsy naïve man

Multiparameric MRI (3T)

MRI in-bore targeted biopsy of all PI-RDAS3-5 lesions/ 2-4 cores

Systematic biopsy (12 cores) including US-lesion

Significant prostate cancer (GG >2) detection rate

van der Leest et al., EurUrol 2018

4M-Study

Detection rate (%) Biopsy avoided (%)

48
60 39
60
49
40 23 25
25 40
14
20 any cancer 20
7 significant cancer 0
4 insignificant cancer 0
0 csPCa only by
systematic
MRI
targeted
Significant cancer = 3+4

van der Leest et al., EurUrol 2018

11
 PRECISION
• n= 500

Kasivisvanathan et al., NEJM 2018

PRECISION
Detection rate (%) Biopsy avoided
48 47
50
38 40
40 28
26
20
30
22 0
20 0
9 any cancer systematic
10 MRI targeted
significant cancer
0 insignificant cancer
systematic
MRI
Significant cancer = 3+4
targeted

Kasivisvanathan et al., NEJM 2018

Indications for MRI-Guided Biopsy

EAU Guidelines:

EAU-EANM-ESTRO-SIOG Guidelines Prostate Cancer 2023

12
Repeat Biopsy: MRI-targeted Vs. systematic
Detection rate (%)

70
60
50 Puech
Miyagawa
40 Rastinehad
Sciarra
30 Fiard
Labanaris
20
Pepe
10 Vourganti
0 Sonn

Van Hove et al., WJU 2014

Indications for MRI-Guided Biopsy

EAU Guidelines:

EAU-EANM-ESTRO-SIOG Guidelines Prostate Cancer 2023

PROMIS
N=576 Patienten

Ahmed et al., Lancet 2017

13
PROMIS: results and the definition of significant PCa

Ahmed et al., Lancet 2017

Influence of definitions on NPV

Ahmed et al., Lancet 2017

Influence of definitions on NPV

Ahmed et al., Lancet 2017

14
Prevalence and NPV

Data from PROMIS

Moldovan et al. EurUrol 2017

Who is at Risk?
n= 288; 14 core systematic biopsy

Washino et al., BJUI 2016

Indications for MRI-Guided Biopsy

EAU Guidelines:

EAU-EANM-ESTRO-SIOG Guidelines Prostate Cancer 2023

15
 Variability of reader performance

Sonn et al., EurUrolFocus 2018

Variability of PI-RADS score

Positive biopsy rate

Sonn et al.,
EurUrolFocus 2018

Influence of expertise on MRI performance

Prostate cancer detection (ROC):

• General Radiologist: 0.66
• Uro-Radiologist: 0.88
Scheidler et al., ROFO 2012

• Before training: 0.74

• After training: 0.88
Garcia-Reyes et al., Abdom Imaging 2015

16
Does MRI work in daily practice?
It works if:
• You do not expect to find every [millimetre of]
significant disease
• You accept that results depend on your definition of
clinical significance
• You quality assure every scanner, optimize the sequences
iteratively, quality control scans and have robust training
for radiologists
• All centres ... evaluate their own data to determine where
their own negative predictive value sits and then strive to
improve upon this through a constant iterative dialogue
between urology and radiology
H. Ahmed, editorial BJUI 2016

MRI in screening cohorts?: Göteborg-2

• n= 38000 invited, 18000 participants
Mostly biopsy naïve men, PSA >3ng/ml

Randomization 2:1

mpMRI 3T, n=796 mpMRI 3T, n=405

targeted biopsy if PI-RADS 3-5 lesions/ 4 cores (or Systematic biopsy (12 cores) + targeted
systemic biopsy if PSA >10ng/ml =3%) biopsies 4 cores

Insignificant prostate cancer (GG =1) detection rate

Hugosson et al., NEJM 2022

Göteborg-2, all participants

Detection rate (%)
2.3 Biopsy taken(%)
2.5

2 1.5 8 6.8
1.1 6
1.5 1.2
0.9
1 4
0.6 2.8
0.5 any cancer 2
significant cancer
0 insignificant cancer 0

Significant cancer = ISUP 2

Hugosson et al., NEJM 2022

17
 Göteborg-2, men with PSA >3ng/ml
Detection rate (%) 34

35 Biopsy avoided (%)

30 22 58
60
25
20 18 17
14 40
15 5
4 20
10 8
any cancer
5 ISUP >=3 0
significant cancer 0
0 insignificant cancer

Significant cancer = ISUP 2

Hugosson et al., NEJM 2022

The role of PSA and biomarkers

Ideal biomarker for prostate cancer detection:

► Detection of significant disease (yes/no)

+ reliable information on
• Prognosis
• Extension

Currently used biomarkers:

• PSA
• %free PSA
• PCA 3
• [-2]ProPSA
• 4k score
• STHLM3
• Genomics

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 Limitations:
• Reference test was randomized systematic biopsy
• High false negative rate associated to systematic biopsy
Gleason

3
4
• The best marker might have been missed? Prostate

How about mpMRI: PROMIS

• mpMRI (index test)
• Template mapping biopsy (refernce test)
• Systematic 12 core biopsy (standard test)

Ahmed et al. Lancet 2017

PROMIS

Ahmed et al.,
Lancet 2017

19
 STHLM 3
• n= 49000 invited, 13000 participants
Mostly biopsy naïve men, PSA >3ng/ml or
STHLM 3>0.11

Randomization 3:2

mpMRI 1.5T or 3T, n=929

Systematic biopsy (10-12 cores)
targeted biopsy if PI-RADS 3-5 lesions/ 3-4 cores +
10-12 systematic cores
and/or STHLM 3 >25%

Significant prostate cancer (GG >2) detection rate

Eklund et al., NEJM 2021

STHLM3, PSA >3ng/ml or STHLM 3>0.11

Detection rate (%) Biopsy avoided (%)

43
50
80
64
40 60

30 21 40
18 11
20 7 20
12 7 0
10 benign 0
4 ISUP >=3
significant cancer
0 insignificant cancer

Significant cancer = ISUP 2

Eklund et al., NEJM 2021

Advantages and disadvantages

Genomics mpMRI
Objective Operator dependent
Reproducible Centre dependent
Quick Time consuming
General risk Risk and location
No target Target identification
No further help for management Information for disease management

Costs? Costs?
Evidence? Level 1 evidence

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 Prostate biopsy

How to biopsy?
• What is the standard in the diagnosis of prostate
cancer?

• How many cores?

• Which route (transrectal vs transperineal)?

Cognitive fusion
biopsy

21
 Software fusion:
3D-navigation devices
• Electromagnetic
• Mechanical
• Image based
• (Optical)
• (Acoustic)

Software fusion: Fusion techniques

MRI US MRI +US
• Rigid:

• Elastic:

Meta analysis cognitive vs. software, vs MRI in

bore:
Comparison detection significant
cancers:
• Cog vs. software: NS
• Cog vs. in bore: NS
• Software vs. inbore: NS

Wegelin et al. EurUrol 2017

22
 Learning curve for targeted biopsy

Gaziev et al, BJUI 2014

How many cores do we need to take?

Leyh-Bannurah et al., J Urol 2019

Where to take the cores?

• Detection rate with “regional” targeting

Raman et al., J Urol 2021

23
The biopsy route
transrectal transperineal

Complications: Sepsis
Transrectal biopsy:
• Current trend:
1991 2005 2020
1% 4,1% 7,6%
Nam et al., J Urol Suppl 2013; Korkmaz et al., Urol J. 2020

Transperineal biopsy: 0,1%

• 577 patients single dose cephazolin

= 1 prostatitis = 0,1%
= no hospital admission
Pepdjonovic et al., World J Urol 2017

Diagnostic performance Sens Spec

Meta-analysis:
• 14 series: 2002 patients
Loy et al., UrolOncol 2020

Sens Spec

No major difference in performance

24
Antibiotics?

EAU-EANM-ESTRO-ESUR-SIOG Prostate Cancer Guidelines 2023

Staging

Staging for prostate cancer

What are we looking for in staging?

Prediction of risk for:

• Extracapsular extension
• Seminal vesicle invasion
• Lymph node invasion
• Metastasis

25
Local staging of prostate cancer
i.e.: mpMRI in detection of EPE

de Rooij et al.EurUrol 2016

“These disappointing results are because MRI cannot detect

microscopic extra-prostatic extension.” EAU prostate cancer guidelines 2015

Cancer volume on MRI

MRI underestimates true cancer volume

T2WI
Sample 95% limits of
Mean difference, %
agreement
All tumours (n=50) -32 -128 to +65

Gleason 6 (11) -5 -96 to +87

Gleason 7 (n=39) -39 -104 to +26

Histological tumour
-24 -133 to +85
volume <1 mL (n=31)
Histological tumour
-44 -112 to +24
volume > 1mL (n=19)
MRI : magnetic resonance imaging

Le Nobin et al., BJUI 2014

Le Nobin et al., J Urol 2015

Sequences and Volume estimation

T2: -54%

DWI:-58% DCE:-18%

Sun at al, AJR 2019

26
Added value of biopsy approaches:
EPE
+MRI data +syst Bx data

Gandaglia et la, EurUrol 2020

Added value of biopsy approaches:

SVI
+MRI data +syst Bx data

Gandaglia et la, EurUrol 2020

• Probability of lymph node invasion after extended pelvic

lymph node dissection
(n=497) -PSA
-clinical stage on MRI
-ISUP GG MRI targeted Bx
-max diameter MRI lesion
-% cores with sign Pca at syst. Bx
Gandaglia et al. EurUrol 2018

27
 Updated Briganti Nomogram + MRI data

• EPLND spared in 57% - LNI missed in 1.6%

Gandaglia et al., EurUrol 2018

Systemic staging: ProPSMA study

68Ga-PSMA-11

Vs. conv. imaging

n= 302 high risk PCa patients

Hofman et al, Lancet 2020

28
 Systemic staging: ProPSMA study
Objectives: AUC, Sens, Spec

Hofman et al., Lancet 2020

ProPSMA study
Difference between PSMA and conventional imaging?

Hofman et al., Lancet 2020

How good is PSMA in

lymph node staging?
PSMA in lymph node staging
Studies with 100

n= 100+ 90

80

70

60

50

40

30

20

10

0
Sensitivity Specificity

Hope Pienta Esen v. Kalmthout Jansen

Hope et al., JAMA Oncol 2021; Pienta et al., Jurol 2021;

Esen et al., EurUrolFocus 2021;
van Kalmthout et al., Jurol 2020; Jansen et al., EJNMMI 2021

29
 18F-DCFPyL-PSMA in primary staging:
SALT trial
Size of lymph node metastases:
• Detected : 5.5mm
• Undetected : 1.5mm
Jansen et al., EJNMMI 2021

5.5 mm
1,5mm

68Ga-PSMA-11 for
prediction of cancer control
Treatment free survival:

Amiel et al., J. Urol 2021

PSMA to rule out the need for PLND

Risk high intermediate

NPV 81% 94%

Sensitivity 51% 91%

“… in high-risk patients, negative PSMA PET/CT cannot replace staging ePLND”

Stabile et al., EurUrolOncol 2021

30
 Efficacy of PLND
Extended :
• 94% correctly staged
• 87% of N+ removed
= 13% missed

Joniau et al., EurUrol 2013; Yee et al.; Urology 2010

EAU guidelines for staging

EAU-EANM-ESTRO-ESUR-SIOG Prostate Cancer Guidelines 2023

PSMA PET and treatment in newly diagnosed

PCa
•“Care should be taken to avoid unproven
treatment decisions that may result in under
treatment [or over treatment] and finally harm
to patients.”
Van der Poel, EurUrol Open Sci 2021

31
????

32
Treatment of localised PCa
Active surveillance, prostatectomie N. Mottet
St Etienne

Disclosures

Type of affiliation / financial interest Name of commercial company

Receipt of grants/research supports: Astellas, Sanofi Pasteur, Pierre Fabre

Receipt of honoraria or consultation fees: Astellas, Jansen, BMS, Bayer, IPSEN, Ferring,
Sanofi, Steba, Astra Zeneca, Carrik, Arquer
diagnostics, GE, Takeda

33
 Risk stratification

EAU-EANM-ESUR- ESTRO-ESUR-ISUP-SIOG guidelines 2023

Major missing point for treatment decision

Individual life expectancy !

Fit Vulnerable Frail

Age is not enough !

Walter JAMA 2001

Remember: potentially curable situations

What are patients dying from ?
Lu Yao JAMA 2009

NB: Non treated patients (or ADT only)

Gleason 5-7

Since screening and PSA

Gleason ≤ 7
10 years specific survival: 85 - 95%

Non specific death is the leading cause of death

34
 Remember: histology changed over time

Gleason has been modified in 2005

Excluding from AS: ductal carcinoma, cribriform, sarcomatoïde, small cells.

extraprostatic extension, lymphovasculare invasion Montironi Virchows Arch 2014

General principle

EAU-EANM-ESUR- ESTRO-ESUR-ISUP-SIOG guidelines 2023

Active surveillance / watchfull waiting ?

Active surveillance Watchfull waiting

Treatment intent curative paliative

Follow up Predefined schedule Patient specific

Assessement DRE, PSA, rebiopsy, MRI Not predefined

Life expectancy > 10 years < 10 years

AIM Minimize treatment related Minimize treatment

toxicity without compromizing related toxicity
survival

35
 AS: systematic review

Willemse. Eur Urol 2022

Most often
(very) low risk

ISUP 1
Few + cores
Short involvement

AS: general principles

Consensus based EAU consensus. Lam Eur Urol 2019

EAU-EANM-ESUR- ESTRO-ESUR-ISUP-SIOG guidelines 2022

AS and gBRCA: an issue ?

Risk for upgrading Carter Eur Urol 2020

Limits: no MRI
N = 26 with a mutation
Survival impact unknown
GG1 GG2

36
 MRI: added value
Initial PIRADS: predictive factor of further GG progression
Wang J Urol 2020

N = 442
AS offered for GG1 / GG2
All with initial mpMRI: systematic + TGx

Progression to GG ≥ 3

MRI: a potential paradoxal risk factor

Remember: most AS protocol: only GG1 without mpMRI

MRI prebiospy: better staging (targets)

Value of finding GG1 on systematic biopsy: potential candidate for AS

However: small targeted lesion: some mm of GG2
Really an exclusion criteria ?

Venderbos Urol Oncol 2021

Luiting prost cancer prosta dis 2021

Follow up strategy

Willemse. Eur Urol 2022

ALL cohorts repeated

DRE
PSA
Biopsy

Differences: the frequency

ONLY 6.8% MRI based for re-biopsy

37
 What if negative rebiopsies ?
Formal SR Rajwa J Urol 2021.

13 studies / 9 for the meta-analysis

Reclassification: GG increase / volume progression / clinical progression
Same results when limited to GG1

Confirmatory biopsy Follow up biopsy

A possible way to decrease follow up pressure ?

MRI: follow up during AS

Rajwa Eur Urol 2021

Main question: PCa progression (≥ GG2)

MRI progression: either institution specific / PRECISE definition Moore Eur Urol 2017

Prospective

MRI: follow up during AS

Rajwa Eur Urol 2021

Therefore MRI alone not enough for follow up

Based on 1000 pts followed by MRI

Would avoid 683 biopsy
While missing 124 PCa progression

38
 AS: follow up strategy

EAU-EANM-ESUR- ESTRO-ESUR-ISUP-SIOG guidelines 2023

EAU-EANM-ESUR- ESTRO-ESUR-ISUP-SIOG guidelines 2022

Reasons for reclassification

Bruinsma J Urol 2021

From 25 cohorts (GAP 3 consortium). N = 5530 patients

@ 1 year: 815/5570 reclassification (13%)
@ 4 years: 205/1515 reclassification (14%) HR HR
@ 1 year @ 4 years
age 1.62 1.45
Higher risk if higher age
PSA 1.46 0.87 (NS)
prostate volume 0.54 NA
How is the link ? cT 1.45 NA
nbre of + biopsies 1.67 1.95

When to stop AS ?
Patient's request
Histological "progression": Gleason / nbre + cores / length of cancer
Expected survival (comorbidity) < 10 years

Clinical progression
MRI progression (T3)
Progression PSA . . . PSA DT < 3 ans Van den Berg Eur Urol 2008 – Klotz J Clin Oncol 2010

Only the first 2 have been (partly) validated

39
 Data available in practice

Willemse. Eur Urol 2022

Most frequent

NR is also VERY frequent !

Anxiety IS an issue
Kirk Cancer 2021

1789 men in AS. Median follow up: 5.6 years

33% treated (increased GG: HR/ 14.5)

10%: treated without any reclassification

Married men: risk factor (HR: 2.63)

The basic AS cohort

N = 993. median follow up: 6.4 years Klotz J Clin Oncol 2015
PSA, DRE / 3 months during 2 years, then / 6 months - Biopsy @ 1 year, then / 3 - 4 years until 80 years of age

Overall: 79% Low risk

65%
94% @ 15 ans

40
 A mature cohort
Maggi J Urol 2020

N = 1450 Inclusion: cT1/2, PSA < 20 ng/ml, CAPRA score 0-5, GG1/2
46% MRI. Median follow up: 77 months
Metastases risk during follow up
15 developed metastases

Available data for AS (2022)

EAU-EANM-ESUR- ESTRO-ESUR-ISUP-SIOG guidelines 2023

Intermediate risk and AS

Metastase Free Survival Yamamoto J. Urol 2016

30 (3%) M+: only 2 initially Gleason 6 Yamamoto J Urol 2016

41
 Intermediate risk

ISUP GG 2

ISUP GG 3

Musunuru J Urol 2016

Musunuru J Urol 2016

EAU guidelines

EAU-EANM-ESUR- ESTRO-ESUR-ISUP-SIOG guidelines 2023

EAU-EANM-ESUR- ESTRO-ESUR-ISUP-SIOG guidelines 2022

Expending the « AS » criteria: ProtecT

Hamdy N Engl J Med 2023

N = 1643 screen detected (T < T3 - PSA < 20 ng/ml)

58% low risk / 40% intermediate risk / 2% high risk

Median follow up: 15 years

AM / RP / EBRT + 6 months ADT

NO MRI
Specific death: 45 [AM: 17 / RP: 12 / EBRT: 16
NO targeted
Overall biopsy
death: 356 [124 / 117 / 115]
NO repeated per-protocol rebiopsy

42
 ProtecT @ 15 years
Hamdy N Engl J Med 2023

Does not mean NO treatment in the AM group

AM: 51 / RP: 26 / EBRT: 27

Therefore AS
Very low risk outdated

Low risk as a whole: IS THE Standard Of Care in the 2023 guideline

Regarding intermediate risk:

based on PSA only: probably
based on ISUP GG: possibly for the “limited” only (caution)
Added value of mpMRI: significant (still some issues)

The future: all protocols to be reconsidered . . . . (decreased pressure)

Next hour !
mpMRI targeted biopsies: unclear situation if some ISUP 2

Radical prostatectomy

43
 RP: general principle

EAU-EANM-ESUR- ESTRO-ESUR-ISUP-SIOG guidelines 2023

EAU-EANM-ESUR- ESTRO-ESUR-ISUP-SIOG guidelines 2022

Open or robot ?
Large RCT Yaxley Lancet 2016
N = 326
PSA: 4.49 ng/ml. Gleason ≤ 3+4: > 60%

Open or robot ?
Yaxley Lancet 2016

In fact
comparison of 2 surgeons
major experience difference . . .

44
 Open or robot ?
Updated results Loughlin Lancet Oncol 2018
24 month follow up.

Relapse No functional difference

% are significantly different (continence / potency)

Impact: surgeon: margins / relapse

7765 RP 4 major US institutions

5 years relapse free survival (paired comparison)
Margins
Bianco J Urol 2008 Vickers J Urol 2010

Impact: surgeon: continence

Auffenberg Jama Surgery 2021
N = 4582 RP, 95 surgeons (Michigan data base)
Prospective (2014-2018) Self administered questionnaires

And top surgeons

- Less margins

- More CR @3 months

45
 Hospital volume: a major factor
Systematic review Van den Broeck Eur Urol 2021

Clear threshold if > 86/ an

SPCG-4
Bill-Axelson N Engl J med 2018

N = 695 RP / WW
75% > T2. mean PSA: 12.8 ng/ml
(trial started BEFORE PSA for early diagnostic)

Mean age: 65 years (both groups)

Latest report: 23 years median follow up

Survival
OS RR (CI 95%)
PR WW SS RR (CI 95%)
Population 0,74 (0,62 – 0,87) Population 0,55 (0,41 – 0,74)
< 65 years 0,62 (0,48 – 0,80) < 65 years 0,50 (0,34 – 0,75)
≥ 65 years 0,86 (0,69 – 1,07) ≥ 65 years 0,63 (0,4 – 0.99)

Median follow up
23 years

Bill-Axelson N Engl J med 2018

46
 RP survival benefit / follow up

Bill Axelson N Engl J med 2014

PIVOT trial

Wilt. N Engl J Med 2012

N = 731 (out of 5023 candidates). 364 PR / 367 WW

T1-2 N0. PSA < 50 ng/ml
< 75 years old. Life expectancy ≥ 10 years
T1c: 50% - Gleason ≤ 6: 70% - Low risk: 40%, intermediate risk: 34%

PIVOT: overall mortality

Wilt. N Engl J Med 2017 Wilt Eur Urol 2020

Follow up: 13 years

Follow up: 18 years
P = 0.04
NS p = 0.06

47
 PIVOT: patient selection ?
Inclusion criteria: 10 years life expectancy
65% ≥ 65 years, mean age 67years ?
Contemporary US : 60 y
Dalela EurUrol 2017

39% Charlson index ≥ 1 ?

Contemporary US: 7%
Dalela EurUrol 2017

Follow-up 10 years 13 years 18 years

Proportion of 48% 64% 75%
patients who died

Wilt et al.; NEJM 2012; Wilt et al. NEJM 2017; Wilt et al EurUrol 2020

Indication for PLND

Most recent externally validated nomogram (MRI based) Gandaglia Eur Urol 2019
7% threshold
N = 497

Still some limits here

Like: Only 62 were pN1

AUC: 86%

PLND value ?
Systematic review Fossati Eur Urol 2017

NO clear oncological benefit (relapse / metastases / survival) compared to NO PLND

NO clear oncological benefit extended / limited
Clear added morbidity

Multicentric large data base: intermediate / high risk, (LN risk > 5% [Briganti])
Preisser J Urol 2019

Matched paired comparison. Nx: 707 / PLND: 9,053 (1717 pN+)

PLND done / not done: NO impact relapse, metastases, specific mortality

48
 PLND: RCT. the definitive answer ?
Lestingi Eur Urol 2020

N = 300. intermediate (62%) / high risk

Median nodes removed. Extended: 17 / limited: 3
Median follow up: 53.9 months

Only biopsy ISUP ≥ 3

N = 69

PLND: RCT. the definitive answer ?

Touijer Eur Urol Oncol 2021

N = 1440. Single center (MSKCC). 9 surgeons

Median nodes removed: extended: 14 / limited: 12

PET PSMA and PLND

N patients (histological confirmation) Sensitivity (%) Specificity (%)

Budäus (2016) 30 33 100

Herlemann (2016) 20 84 82

Maurer (2016) 130 74 99

Van Leeuwen (2017) 30 58 100

Hofman (2020) 83 85* 98*

Hope (ASCO 2020) 277 40 95

Amiel (2021) 230 48 96

 Se not enough to avoid ePLND . . .

49
 Nerve sparing: when ?
Pre-surgery erections

Nerve sparing: improved continence Michl EurUrol 2016, Avulova J Urol 2018
More the dissection then the conservation itself ?

Extra, inter ou intrafascial dissection

The closer, the better the sparing Steineck Eur Urol 2015

Antegrade / retrograde ? Ko Eur Urol 2013, High level release Nielsen J Urol 2008

No coagulation, No traction Tewari World J Urol 2013

Selection: various criteria(cT, nbre of + cores / high ISUP / MRI)

Nerve sparing and margins

Systematic review: 1990-2020. 18 études. 21 654 RP Morris Eur Urol Focus 2021

Ajustement: side of sparing / risk per side

Link between: sparing and margin risk (RR: 1,42 / 1,53 depending on model)
Most patients: low risk, few + cores / sparing side

Overall quality data: limited

No for relapse difference after 12 mois minimum follow up

Anatomical factors and continence

Lardas Eur Urol focus 2021

Systematic review (119 cohorts. 131 379 men)

Continence 3 months Continence 12 months
age + +
Urethral length(IRM) + +
prostate size + +
CCI +

50
 Reconstruction: impact on continence ?
Anterior / posterior reconstruction

Overall
Potentiel short term benefits with anterior and posterior suspension
Hurtes BJUInt 2012, Student Eur Urol 2017, Noguchi BJUInt 2008

No long term benefit

No negative impact: side effects or oncologiocal

Impact of a delay and outcome

Systematic review Laukhtina World J urol 2021

Intermediate or High risk

NO impact for up to 3 months for: BCR, survival

High risk: RP
N = high risk 1360 (PR ± adjuvant / salvage)

“Simplified" model
Joniau Eur Urol, 2014
-low risk : 1 facteur
-Intermédiate risk: PSA > 20 ng/ml and T3-4
- High risk: all 3 factors

51
 High risk: PR

We are discussing multimodal therapy Joniau Eur Urol 2014

Radical prostatectomy

One local therapy option (not THE best local therapy)

Leading to some survival benefit (local disease)
Associated with some side effects

Key point: surgical experience is the key factor

52
Treatment of localised PCa N. Mottet
Radiation / focal . . . . St Etienne

Disclosures

Type of affiliation / financial interest Name of commercial company

Receipt of grants/research supports: Astellas, Sanofi Pasteur, Pierre Fabre

Receipt of honoraria or consultation fees: Astellas, Jansen, BMS, Bayer, IPSEN, Ferring,
Sanofi, Steba, Astra Zeneca, Carrik, Arquer
diagnostics, GE, Takeda

53
 Radiotherapy: some reminders
Mostly through photons (protons also used)
Tissue interactions leading to ionization. Energy absorbed by DNA (high lineal energy transfer) / free radicals from
water (low linear energy transfer) also interacting with DNA

DNA interactions leading to DNA damage, leading to various outcomes: irreversible block, apoptosis, mitotic death,
or colony formations.

Principle of fractionation: balance between cell death / DNA repair – cell surviving.

Factors influencing radiation sensitivity: dose-rate effect, tissue itself, oxygenation.

2 ways to deliver: external beam / interstitial (brachtherapy)

Radiotherapy: some definitions

EXTERNAL BEAM
IMRT: intensity modulated RT. The intensity of each beam is modulated, as well as dynamic multileaf
colimator. Increasing dose to target, decreasing dose to surounding tissues. And concave /curved targets limits
VMAT: volumetric modulation RT. A form of IMRT where the beam rotates continuously over a 360°
curve (ie quicker compared to IMRT)
IGRT (image guided radiotherapy). Mandatory with the increased doses. Prostate moves !

BRACHYTHERAPY

Radiotherapy: general principles

EAU-EANM-ESUR- ESTRO-ESUR-ISUP-SIOG guidelines 2023

EAU-EANM-ESUR- ESTRO-ESUR-ISUP-SIOG guidelines 2022

54
 EBRT dose matters

Key point: at least 76 Gy

(conventional fractionation)

Combined modality to increase the dose

Proton boost

Brachytheray boost

Combination EBRT and ADT

Both from Bola

55
 EORTC 22863
ADT: 3 years
Bolla Lancet Oncology 2010

OS Specific death

EORTC 22961
Bolla NEJM 2009

N = 970
Median PSA: 18,4 ng/ml

At 5 years:
Specific death: 4.7% / 3.2%
HR: 1.71 P = 0.002

Overall death: 15.2% / 19%

HR: 1.42

Canada PCS 4
Nabid Eur Urol 2018

N = 630. T3 - T4 or PSA > 20 ng/ml or Gleason > 7 (60%). 18 vs 36 months ADT

Primary objective: OS Superiority trial
To consider:
Median follow-up: 9.4 years
- NOT locally advanced (76% < T3) – median PSA: 16 ng/ml – However: 60% Gleason ≥ 8

- Non compliance: an issue ! (50% in the 36 months arm)

OS

SS

Overall QoL: same. Less sexual Pb / hot flushes

56
 ADT value and EBRT dose increase

Benefit of adding ADT irrespective of EBRT dose

From GICOR trial Zapatero J Clin Oncol 2005

DART01/05GICOR Zapatero lancet 2015
EORTC Bola J Clin Oncol 2016

Ie: no compensation between dose and ADT

An example: EORTC 22991

Bolla J Clin Oncol 2016

N = 819. T1b-T2a. PSA > 10 or Gleason ≥ 7 OR T2b-4, PSA > 12 UNL

Overall: 44% T1c, 50% T2a, 90% Gleason < 8, Median PSA: 10 ng/ml

BCR

cDFS

When ADT is used: is EBRT needed ?

57
 An example: MRC PR07
Mason J Clin Oncol 2015

N = 1205. T3-4 / T1-2 PSA > 40 ng/ml OR PSA 20-40 ISUP ≥ 4

Median follow up: 8 years

Moderate hypofractionation

Moderate hypofractionation: SOC

60 Gy / 20 – 70 Gy / 28

Bed: 76 Gy

An example: CHHiP trial

Dearnaley lancet Oncol 2016

Median follow up: 62 months Acute side effects

60 at least equal

BCR free survival

57 is inferior

58
 QoL hypofractionation (CHHiP)
Staffurth Eur Urol Oncol 2021

PROM. 5 years follow up (1145 feed back out of 2011 @ 5 years)

Of note: OR < 1 equals better QoL

Ultra hypofractionation

Systematic review
Jackson Int J radiat Oncol Biol physics 2019

Major limit: media follow up: 39 months

EAU position: Not yet ready to be considered as SOC

59
 LDR Brachytherapy

Pre TURP is NOT a CI provided:

> 3 months. At least 1 cm prostate tissue

Modified upper limit: 12-14

ABS guideline: Davis. Brachytherapy 2012

ASTRO/ACR guidelines: Rosenthal IJROBP 2011
GEC ESTRO/EAU: Kovacs. Radiother Oncol 2005
ASCO/Cancer Care Ontario: Chin. JCO 2017

LDR Brachytherapy

1669 pts
Median follow-up: 10 y (5-19)
Stone J. Urol 2014

Patients

Prostate Cancer Specific Survival

Other modalities

EAU-EANM-ESUR- ESTRO-ESUR-ISUP-SIOG guidelines 2023

EAU-EANM-ESUR- ESTRO-ESUR-ISUP-SIOG guidelines 2022

60
 Alternative therapies
Formal systematic review Hopstaken Eur Urol 2022
N = 5827 patients from 72 cohorts.
Functional results: 95% pad free / 85-90% without significant PCa
Major limits: 42% ISUP 1. Overall quality evidence low (retrospective, single center,
non comparative, heterogeneous def)

Propensity matched from multicenter databases Shah prostate Cancer prostic Dis 2021
2 groups (246 each). 60% ISUP 2/3. 45% bilateral cancer
@ 8 years FFS (= need for salvage) BCR

Focal 83% 23.9% Limits: second focal allowed

RP 79% 24.8% (not considered as failure)

Alternative therapies
Largest oncological outcome Guillaumier Eur Urol 2018
N = 625. 599 at least 6 months Follow up, 84% intermediate / high risk
Median follow up: 56 months
Primary objective: FFS (freedom from radical / systemic therapy, metastases, and cancer specific mortality.

Limits: Repeated focal: 25% of cases

75% PSA < 10 ng/ml
All patients classified using targeted + systematic biopsies
28% Gleason score = 6 / 55%
T stage = 7 (3+4)?
definition
72% T2. 14% T3a/b
Intermediate: 53%, High 32%

PDT: CLIN1001 PCM301

Azouzi Lancet 2016

N 499: only RCT

comparing PDT / AS

3/2011 – 4/2013

Inclusion criteria
Low risk [Gleason 6 (3+3)]
1 core 3-5 mm OR
2-3 cores, each < 5 mm

61
 PDT: CLIN1001 PCM301
Azouzi Lancet 2016

N 499: PDT / AS
End points: progression (higher risk group) / cancer free @ 2 years

Focal therapy

Worth studying YES

Evidenced based NOT YET

Possible treatment paradigm change MAYBE

Therefore in practice STILL INVESTIGATIONAL ONLY

Low risk

Local active therapy no longer mentionned

EAU-EANM-ESUR- ESTRO-ESUR-ISUP-SIOG guidelines 2023

EAU-EANM-ESUR- ESTRO-ESUR-ISUP-SIOG guidelines 2022

62
 Intermediate risk

Unfavourable: ISUP 3,
and/or 50% + cores
and/or 2 intermediate
risk factors
EAU-EANM-ESUR- ESTRO-ESUR-ISUP-SIOG guidelines 2023

EAU-EANM-ESUR- ESTRO-ESUR-ISUP-SIOG guidelines 2022

Expending the « AS » criteria: ProtecT

Hamdy N Engl J Med 2023

N = 1643 screen detected (T < T3 - PSA < 20 ng/ml)

58% low risk / 40% intermediate risk / 2% high risk

Median follow up: 15 years

AM / RP / EBRT + 6 months ADT

NO MRI
NO targeted biopsy
NO repeated per-protocol rebiopsy

Expending the « AS » criteria: ProtecT

Hamdy N Engl J Med 2023

N = 1643 screen detected (T < T3 - PSA < 20 ng/ml)

58% low risk / 40% intermediate risk / 2% high risk

Median follow up: 15 years

AM / RP / EBRT + 6 months ADT

NO MRI
Specific death: 45 [AM: 17 / RP: 12 / EBRT: 16
NO targeted
Overall biopsy
death: 356 [124 / 117 / 115]
NO repeated per-protocol rebiopsy

63
 ProtecT @ 15 years
Hamdy N Engl J Med 2023

Does not mean NO treatment in the AM group

AM: 51 / RP: 26 / EBRT: 27

ProtecT: Overall QoL @ 10 years

Donovan N Engl J Med evidence 2023

Self administered questionnaires Returned: 80% @ 7-12 years

Overall: NO difference on global QoL (SF-12, QLQ–C30)

ProtecT: PROM and side effects

Donovan N Engl J Med evidence 2023

64
 Side effects. Recent tools

Barocas et al, JAMA 2017

High risk localized

EAU-EANM-ESUR- ESTRO-ESUR-ISUP-SIOG
EAU-EANM-ESUR-
guidelines
ESTRO-ESUR-ISUP-SIOG
2023 guidelines 2022

To conclude

Many effective treatment modalities

Not one best modality

Patient MUST be involved in the decision / realistic expectations

EAU-EANM-ESUR- ESTRO-ESUR-ISUP-SIOG guidelines 2023

EAU-EANM-ESUR- ESTRO-ESUR-ISUP-SIOG guidelines 2022

65
 Locally Advanced Prostate Cancer
Dr JPM Sedelaar, onco-urologist Radboudumc Nijmegen, The Netherlands

Conflict of Interest Disclosure

“I have no potential conflict of interest to report…

except that I am a prostate-cancer urologist, I work in the

Prostate Cancer Center Prosper with a focus on Robot-
Prostatectomy….“

Henk J, 69 years old

• Past medical history: none

• Family history: father died from prostate cancer at 80 years old

• PSA: 19ng/ml

• DRE: T3 , Biopsies: Gleason 8 (4+4) on 5 out of 12 biopsies

66
QUESTION:

Which examens do you need?

1- Conventional (CT Scan, Bone Scan) +/- MRI prostate

2- Choline PET –CT +/- MRI prostate
3- PSMA-PET-CT +/- MRI prostate

QUESTION:

Which additional investigations do you need?

1- Conventional (CT Scan, Bone Scan) +/- MRI prostate

2- Choline PET –CT +/- MRI prostate
3- PSMA-PET-CT +/- MRI prostate

High-risk locally advanced, staging

67
 cT3b, Gleason 4+4, ISUP4, cN0, cM0 PCa

Risk stratification

Natural History of T3/T4 M0 Cancers

Akre et al Eur Urol 2011 Sep;60(3):554-63.

68
Is it worth to treat high risk locally advanced PCa or is
this systemic disease?

active treatment vs. pall. ADT

Very high-risk Patients (T2-T4, M0)

12.3 % benefit in CSS for ADT plus

Radiation after 10 years

Widmark et al., Lancet 2009; 373

Very high risk Patients (T2-T4, M0) ADT +/- Radiotherapy (T2-T4, M0)

11 % benefit in CSS for ADT plus

Radiation after 7 years

Warde et al., Lancet 2011; 378

69
(A) PCA-specific and Overall survival (B) in men not
suitable for ProtecT-Trial
Only a smallproportion of men who received radical treatment (RP 4%, RT
5%) died from PCa, which adds to increasing evidence that
radical treatment of locally advanced or high-risk disease
delivers good oncologic outcomes

Johnston TJ et al., Eur Urol. 2017 Mar;71(3):381-388.

How to treat Henk?

cT3b, Gleason 4+4, ISUP4, cN0, cM0 PCa

Deferred
Treatment?
Radiation
Surgery
(+ADT)?
(+Radiation)? ADT alone

70
 Surgery- Surgical technique

• Wide excision radical prostatectomy (open or robotic)

• No nerve sparing technique (in most cases)

• Includes extended pelvic lymphadenectomy

• Possible adjuvant therapy regarding specimen examination

• The most accurate method for staging lymph node still remains an ePLND

• This includes the lymph nodes overlying the external iliac axis, those in the obturator fossa and
around the internal iliac artery

• This template includes 75% of the potential anatomical landing sites of nodal metastases

NEVER SHOWED TO
IMPROVE CANCER
CONTROL IN
PROSPECTIVE
STUDIES!!!!

71
 Surgery

Impact of local therapy on survival in pN1 PCa

N= 158, Martini-Klinik1 N= 938, Munich Cancer Registry2 N= 2991, SEER3

pN+ and RP
pN+ and RP

pN+ no RP pN+ no RP

3 Independent, retrospective studies demonstrating the impact of local therapy on PCa survival in pN1

(1) Steuber et al. BJU Int. Oct 2010, (2)Engel et al. Eur Urol Oct 2013
(3) Rusthoven et al. Int J Radiation Oncol Biol Phys 2014

Optimal outcome by optimal/multimodal therapy

• retrospective, multi-center study

• 6004 high risk patient, NCCN, 2000 - 2014

• optimal RP vs. optimal EBRT

72
 Optimal outcome by optimal/multimodal therapy

• retrospective, multi-center study

• 6004 high risk patient, NCCN, 2000 - 2014

• optimal RP vs. optimal EBRT

Evidence...meta-analysis from 10 trials!

BCR-free survival post RP +/- neoadjuvant ADT

73
 Discussion

Historical neoadjuvance studies Modern neoadjuvance studies

• classic ADT • more „potent“ ADT (NHA)
• more low risk intermediate risk • real high-risk
• pCR not included • pCR included
• limitited long-term follow-up • long-term follow-up

Pathologic response more potent neoadjuvant ADT

Presented By Rana McKay at TBD

74
 PROTEUS study, RCT, >2000 pt

Let´s talk about Henk

Henk had robot surgery: non nerve sparring, ePLND:

pT3b R0 pN0 (0/23) Gleason 4+4. At 6 weeks of 0.01ng/ml

How to treat Henk?

pT3b, Gleason 4+4, ISUP4, R0 pN0 PCa

adjuvant ADT?
Radiation
(+ADT)?
PSA based
surveillance?

75
Guidelines for adjuvant treatment in pN0 or pN1 PCa
after radical prostatectomy

Multimodality approach
Surgery AND radiation therapy

ARTISTIC Meta-Analysis

Kneebone et al., Lancet Oncology, 2020

76
 ARTISTIC Meta-analysis

However limited number of men included with adverse pathology at RP (less than 20%
with Gleason score ≤8, max. 20% SVI, only 0-5% pN1)!!!

Kneebone et al., Lancet Oncology, 2020 34

Retrospective validation study, adjuvant vs. early salvage RT

Without adverse pathology With adverse pathology

(0.33 [0.13-0.85]; P = 0.02)

(PRADICALS-RT p=0,49, PRAVES p=0.22, und GETUG-AFU 17 p=0.0504).

Tilki et al.; J Clin Oncol Vol. 39, 2021 35

Radiotherapy

77
 Evolution of Radiation IMRT: Intensity modulated Radiotherapy

High Dose Rate Brachytherapy plus boost EBRT

HDR for Locally Advanced Ca Prostate

• Any PSA
• Any Gleason
• T3 or less
• Any volume
• No specific exclusion on IPSS

Radiotherapy

• Standard recommended RT dose in many European Centres is now ≥

76-78 Gy in 37 fractions compared to 64 Gy in 32 fractions

39

78
 Fractions

Conventional fractions : 1.8-2.0 Gy/Fraction

Moderate Hypofractions: 2.4 -4.0 Gy/Fraction
Extreme Hypofraction: 6-10 Gy/Fraction
Arcangeli S. Nature Reviews, Urology 2016 40

Radiotherapy

Radiotherapy
36 months ADT+RTX vs RTX alone (EORTC 22863)
N=415 patients – duration of ADT 3 years

10 yr Overall Survival -
 by 20%

10 yr Disease Specific
Survival  by 20%

Cardiovascular
Mortality Not
Different

Bolla M et al. Int J Rad Oncol Bio Phys 2008;72

Bolla M et al. Lancet 2002;360:103

79
 ADT+RTX: 36 months vs. 18 months (EORTC 22961)

Nabid A. et al; Eur Urol. 2018 Oct;74(4)

Multimodal/optimal RT includes…

• Additional/adj. long-term ADT (at least 2yr)

• Add modern systemic treatment (NHA)??

ADT plus Abiraterone for 2 years plus Radiation, STAMPEDE M01

1http://www.stampedetrial.org/centres/information-on-stampede/

80
 STAMPEDE M01

1http://www.stampedetrial.org/centres/information-on-stampede/

Design
• Radiatio (74Gy)
• SOC: ADT (Abi / LHRH) for 3 years
• Trial 1: Abirateron* / Prednislon 1000mg/5mg 1x1/d for 2 yr oder until progress
• Trial 2: Abirateron* / Prednislon 1000mg/5mg 1x1/d ± Enzaltuamid* 160mg 1x1/d
for 2 yr or until progress

• Primary endpoint: Metastasis-free survival ( Mx or detah)

• Secondary endpoint: OS, CSS, BCRF, Mx, local progression, Tox., SAE/AE
• Median follow-Up: 72months (Trial 1: 85 months; Trial 2: 60 months)

Metastasis-free survival
Cave:
Primary endpunkt MFS
incl. Mortality

SOC + Abi±Enza: 52%

death, 48% Mx

SOC: 38% death, 62% Mx

6y MFS:
82% vs. 69%

81
 Overall survival

6y OS:
86% vs. 77%

6y PCsOS:
93% vs 85%

No additional effect by adding Enzalutamide

82
 Immediate or deferred hormonal therapy
for locally advanced PCa

Immediate or deferred hormonal therapy

• EORTC 30891; 985 patients; Mean age 72
• Immediate orchiectomy or buserelin vs. deferred
• Follow-Up 7.8 years, 541 deaths
• 46 % T3-4; 57% N1-2; Mean PSA 16,3 ng/ml

Androgen Deprivation
Endpoint at 8 years Immediate (n = 492) Deferred (n = 493)
n % n %
Dead by any cause 257 52.2 284 57.6
Dead from PCa 94 19.1 99 20.1
Dead from CV disease 88 17.9 97 19.7

Cancer Specific Survival and Progression to Hormone Refractory Disease did not
differ in 2 arms. Overall Survival just favored Immed: arm (p=0.06)
Studer UE, J Clin Oncol. 2006 Apr 20;24(12)

Immediate or deferred hormonal therapy

Baseline PSA >
50 ng/ml – 4 fold
higher risk

Risk Factors
Associated with
Significantly
Worse Outcome
PSA doubling
Time < 12
Months

Deferred treatment appropriate in patients with PSA < 50ng/ml and

PSA doubling time > 12 months (LE 1)

Studer UE et al. J Clin Oncol 2006;24:1868

83
 Summary
• Multimodal approach, best results
• Surgery
• with extended lymph node dissection
• Discussion about adjuvant RxTh and ADT
• +NHA in the future?
• If Radiation therapy:
• high dose
• >2yrs of ADT
• add 2 yrs of abiraterone for cT3 a/o cN1 a/o PSA>40ng/ml (2 or more)
• If ADT alone:
• immediate for PSA>50ng/ml and PSADT<12months

Best approach?

„Urologists do bad in performing randomized trials, most

evidence arises from retrospective, single- or multi-institutional
case control trials, which need to be interpreted with caution!“

„Old habits are difficult to adjust or alter“

84
 Metastatic Prostate Cancer
Dr JP Michiel Sedelaar, Onco-Urologist, Nijmegen The netherlands

Conflict of Interest Disclosure

I have no conflict(s) of interest to report

Paul, 61 years

Patient medical history:

• Urologic Evaluation for LUTS

• Hypertension
• DRE non suspicious, 50cc prostate

85
 mHSPC case debate: Paul, 61 years
Lab
PSA (ng/ml) 65.8
LDH (U/L) 210
AP (U/L) 98
Hb (g/dl) 15.2

• Gleason 4+4, 4/4 Bx

Staging, cT1c, Gleason 4+4, cM1b

Hormonal therapy agents

Surgical castration: gold standard of ADT
The effect of castration on advanced carcinoma of
the prostate gland. Arch Surg, 1941
600

500 Within 12 hours

Cost Effective
Testosterone (ng/dL)

400

300

200
Charles HUGGINS
1901–1997 100
1966 Nobel Prize
0
-14 0 1 3 7 14 21 28 29 31 35 56 57 59
Days post castration

86
 Hormonal therapy agents
GnRH agonists and antagonists
Leuprolide
Firmagon 240/160mg
Firmagon 240/80mg Testosterone

Leuprolide 7.5mg Day 3

+70%
Firmagon
Testosterone
Day 3
- 96%

In Degarelix as opposed to GnRH agonist there is significant drop in Sr Testosterone

levels by Day 1 & Castrate Levels by Day 3

(1) Klotz L et al. BJU Int 2008; 102: 1531-1538.

Hormone therapy side effects

• Loss of libido and sexual interest, erectile dysfunction, impotence

• Fatigue
• Hot flushes
• Decline in intellectual capacity, emotional liability, depression
• Decrease in muscular strength
• Increase in (abdominal) fat apposition, Diabetes, risk of CV events
• Osteoporosis

Hormone therapy side effects and treatment options

87
 Change of paradigm in mHSPC: ADT plus…
Docetaxel Abiraterone
CHAARTED1 LATTITUDE3

2015 2016 2017 2018 2019

Docetaxel, Abiraterone Apalutamide
STAMPEDE2 TITAN4
Enzalutamide
ARCHES5
ENZAMET6

• mHSPC, metastatic hormone-sensitive prostate cancer.

1Sweeney CJ, et al. N Engl J Med. 2015;373.2James ND, et al. Lancet. 2016;387:1163-77.
3Fizazi K, et al. N Engl J Med. 2017;377:352-60, 4Chi K. et al, J Clin Oncol 2021 Jul 10;39(20)
5 Armstrong AJ et al. J Clin Oncol. 2019 Nov 10;37(32), 6Davis ID et al, N Engl J Med. 2019 Jul 11;381(2)

Staging, cT1c, Gleason 4+4, cM1b, high risk/volume,

no symptoms
• ADT alone

• ADT/Abiraterone

• ADT/ Docetaxel, 6 cycles

• ADT/Enzalutamid/Apalutamid

• Triple (ADT/Doce/NHA)

Guidelines 2023, first line treatment of mHSPC

88
 M1 according to disease volume
M1 High volume M1 High Risk
„CHAARTED Criteria“ „LATITUDE Criteria“

• ≥ 4 bone metastasis, 2 out of 3 criteria:

1 outside vetebral • ≥ 3 bone metastasis,
spine/pelvis • visceral metsastasis
• or visceral metsastasis • ≥ Gleason 8

Sweeney CJ et al. N Engl J Med 2015; 373 Fizazi K et al. N Engl J Med 2017; 377

ADT + Doc shows an OS benefit in long-term follow-up

GETUG AFU-151
ADT + Doc
CHAARTED2
OS in the overall population (proportion)

1.0
OS in the overall population (proportion)

ADT alone
0.9
Median OS (months)
0.8
ADT: 48.6 (40.9–60.6)
0.7 ADT + Doc: 62.1 (49.5–73.7)
HR 0.88, 95% CI 0.68–1.14;
0.6 p = 0.3
0.5

0.4

0.3

0.2

0.1

0
0 1 2 3 4 5 6 7 8

Follow-up (years) Time (months)

No. of patients at risk:
ADT + Doc 192 175 145 119 102 87 72 32 397 366 314 245 155 67 28 7 2 0
ADT alone 193 171 148 116 94 76 61 33 393 352 278 198 126 45 21 2 0 0

1Gravis G, et al. Eur Urol. 2016;70:256-62.

2Kyriakopoulos CE, et al. J Clin Oncol. 2018;36:1080-7.

STAMPEDE: multi-arm, multistage, multi-center,

open-label randomized clinical trial

A SOC = ADT (± RT)

C SOC + Doc

SOC + AA
G

• http://www.stampedetrial.org/media/2176/stampede-
treatments-overview_v20-nov18.pdf Last accessed Feb 2019

89
 ADT + Doc shows an OS benefit in STAMPEDE long-term follow-up (cont.)

all patients M1 disease

100 1.0
HR 0.78, 95% CI 0.66–0.93;
p < 0.006 SOC + Doc
80 0.8

SOC
60 0.6
OS (%)

OS (%)
40 0.4
SOC by Kaplan–Meier
SOC by flexible parametric model
20 SOC + Doc by Kaplan–Meier 0.2
HR 0.76, 95% CI 0.62–0.92;
SOC + Doc by flexible parametric model p = 0.005
0 0
0 12 24 36 48 60 72 84 0 12 24 36 48 60 72
Time from randomisation (months) Time from randomisation (months)

No. of patients at risk (events)

SOC + Doc 1,184 (73) 1,093(134) 876 (92) 538 (60) 322 (35) 166 (17) 87 (2) 43 362 326 250 155 91 38 25
SOC 592 (33) 545 (52) 447 (35) 290 (22) 181 (12) 93 (13) 51 (6) 20 724 646 474 262 137 60 26

James ND, et al. Lancet. 2016;387:1163-77 .

ADT + AAP shows an OS benefit in long-term follow-up in mHSPC

LATITUDE1 STAMPEDE2
(de novo high-risk mHSPC patients) (full cohort)

100

80 Abiraterone
ADT + AAP, 53.3
months
OS (%)

60 Median treatment exposure: PBO

ADT + AAP: 25.8 months
ADT + PBO: 14.4 months
40 No. of events:
ADT + AAP: 275 (46%)
ADT + PBO: 343 (57%) ADT + PBO, 36.5 months
HR 0.63, 95% CI 0.52–0.76;
20
HR 0.66, 95% CI p < 0.001
0.56–0.78;
p < 0.0001
0
0 6 12 18 24 30 36 42 48 54 60 66
No. of patients at risk
Time (months)
ADT + AAP 597 565 529 479 425 389 351 311 240 124 40 0
ADT + PBO 602 564 505 432 368 315 256 220 165 69 23 0

1. Fizazi K, et al. N Engl J Med 2017; 377.

2. James ND, et al. N Engl J Med. 2017;377:338-51.

Is ADT + Doc effective in low-volume mHSPC?

High-volume mHSPC Low-volume mHSPC

A uniform effect was noted for ADT + Doc in the STAMPEDE study
Kyriakopoulos CE, et al. J Clin Oncol. 2018;36:1080-7.

90
 AAP-treated patients had significant improvements in OS in both low- and
high-risk categories
Low risk High risk
1.0 1.0

82.4%
0.8 ADT + AAP 0.8
78% 64.7%
Probability of OS

Probability of OS
0.6 0.6
ADT + AAP
ADT

0.4 0.4 43%

0.2 Difference in OS: 4.4% 0.2 Difference in OS: 19.7% ADT

HR 0.66, 95% CI 0.44–0.98; HR 0.54, 95% CI 0.41–0.70;
p = 0.041 p < 0.001
0 0
0 6 12 18 24 30 36 42 48 54 0 6 12 18 24 30 36 42 48 54
Months since randomisation Months since randomisation
No. of patients (events) No. of patients (events)
AAP 208 (2) 205 (17) 186 (16) 131 (5) 45 AAP 241 (17) 220 (29) 190 (35) 106 (12) 28
ADT alone 220 (6) 210 (21) 186 (19) 125 (7) 43 ADT alone 232 (25) 204 (51) 148 (44) 71 (15) 13

Hoyle AP, et al. Oral presentation at ESMO 2018; abstract LBA4.

„All-comer population“ (high, low risk/volume, synchron, metachron)

tested with Enzalutamide and Apalutamide

• Chi K et al. N Engl J Med. 2019 • Davis ID et al. N Engl J Med 2019

Enzalutamid and Apalutamid also effective in mHSPC

ARCHES

Chi K et al. N Engl J Med. 2019 Davis ID et al. N Engl J Med 2019

91
 Paul, 61 years Is triple therapy
an option??

PEACE-1 Study design

SoC
Inclusion criteria (N=296)
• De novo mHSPC
• ≥1 mets, conventional imaging SoC (+/-
• ECOG PS 0-2 Radiation)
SoC + Abirateron (N=589)
(N=292)
Permitted
R
• ADT ≤3 months
1:1:1:1
(N=1173)
Stratification SoC +
• ECOG PS (0 vs 1-2) Radiotherapy SoC + Abirateron
• localisation (N=293) (+/- Radiation)
(LN vs bone vs visceral) (N=583)
• Castration (Orchidectomy vs LHRH-
Agonist vs LHRH-Antagonist) SoC + Abirateron
• Docetaxel (yes vs no) + Radiotherapy
(N=292)

SOC
• continuous ADT
Amendement PEACE-1, SoC changed over time:
• +/- Docetaxel 75mg/m2/3w x 6 (G-CSF recommended)
• Nov 2013-2015: only ADT (N=273)
• 2015-2017: Docetaxel allowed as part of SoC (N=592) Therapy
• 2017-Dec 2018: Docetaxel obligatory for SoC (N=308) • Abirateron 1000 mg/d + Prednison 5 mg x2/Tag until progression or intolerance (plus Docetaxel)
• Radiotherapy (RXT) prostate 74 Gy in 37 fractions

Fizazi K | Abstract 5000 | ASCO 2021, virtuell

Fizazi K ESMO 2021; abstract LBA5_PR.

OS, ADT/Docetaxel vs. ADT/Docetaxel/Abirateronen

(both +/- radiation prostate)
high Volume low Volume

Major limitation: - SoC today ADT/NHA, not ADT/Doce,

- impact of Doce unclear
-add relevant toxicity
Fizazi et al The Lancet 2022.

92
 Summary: first line mHSPC treatment
• Docetaxel, best data for high volume mHSPC (Chaarted definition)

• Abiraterone, probably effective in all categories, approval only for high

risk mHSPC (LATTITUDE trial)

• Enzalutamide/Apalutamide: good evidence for „all comer“

including high and low volume/risk, primary and metachron mHSPC

• Triple therapy (ADT/Doc/NHA) better than ADT/Doc, which patient?

Paul, 61 years What about

my prostate?

Local treatment in mHSPC, prospective trials

Study Details Type/location Intervention Endpoints
BST or BST + definitive treatment Phase 2 MDACC, TX, USA RP or RT + systemic Tx vs PFS, OS
(RT or surgery) 1 N = 120 systemic Tx QoL
Systemic Tx in advancing or Phase 3 Multicentre; SOC (ADT) vs SOC + RT OS, PFS
metastatic prostate cancer: 2005–2017 UK and
evaluation of drug efficacy. Switzerland
STAMPEDE trial, Arm H 2,3
HORRAD study: RT vs no RT4,5 N = 446 Multicentre; ADT vs ADT + RT OS, PFS,
2004–2011 Netherlands QoL
completed
EORTC-1201-GUCG-ROG N = 15, 501 Multicentre; ADT ± Doc (Arm A) vs ADT ± OS
(PEACE-1) 6 2004–2012 Europe Doc + AA (Arm B) vs Arm A + RT PFS,
(Arm C) vs Arm B + RT (Arm D) QoL
AP 75/G_RAMPP: Multicentre, N = 452 Multicentre; Systemic Tx (ADT ± Doc) vs OS
prospective, randomised study1 2015–2025 Germany systemic Tx (ADT ± Doc) + RP PFS

• 1. ClinicalTrials.gov Identifier: NCT01751438. 2. ClinicalTrials.gov Identifier: NCT00268476.

3. Parker C, et al. Lancet. 2018;392:2353-66. 4. ISRCTN Registry number: ISRCTN06890529.
5. Boevé LMS, et al. Eur Urol. 2019;75:410-8. 6. ClinicalTrials.gov Identifier: NCT01957436.7.

ClinicalTrials.gov Identifier: NCT02454543 .

93
 HORRAD: Effect on survival of ADT alone vs ADT combined with concurrent
RT to the prostate in primary bone-metastatic prostate cancer patients

• KM estimates of overall survival (intention to treat).

ADT, androgen deprivation therapy; KM, Kaplan–Meier; RT radiotherapy.

Boevé LMS, et al. Eur Urol. 2019;75:410-8 .

OS benefits similar in similar patient subgroups in both

the HORRAD and STAMPEDE trials
OS
Trial and HR
subgroup (95% CI)
HORRAD
< 5 metastases 0.68 (0.42–1.10)
≥ 5 metastases 1.06 (0.80–1.39)
All 0.90 (0.70–1.14)

STAMPEDE
Low burden 0.68 (0.52–0.90)
High burden 1.07 (0.90–1.28)
All 0.92 (0.80–1.06)

0.50 0.75 1.00 1.33 2.00

Favour ADT + RT Favours ADT only

Benefit was observed in patients with low-volume disease, so ADT alone is no longer adequate
Limitation: Systemic Tx mainly ADT only, effect of local Tx with modern Tx unclear
.
Parker C, et al. Lancet. 2018;392:2353-66
Boevé LMS, et al. Eur Urol. 2019;75:410-8

Guidelines, first line treatment of mHSPC,

local therapy

94
 Bone health, mHSPC
The routine use of biphosphonates or denosumab to prevent skeletal complications in patients
undergoing ADT is not recommended unless there is a documented risk for fracture or
castration-resistant PCa with skeletal metastasis.

Preventive therapy with biphosphonates or denosumab using specific doses (which differ from
those used in the CRPC stage) should be considered in patients who have an initial T-score of
less than -2.5 on dual-energy X-ray absorptiometry (DEXA), which is the definition of
osteoporosis.

Summary , treatment landscape mHSPC

metastatic, hormon-sensitive metastatic CRPC metastatic,CRPC

ADT

bisphosphonates or Denosumab

Docetaxel

Abirateron

Enzalutamid

Apalutamid

Conclusion, mHSPC
• ADT with GnRH analogues/antagonists standard, Testosteron level
should be <50 ng/dl (castration level)
• Early Abi, Apa, Enza, Doce valid options for mHSPC (individual
decisison)
• Radiation of the prostate beneficial im men with low volume
diseae, effect of surgery on survival not yet proven
• Metastasis directed therapy experimental
• Bone helath agents (bisphoshonates / Denosumab) for men with
risc of osteoporotoc fractures

95
 120 PSA
110
100
90
80
70
60
50
40
12 ng/ml
30
20 6 ng/ml
10 5 ng/ml
0
May Jun Jul Oct Jan Apr Jul Oct Jan Jan Feb

Castration-Resistant PCa: Definition

Castrate serum testosterone < 50 ng/dL or 1.7 nmol/L plus either:

a. Biochemical progression: Three consecutive rises in PSA at least one week apart resulting
in two 50% increases over the nadir, and a PSA > 2 ng/mL

or

a. Radiological progression: The appearance of new lesions: either two or more new bone
lesions on bone scan or a soft tissue lesion using RECIST (Response Evaluation Criteria in
Solid Tumours) [1188]. Symptomatic progression alone must be questioned and subject to
further investigation. It is not sufficient to diagnose CRPC.

Mechansim of AR-resistance: Mechansim of AR-resistance II:

Ligand dependent Ligand – independant

1.Endogene Androgen- and DHT-Synthesis 1.Modification of AR through

despite castration Phosphorylisation or „Cross-talk“ with other
pathways

2. Mutation of Androgenreceptors (AR)

increases affinity, activation by non- 2.Imbalance btw. Co-Activators and Co-
steroidal Ligands Repressors increases AR-Activity.

3. Increase of AR-Density through 3.Bypass-pathways independent of AR-Activity

amplification increases AR sensitivity by up-regulation of antioptotoc molecules
(i.g.. Bcl-2)

96
 Homon refractory
Castration resistant

Evolution of mCRPC drug development

2004 2010 2011/2013 2013. 2013

Drug: Docetaxel Cabacitaxel Abiraterone Enzalutamide Radium 223

Trial: TAX 3271 TROPIC3. COU-3015 AFFIRM7 ALSYMPCA9
SWOG-99162 PROSELICA4. COU-3026 PREVAIL8

1Tannock et al. NEJM 2004;351:1502-12, 2Petrylak et al. NEJM 2004;351:1513-20

5 De Bono et al, New Engl J Med 2011, 6Ryan et al, Lancet Oncol 2015;
7Scher H et al, N Engl J Med 2012; 367, 8Beer et al. N Engl J Med 2014;371
9Parker et al. NEJM 2013;369:213-23

Evolution of mCRPC drug development

2021 2022 (?)

Oplaparib Lu177-PSMA-Ligand therapy

PROFOUND1 VISION2
TheraP3

1de Bono J, et al. N EnglJ Med. 2020;382(22):2091–2102

2Sartor O et al, N Engl J Med 2021; 385:1091-1103

97
Treatment landscape, metastatic prostate cancer

metastatic, hormon-sensitive metastatic CRPC metastatic,CRPC

ADT

Zoledronsäure oder Denosumab

Lu177-PSMA
Docetaxel

Abirateron Radium-223

Enzalutamid Olaparip/HRR+

Apalutamid
Cabacitaxel

Precision medicine?
EAU guideline recommendation
for germline testing

98
PROfound: Olaparib in mCRPC post NHA +/- Docetaxel

de Bono J, et al. N EnglJ Med. 2020;382(22):2091–2102

PROfound results

de Bono J, et al. N EnglJ Med. 2020;382(22):2091–2102

99
Theragnostics: First published case report of Lu177-PSMA-617 treatment

PSA 38 PSA 4.6

2 Cycles,
Lu177-PSMA-617
7.4 GBq

PSMA-Lutetium

Kratochwil C et al. Eur J Nucl Med Mol Imaging . 2015 May;42(6).

Open-label study of protocol-permitted standard of care ± 177Lu-PSMA-617 in adults with PSMA-positive mCRPC

Sartor O et al, N Engl J Med 2021; 385:1091-1103

Primary endpoints: 177Lu-PSMA-617 prolonged OS<br />

Sartor O et al, N Engl J Med 2021; 385:1091-1103

100
 How about sequencing?

mHSPC L1mCRPC ? L2mCRPC ? L3mCRPC ?

Most common sequence, start with NHA for mHSPC

mHSPC L1 mCRPC L2 mCRPC L3 mCRPC L4 mCRPC

Cabacitaxel

Olaparip* DOC TheraP

Apalutamid/Abirater
one/Enzalutamide PSMA.Lutetium

other NHA

Cabacitaxel
Radum223l

DOC

PSMA.Lutetium

* only BRCA ½ mutated

Less common sequence, start with Doce for mHSPC

mHSPC L1 mCRPC L2 mCRPC L3 mCRPC L4 mCRPC

Cabacitaxel PSMA.Lutetium

Abiraterone/
Enzautamide
Olaparip* Cabacitaxel Radum223
Docetaxel

Cabacitaxel
PSMA.Lutetium

Cabacitaxel Abiraterone/ PSMA.Lutetiuml

Enzautamide

* only BRCA ½ mutated Olaparip* Radum223l

101
How about bone supportive drugs in mCRPC?

SRE= Skeletal related Events (SRE)

Spinal Cord
Pathologic Fracture Radiation Surgery
Compression

Acute Complications Therapeutic Intervention

22% 7% 29% 3%

Bone tissue
RANK-Ligand
RANK

Growth factor, cytokine

Ca2+

activated osteoclast

Osteoblasten

Nach Boyle, et al. Nature 2003;423:337–42;

Roodman. N Engl J Med 2004;350:165564;
Roodman. Leukemia 2009;23:43541.

102
 RANK Ligand
RANK
RANK Ligand inhibitor

Denosumab

X RANK
Ligand XX
Growth factors
Cytokines
Ca2+

➨
Osteoclasts

Osteoblasts

Zoledronic acid.
N Engl J Med 2004; 350:1655.

Zoledronic Acid and Denosumab to prevent SRE in mCRPC

Median time to first SRE (months)

Median time to first SRE (months)

20.7
16.0
17.0
HR 0.82
10.7 (95% CI: 0.71- 0.95)
P = 0.0002 (Non-inferiority)
P = 0.008 (Superiority)

Placebo Zoledronic acid Zoledronic acid Denosumab

Saad, et al. J Natl Cancer Inst 2004;96:879-82;

Fizazi, et al. J Clin Oncol 2010;28 (suppl 18) LBA4507.

Side effects, Zoledronic acid vs. Denosumab (120 mg)

Zoledronic acid Denosumab
Subject incidence, n (%)
(n = 945) (n = 943)
Infectious AEs 375 (39.7) 402 (42.6)
Infectious serious AEs 108 (11.4) 130 (13.8)
Acute phase reactions (first 3 days) 168 (17.8) 79 (8.4)
Renal AEs* 153 (16.2) 139 (14.7)

Cumulative rate of osteonecrosis of the jaw (ONJ) † 12 (1.3) 22 (2.3)

Hypocalcaemia 55 (5.8) 121 (12.8)
New primary malignancy 10 (1.1) 18 (1.9)
*Includes renal failure, increased blood creatinine, acute renal failure, renal impairment, increased blood urea, chronic renal failure, oliguria,
hypercreatininaemia, anuria, azotaemia, decreased creatinine renal clearance, decreased urine output, abnormal blood creatinine, proteinuria,
decreased glomerular filtration rate, and nephritis. †P = 0.09

103
 Do not use bone protective agents in
hormone sensitive, bone metastatic PCa!!

Who to treat? (Fit for treatment?)

Geriatric assessment using the G8 score

104
 Rules for mCRPC sequencing

• Expose to as many drug as possible („window of opportunity“)

• Change „mode of action“ (Abi/Enza or Enaz/Abi both bad performance)

• Consider availability, patient preference an comorbidity („fit for treatment!?)

• Consider metastatic side (visceral, bone, LN), pain, ECOG

Multidisciplinary Team
Neuro-surgeon

Surgeon

Cardiologist

Geriatric

Radiologist

Urologist

Radio-Oncology Med. Oncologist

Pathology
Nuclear Medicine

105
Diagnosis and Medical Treatment
of male voiding LUTS
Sascha Ahyai, Professor&Chairman of Urology,
Medical University of Graz (MUG)

What is the percentage of men above

65 years with LUTS?

“The younger elder“

• 15%
• 30%
• 50%
• 70%

C Werbefoto Boehringer Ingelheim 2

Age-specific prevalence of LUTS/ BPH

around 20% men with LUTS will finally undergo prostate surgery (Wheelahan, 2000)

106
 Terminology
• LUTS (Lower Urinary Tract Symptoms)
• BPE (Benign Prostatic Enlargement)
• BPH (Benign Prostatic Hyperplasia)
• BPO (Benign Prostatic Obstruction)
• BOO (Bladder Outlet Obstruction)

The patient has LUTS suggestive of BPO caused by BPE with

underlying BPH

The prostate
BPH

• Glands (30%)

• Stroma (70%)
=> Smooth muscle

https://www.auanet.org/education/auauniversity/education-products-and-resources/pathology-for-urologists/prostate/non-neoplastic-
lesions/benign-prostatic-hyperplasia

Pathophysiology
• Stromal und epithelial cellnumber 
• Glandular cells  Secretion capacity 
• Smooth muscle cells 
• Androgen dependent

• Prostate size ≠ BPO

107
 Benign Prostatic Obstruction

c prostata-balance.net

• Dynamical component • Mechanical component

Goals of LUTS Assessment

• Identify cause of LUTS

• Is treatment neccessary?
• Risk for progression?
• What kind of treatment?

Basic Clinical Evaluation – EAU

• History
• Assessment of Symptoms / Bother –
Scores
• Frequency Volume Charts/Bladder
diaries
Recommended • Digital Rectal Examination
Tests • Urinalysis
• Blood Tests
• Creatinine/eGFR
• PSA
• Flow rate and Post Void Residual Urine
Gravas et al., EAU Guidelines 2017

108
History

Storage Voiding Post micturition

symptoms symptoms symptoms
• Altered bladder • Hesitancy • Feeling of
sensation • Intermittency incomplete
• Increased daytime • Slow stream bladder emptying
frequency • Splitting/spraying • Post micturition
• Nocturia • Straining dribble
• Urgency • Terminal dribble
• Urinary
incontinence

Symptom Scores

Voiding syptoms:
• Incomplete emptying
• Intermittency
• Weak stream
• Straining

Storage syptoms:
• Frequency
• Urgency
• Nocturia

Symptom Scores
IPSS: 7 symptom questions and 1 QoL question

IPSS 0: a symptomatic
IPSS 1-7: mildly symptomatic
IPSS 8-19: moderately symptomatic
IPSS 20-35: severly symptomatic

Limitation:no association of bother with individual symptom, no

assessment of incontinence and post micturition symptoms

109
 Physical examination + DRE
• DRE underestimates prostate volume
compared to TRUS
• DRE is sufficient to discriminate between
prostate volume > or < 50 mL

Urinalysis

Blood tests
• PSA >1.5 ng/mL excellent predictor of prostate
volume >30 mL
• Baseline PSA predicts future prostate growth

Uroflowmetry and Post-void residual urine

SPEC PPV SENS
Qmax 10 ml/sec 70% 70% 47%
Qmax 15 ml/sec 38% 67% 82%

• Qmax is limited in detecting BOO

• High baseline PVR is predictive for future

symptom progression

110
Frequency volume charts / bladder diaries
• Voiding Frequency/ Volumes
• Fluid intake
• Use of pads
• Activities
• 3 (– 7) days (sampling errors compliance)
Yap et al, review BJUI 2007
Bright et al Neurourol Urodyn 2012

Specialised Evaluation ?
Pressure Flow Studies (PFS) (>80 and <50 ys.; Qmax <
10 mL/s, BOO is likely and PFS is not necessarily needed)
Endoscopy (middle lobe, gross hematuria, U-stricture, bladder
cancer)
Upper Urinary Tract US Scan (PVR, hematuria, Optional Tests
stones?)
Transrectal Ultrasound (TRUS) (before medical/
surgical therapy)
Detrusor Wall Thickness (DWT)(>2 mm&250ml)
Intraprostatic protrusion(>10mm)

• Intravenous Uro-graphy (IVU), CT or

MRscan
Not recommended
• Retrograde Urethrogram

EAU Guideline 2023

3

Gravas et al., EAU Guidelines 2021

Malde et al., Eur Urol. 2017

111
 What is BPH progression?

• Deterioration of symptoms and HRQoL

• Decreased Qmax
• Increased prostate size

• Unfavourable outcomes
- AUR
- Prostate surgery

BPH Progression – Risk of Acute Urinary Retention –

Community Study

Age
AUA
Symptoms 70-79 yrs
Qmax Mod-Severe 8 times
<12 mls/sec 4 times
BPE
4 times
>30 mls
3 times
Jacobsen SJ, et al. Natural history of prostatism: risk factors for acute urinary retention.
J Urol. 1997;158:481.

112
BPH Progression – PSA Predicts Future Prostatic Growth
PLESS – Proscar Long-Term Efficacy and Safety Study (Roehrborn CG et al J Urol 2000)

3.3
Annual Growth Rate in

2.5
2.1
2
0.7
1.5
mls

1
0.5

0
≤ 1.3 >1.4 to 3.2 ≥3.3
Baseline PSA
PSA is a Strong Predictor of Prostate Growth in Placebo Treated Patients

Risk of BPH Progression in Patients

Receiving Placebo vs MT (Doxazosin/ Finasterid/ combination therapy)

MTOPS – Medical Therapy of Prostatic symptoms

PSA ≥1.6 (ng/mL)

Probability of BPH Progression (%)

TPV ≥ 31 (mL)
Probability of BPH Progression (%)

25 25

20 20 (p<0.0009)
(p<0.0001)
15 15 PSA ≤1.6 (ng/mL)
TPV ≤ 31 (mL)
10 10

5 5

0 0
0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0 4.5 5.0 5.5 0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0 4.5 5.0 5.5
Time in study (yrs) Time in study (yrs)

QMAX <10.6 (mL/sec) PVR ≥39 (mL)

Probability of BPH Progression (%)
Probability of BPH Progression (%)

25 25

20 7 (p=0.011) 20 (p<0.0008)
6
15 15
PVR ≤39 (mL)
5
4 QMAX >10.6 (mL/sec)
10 3
10
2
5 5
1
0
0 0
0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0 4.5 5.0 5.5 0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0 4.5 5.0 5.5
Time in study (yrs) Time in study (yrs)

Crawford D E et al. J Urol 2006;175:1422

Management Options – Behavioural Treatment

Watchful waiting – Behavioural Treatment

Men with mild-to-moderate uncomplicated LUTS who are not too troubled by their symptoms are suitable for WW

• Mild (to moderate) LUTS

• After first line assessment

• Explain the condition

• Reassure your patient “it is not cancer”
• Offer periodic monitoring

Flanigan et al. J Urol 1998, 160(1);12-6

Wasson et al. NEJM 1995, 332(2);75-9
Netto et al. Urology 1999, 53(2);314-6

113
 Management Options – Behavioural Treatment

• Lifestyle advice

• Reduction in Fluid intake (not below 1500mls in a day)

• Avoidance/ Moderation of Caffeine and alcohol intake
• Urethral Milking to avoid post micturition dribbling
• Distraction techniques – breathing exercises, mental tricks
• Bladder re-training (to around 400 mls)
• Treatment of constipation

Phytotherapy – Plant Extracts

Drugs – Cucurbita pepo, Hypoxis rooperi, Pygeum
africanum, Secale cereale, serenoa repens and urtica
dioica
> 20 RCTs mentioned in the guidelines

Different concentrations and combinations of active

ingredients in different brands

Guidelines committee focus on Hexane extracted Serenoa

repens (HESR)

Take home Phytotherapy

• No general recommendation

• Option for patients with mild to moderate LUTS

who dislike conventional medical therapy

• No impact on BOO or prostate volumen

114
 Management Options – Stratified Medicine

Spectrum of complaints

Risk of progression

Presence of complications

Side effects (+costs) of

treatment

Most frequent strata

surgery
WaWa

antimuscarinics
+/- α-blocker
Male LUTS α-blocker

desmopressine 5 ARI +/- α-

blocker
PDE 5
inhibitor

John, 55 year-old business man

• LUTS since 6 months: Urgency, Frequency, Nocturia
2x, limited weakness of flow
• Severely bothered by these symptoms
• Sexually active

• IPSS 17
• Qmax 15 mL/sec, PVR 10 mL
• Urinalysis: negative
• PSA 1.15 ng/mL
• TRUS volume: 25 mL

115
John, 55 year-old business man
• LUTS since 6 months: Urgency, Frequency, Nocturia
2x, limited weakness of flow
• Severely bothered by these symptoms
• Sexually active

• IPSS 17
• Qmax 15 mL/sec, PVR 10 mL
• Urinalysis: negative
• PSA 1.15 ng/mL
• TRUS volume: 25 mL

Which treatment?
1. Watchful waiting + behavioural treatment
2. Alpha-blocker
3. 5-alpha reductase inhibitor
4. PDE-5 inhibitor
5. Antimuscarinic drug
6. Desmopressin

α Blockers
α1-blockers have little effect on urodynamically determined bladder outlet resistance (Kortmann, B.B., et al. Urology. 2003).
Treatment-associated improvement of LUTS correlates poorly with obstruction (Barendrecht, M.M., Neurourol Urodyn, 2008).

Lepor H.Rev Urol 2011;13(1):20-33

116
 Alpha 1 Adrenoreceptors – Fast Facts

✔ Improve symptoms/flow Alpha 1-blockers can reduce both storage and voiding LUTS.

Onset of symptom relief within 1–2 weeks

✔ may improve resolution of AUR

Prevent symptomatic progression

✔ in the short term α1-blocker treatment appears to be maintained over
at least four years.

✔ Low rate and severity of side effects

✔ Well studied (LoE 1a, GR A)

✗ Reduce prostate volume

✗ Reduce longer-term risk of AUR and surgery

Madersbacher et al. Eur Urol 2004;46:547–54

Alpha Blockers - Efficacy

Alfuzosin Doxazosin GITS
Terazosin TAM 0.4 Placebo
Doxazosin TAM 0.8
50%
% improvement in total symptom score

40%

30%

20%

10%

0% 2 3 5a 4 5b 6 7 8a 8b 11 12 13 14 16 17a 17b 18 19 21 22 23a 24a 23b 24b 25 26 27a 28a 27b 28b

ALF IR ALF SR ALF XL TER DOX S DOX GITS TAM 0.4 TAM 0.8

Djavan B et al. Urol 2004;64:1081

• 16 placebo controlled trials

• All a1-blockers superior to

placebo

• Symptom score improved by 30

to 45% (5 to 8 points in the
IPSS)

• Qmax improved by 15 to 30%

• No significant differences
between a1-blockers

Gravas et al., EAU Guidelines 2017

117
 Alpha Blockers – Tolerability and Safety

• Driven by distribution into LUT tissue, subtype selectivity and

pharmacokinetic
• Most frequent: asthenia, dizziness, (orthostatic) hypotension
• Vasodilatation effect low in Alfuzosin & Tamsulosin (not significant to
placebo)
• Silodosin: frequency of hypotension comparable to placebo
• Retrograde ejaculation: tamsulosin 8.5x and silodosin 32.5x
more frequent than placebo
• IFIS (intraoperative floppy iris syndrome) rare, but 40x more
frequent with tamsulosin

Practical Considerations:
Take home Phytotherapy
• A1-blockers often considered 1-st line drug - • Option for patients with mild to moderate LUTS
rapid onset, good efficacy, low rate and severity • No reduction of risk of progression
of AE´s
• No relevant impact on BOO or prostate volumen
• Ophthalmologist should be informed before
cataract surgery!

Jeff, 65 year-old retired postman

• Progressively increasing LUTS since 2 years: some
Frequency, Nocturia 2x (since 5 years), weakness of
flow++
• Moderately bothered by these symptoms
• Not sexually active

• IPSS 8
• Qmax 8 ml/sec, PVR 100 ml
• Urinalysis: negative
• PSA 2.5 ng/mL
• TRUS volume: 45 ml

118
Which treatment?
1. Watchful waiting + behavioural treatment
2. Alpha-blocker
3. 5-alpha reductase inhibitor
4. PDE-5 inhibitor
5. Antimuscarinic drug
6. Desmopressin

Conversion of testosterone to DHT

requires the enzyme 5α-reductase
• 5α-reductase exists as two isoenzymes
• Type 1 (skin & liver +++, prostate +)
• Type 2 (prostate +++)

5AR type 1
Testosterone DHT
OH OH

5AR type 2
O O
H

Andriole G et al. J Urol 2004;172:1399–1403

5 Alpha Reductase Inhibitors (5ARI)

Competitive Inhibition of 5 Alpha Reductase

• Finasteride – Type 2 (Mainly prostate)
• Dutasteride – Type 1* & 2

Slow Onset of Action (6 – 12 months)

Prostate Volume Reduction by 15 – 28%

PSA decreased by 50% after 6 months

*5 Alpha reductase Type 1 – minor expression in prostate but

predominantly in skin and liver

119
 5 Alpha Reductase Inhibitors (5ARI)

✔ Improve symptoms/flow
Prevent symptomatic progression
✔ in the short term

✔ Sustained symptomatic benefit

✔ Reduce prostate volume

✔ Maintain reductions in PV

✔ Reduce longer-term risk of AUR and surgery

✗ Onset of symptom relief within 1–2 weeks

Madersbacher et al. Eur Urol 2007;51:1522–33

RCT´s with 5ARI´s in men with LUTS & BPE

44
2014

Finasteride – PLESS Findings

Probability of Surgery (%)

15

10 Placebo 4 yr Study of
5
P<0.001 Finasteride VS
Finasteride Placebo
0
0 1 2 3 4

15

• Mean Prostate Volume 55mL

Urinary Retention (%)
Probability of Acute

10
• Over 50% rel. Risk Reduction
Placebo in surgery for BPH (55%) and
5
P<0.001 AUR (57%) (10% vs. 5%/ 7% vs. 3% absolute RR)
Finasteride • Risk Reduction higher in pts
0
0 1 2 3 4 with PSA >1.4ng/ml
Year

McConnell JD et al. NEJM 1998;338:557

120
Practical Considerations:

• ARI candidates: enlarged prostate (>40 ml), moderate to

severe LUTS and/or PSA (>1.4-1.6 ng/ml)
• Slow onset: suitable only for long-term treatment
• Consider effect on PSA!

Take home ARI

• Option for patients with mild to moderate LUTS
• Long term therapy (>6 m.)
• Needs a prostate vol. > 40 ml
• Low impact on BOO

46

Combination Treatment - MTOPS

Doxazosin + Finasteride
*Mean Reduction in Symptom Score was 7 points

> 4 points in AUA

Retention of Urine
Score*
25
Cumulative Incidence of

Placebo
20
Progression (%)

Finasteride Long-Term Combination

15 (P=0.002) Therapy – Doxazosin +
10
Doxazosin
(P<0.001)
Finasteride Significantly
More Effective Than Either
5 Combination Therapy Drug Alone in Reducing Risk
(P<0.001)
0
of Overall Clinical
0 0.5 1.0 1.5 2.0 2.5 2.5 3.5 4.0 5.0 5.5 Progression of BPH
Years
No at Risk
Renal
Recurrent UTI’s
Placebo 737 712 670 631 612 588 575 555 492 337 218 84
Doxazosin 756 735 715 698 675 660 641 627 565 387 259 93
Finasteride
Combination Therapy
768
786
737
762
699
747
675
733
659
726
634
715
617
697
599
683
530
599
379
426
257
280
105
112 Insufficiency

McConnell JD et al.NEJM 2003;349:2387

Combination Treatment - CombAT

Tamsulosin + Dutasteride
• Dutasteride + Tamsulosin
Adjusted mean change from baseline
In IPSS ±standard error
– Significant Improvements in IPSS
0
• From Month 3 (vs Dutasteride)
-1 • From Month 9 (vs Tamsulosin)
Combination (n=1575)
-2
-2.8
Dutasteride (n=1592) • Increase in Adverse events
-3 -3.4 Tamsulosin (n=1592)
-4.0 -4.2
-4 -4.5 -4.4 -4.5 -4.4 -4.3
-4.7 -4.8
-5 -4.5 -4.8
-4.8 -4.8 -4.9 -5.0 -4.9
-6 -5.4
-5.6
-6.0 -6.0 -6.2
-6.2
-7
Baseline 3 6 9 12 15 18 21 24

Study month

Roehrborn et al. J Urol 2008; 179: 616–21

121
 Limitation of med. Therapy

Long term Discontinuation of medical therapy (up to >30%)

5 Alpha Reductase Inhibitors (5ARI) –

Sexual Side Effects
Patients with adverse events (%)
5ARI Alpha-blocker Combination
CombAT (dutasteride + -tamsulosin)
Decreased libido 3 2 4
ED 7 5 9
Semen volume <1 <1 2
decrease
Retrograde <1 1 4
ejaculation
MTOPS (finasteride +- doxacosin)
Decreased libido 2.4 1.6 2.5
ED 4.5 3.6 5.1
Abnormal 1.8 1.1 3.1
ejaculation

Practical Considerations – 5ARI and a1-blocker:

• Effective in prostate volumes >30-40 ml and treatment
duration >1 year
• <1year = monotherapy a1-blocker as effective
• Combination = slightly increased AE´s
• Unclear if effect is sustained after >6 years

122
 John, 62 year-old business man
• On alpha-blocker since 7 years
• Increased Urgency & Frequency, Nocturia 2x, progressively increased
weakness of flow
• Quite bothered by these symptoms
• Sexual activity: less important

• IPSS 15
• Qmax 12 mL/sec, PVR 90 mL
• Urinalysis: negative
• PSA 1.9 ng/mL
• TRUS volume: 35 mL

Which treatment?
1. Add antimuscarinic
2. Switch to 5-alpha reductase inhibitor
3. Add PDE-5 inhibitor
4. Add 5-alpha reductase inhibitor
5. Add desmopressin

Muscarinic Receptor Antagonists - Facts

• Main neurotransmitter in the bladder (acetylcholine)

stimulates muscarinic receptors of detrusor smooth
muscle cells

• 5 muscarinic receptor subtypes (M1-M5) described,

M2 (80%) & M3 (20%) predominantly in the detrusor

• M3 receptors involved in bladder contraction in

healthy humans

54

123
Antimuscarinic drugs licensed in Europe for
OAB/ storage symptoms

Trials with antimuscarinic drugs in elderly

men with LUTS

Reduction in

• Voiding frequency
• Nocturia
• Urge incontinence
• IPSS

• More effective in
small prostates

Muscarinic Receptor Antagonists –

side effects

• Generally well tolerated (3-10% withdrawals)

• Dry mouth (<16%), Constipation (< 4%), Dizziness (< 5%)

• Careful in BOO (PVR can increase, no increased rate of

AUR) (Yokoyama et al 2009)

• No comparative data between drugs, no long-term data

• Regular monitoring of IPSS & PVR

57

124
 Combination a1-blocker & anti-muscarinic drug

• Mainly assessed as „Add-on“ to a1-blocker

• Inconsistent data/ heterogeneous study
populations & designs
• „add-on“ in insufficient monotherapy
• Safe in PVR < 150ml
• No data on safety & efficacy > 4months

Practical considerations:

• Not all antimuscarinics have been tested in elderly men

• Long-term studies in men with LUTS not available
• Only men with low baseline PVR included
• Check PVR and IPSS regular

Take home antimuscarinics

• In patients with predominantly storrage symptoms

Lately approved for OAB

Beta-3 adrenoceptors are the predominant beta receptors expressed in the smooth muscle cells of the detrusor and their stimulation is thought to induce
detrusor relaxation. The mode of action of beta-3 agonists is not fully elucidated

• Mirabegron, selective ß3 receptor agonist

• Mirabegron mediates relaxation of the detrusor muscle

during the storage phase of the micturition cycle, thus
increasing bladder storage capacity

125
 • Favourable vs Placebo
• Equivalent to Antimuscarinics

Mirabegron combination therapy

• Mirabegron 25/50 mg and Solifenacin 5/10mg was associated
with sig. better Outcome & QoL than Solifenacin and placebo
Abrams, P., et al., World J Urol, 2017

• combination therapy was associated with greater improvements

in OAB symptom score, storage subscore of the IPSS, and in the
QoL index compared to monotherapy with tamsulosin
Matsuo, T., et al., BMC Urol, 2016
• fesoterodine add-on therapy to sildosin showed a significantly
greater improvement then mirabegron add-on therapy to
silodosin in OAB and alleviating DO (53% vs. 29%)
Matsukawa, Y., et al., Neurourol Urodyn, 2019.

Mirabegron: tolerability & safety

• Contraindicated in not well

controlled hypertension (≥ 180
mmHg or diastolic blood
pressure ≥ 110 mmHg)
hypertension,
• Higher incidence of CV events!
UTI, headache nasopharyngitis

126
Alex, 50 year-old colleague
• LUTS since 4 months: Limited Urgency & Frequency,
Nocturia 1x, limited weakness of flow
• Severely bothered by these symptoms
• Sexually active, and is concerned about progressively
increasing ED

• IPSS 9
• Qmax 15 mL/sec, PVR 0 mL
• Urinalysis: negative
• PSA 0.8 ng/mL
• TRUS volume: 20 mL

Which treatment?
1. Watchful waiting + behavioural treatment
2. Alpha-blocker
3. 5-alpha reductase inhibitor
4. PDE-5 inhibitor
5. Antimuscarinic drug
6. Desmopressin

The role of PDE-5 inhibitors in LUTS

Phosphodiesterase 5 inhibitors (PDE5Is) increase intracellular cyclic guanosine monophosphate, thus reducing smooth
muscle tone of the detrusor, prostate and urethra.

• PDE -5 inhibitors – Sildenafil, Tadalafil, Avanafil and

Vardenafil

• NO stimulates synthesis of cyclic GMP which reduces

smooth muscle tone of detrusor, prostate and urethra.

• PDE-5 inhibitors prevent hydrolysis of

cyclic GMP

66

127
 The role of PDE-5 inhibitors in LUTS
• Proposed working mechanisms
• Smooth muscle relaxation in LUT (detrusor, prostate, urethra)
• Smooth muscle relaxation in vasculature  better perfusion and oxygenation of bladder and
prostate
• Direct influence on afferent sensory output of bladder

PDE-5 inhibitors in LUTS

• 16 RCT available
• Consistent, significant IPSS reduction (17-
37%)
• Storage & Voiding symptoms
• Significant QoL improvement vs. placebo
• Qmax not significant to placebo

68

Practical Considerations:
• Qmax improvement only for tadalafil in 1 study

• Longterm data are missing

• Safety and Tolerability
 flushing, gastroesophageal reflux,headache,dyspepsia,back pain,nasal congestion

• Cave: contraindications of PDE5 inhibitors

 in patients using nitrates, the potassium channel opener nicorandil,
 or the α1-blockers doxazosin and terazosin.
 unstable angina pectoris, recent myocardial infarction (<3ms) or stroke (<6ms),
 myocardial insufficiency (NYHA stage > 2), hypotension, poorly controlled bl. Press.
 significant hepatic or renal insufficiency, or if anterior ischaemic optic neuropathy

Take home PD5-Inhibitors

• Option for patients with mild to moderate LUTS
• improves erectile function
• no rel. Impact on BOO

69

128
 Combination a1-blocker & PDE5 inhibitors

Gacci M, et al. Eur Urol 2012; 61:994-1003

Combination 5-ARI & PDE5 inhibitors

Casabé, et al. J Urol 2014

Joseph, 75 year-old retired bank director

• LUTS since long time: Some Urgency & Frequency, limited
weakness of flow
• Severely bothered by the nocturia, which increased to 3
times/night over the last 6 months. Sleep deficit.
• Not sexually active

• IPSS 16
• Qmax 15 mL/sec, PVR 50 mL
• Urinalysis: negative
• PSA 3.5 ng/mL
• TRUS volume: 45 mL

129
Which treatment?
1. Watchful waiting + behavioural treatment
2. Alpha-blocker
3. 5-alpha reductase inhibitor
4. PDE-5 inhibitor
5. Antimuscarinic drug
6. Desmopressin

Vasopressin analogue - desmopressin

• AVP (antidiuretic hormone arginine vasopressin) binds to V2
receptor in renal collecting duct
• Desmopressin = synthetic analogue
• Water re-absorption , water excretion , urine volume

74

Clinical trials with desmopressin in adult men

with nocturnal polyuria

• Nocturnal diuresis (0.6-0.8 ml/sec = -40%)

• Nocturnal voids (0.8-1.3 x / = -40%)
• Extent of time to 1st void 1.6-2.1 hrs.
• Night time urine volume

• Stable over 10-12 months

75

130
Practical Considerations:

• Once daily before sleep / not associated with fluid intake

• Dose titration (0.1 mg/day up to 0.4 mg/day)
• Regular check of sodium concentration

76

Gravas et al., Eur Urol

Focus. 2022

131
Diagnosis and Medical Treatment
of male voiding LUTS
Sascha Ahyai, Professor&Chairman of Urology,
Medical University of Graz (MUG)

What is the percentage of men above

65 years with LUTS?

“The younger elder“

• 15%
• 30%
• 50%
• 70%

C Werbefoto Boehringer Ingelheim 2

Age-specific prevalence of LUTS/ BPH

around 20% men with LUTS will finally undergo prostate surgery (Wheelahan, 2000)

132
 Terminology
• LUTS (Lower Urinary Tract Symptoms)
• BPE (Benign Prostatic Enlargement)
• BPH (Benign Prostatic Hyperplasia)
• BPO (Benign Prostatic Obstruction)
• BOO (Bladder Outlet Obstruction)

The patient has LUTS suggestive of BPO caused by BPE with

underlying BPH

The prostate
BPH

• Glands (30%)

• Stroma (70%)
=> Smooth muscle

https://www.auanet.org/education/auauniversity/education-products-and-resources/pathology-for-urologists/prostate/non-neoplastic-
lesions/benign-prostatic-hyperplasia

Pathophysiology
• Stromal und epithelial cellnumber 
• Glandular cells  Secretion capacity 
• Smooth muscle cells 
• Androgen dependent

• Prostate size ≠ BPO

133
 Benign Prostatic Obstruction

c prostata-balance.net

• Dynamical component • Mechanical component

Goals of LUTS Assessment

• Identify cause of LUTS

• Is treatment neccessary?
• Risk for progression?
• What kind of treatment?

Basic Clinical Evaluation – EAU

• History
• Assessment of Symptoms / Bother –
Scores
• Frequency Volume Charts/Bladder
diaries
Recommended • Digital Rectal Examination
Tests • Urinalysis
• Blood Tests
• Creatinine/eGFR
• PSA
• Flow rate and Post Void Residual Urine
Gravas et al., EAU Guidelines 2017

134
History

Storage Voiding Post micturition

symptoms symptoms symptoms
• Altered bladder • Hesitancy • Feeling of
sensation • Intermittency incomplete
• Increased daytime • Slow stream bladder emptying
frequency • Splitting/spraying • Post micturition
• Nocturia • Straining dribble
• Urgency • Terminal dribble
• Urinary
incontinence

Symptom Scores

Voiding syptoms:
• Incomplete emptying
• Intermittency
• Weak stream
• Straining

Storage syptoms:
• Frequency
• Urgency
• Nocturia

Symptom Scores
IPSS: 7 symptom questions and 1 QoL question

IPSS 0: a symptomatic
IPSS 1-7: mildly symptomatic
IPSS 8-19: moderately symptomatic
IPSS 20-35: severly symptomatic

Limitation:no association of bother with individual symptom, no

assessment of incontinence and post micturition symptoms

135
 Physical examination + DRE
• DRE underestimates prostate volume
compared to TRUS
• DRE is sufficient to discriminate between
prostate volume > or < 50 mL

Urinalysis

Blood tests
• PSA >1.5 ng/mL excellent predictor of prostate
volume >30 mL
• Baseline PSA predicts future prostate growth

Uroflowmetry and Post-void residual urine

SPEC PPV SENS
Qmax 10 ml/sec 70% 70% 47%
Qmax 15 ml/sec 38% 67% 82%

• Qmax is limited in detecting BOO

• High baseline PVR is predictive for future

symptom progression

136
Frequency volume charts / bladder diaries
• Voiding Frequency/ Volumes
• Fluid intake
• Use of pads
• Activities
• 3 (– 7) days (sampling errors compliance)
Yap et al, review BJUI 2007
Bright et al Neurourol Urodyn 2012

Specialised Evaluation ?
Pressure Flow Studies (PFS) (>80 and <50 ys.; Qmax <
10 mL/s, BOO is likely and PFS is not necessarily needed)
Endoscopy (middle lobe, gross hematuria, U-stricture, bladder
cancer)
Upper Urinary Tract US Scan (PVR, hematuria, Optional Tests
stones?)
Transrectal Ultrasound (TRUS) (before medical/
surgical therapy)
Detrusor Wall Thickness (DWT)(>2 mm&250ml)
Intraprostatic protrusion(>10mm)

• Intravenous Uro-graphy (IVU), CT or

MRscan
Not recommended
• Retrograde Urethrogram

EAU Guideline 2023

3

Gravas et al., EAU Guidelines 2021

Malde et al., Eur Urol. 2017

137
 What is BPH progression?

• Deterioration of symptoms and HRQoL

• Decreased Qmax
• Increased prostate size

• Unfavourable outcomes
- AUR
- Prostate surgery

BPH Progression – Risk of Acute Urinary Retention –

Community Study

Age
AUA
Symptoms 70-79 yrs
Qmax Mod-Severe 8 times
<12 mls/sec 4 times
BPE
4 times
>30 mls
3 times
Jacobsen SJ, et al. Natural history of prostatism: risk factors for acute urinary retention.
J Urol. 1997;158:481.

138
BPH Progression – PSA Predicts Future Prostatic Growth
PLESS – Proscar Long-Term Efficacy and Safety Study (Roehrborn CG et al J Urol 2000)

3.3
Annual Growth Rate in

2.5
2.1
2
0.7
1.5
mls

1
0.5

0
≤ 1.3 >1.4 to 3.2 ≥3.3
Baseline PSA
PSA is a Strong Predictor of Prostate Growth in Placebo Treated Patients

Risk of BPH Progression in Patients

Receiving Placebo vs MT (Doxazosin/ Finasterid/ combination therapy)

MTOPS – Medical Therapy of Prostatic symptoms

PSA ≥1.6 (ng/mL)

Probability of BPH Progression (%)

TPV ≥ 31 (mL)
Probability of BPH Progression (%)

25 25

20 20 (p<0.0009)
(p<0.0001)
15 15 PSA ≤1.6 (ng/mL)
TPV ≤ 31 (mL)
10 10

5 5

0 0
0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0 4.5 5.0 5.5 0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0 4.5 5.0 5.5
Time in study (yrs) Time in study (yrs)

QMAX <10.6 (mL/sec) PVR ≥39 (mL)

Probability of BPH Progression (%)
Probability of BPH Progression (%)

25 25

20 7 (p=0.011) 20 (p<0.0008)
6
15 15
PVR ≤39 (mL)
5
4 QMAX >10.6 (mL/sec)
10 3
10
2
5 5
1
0
0 0
0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0 4.5 5.0 5.5 0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0 4.5 5.0 5.5
Time in study (yrs) Time in study (yrs)

Crawford D E et al. J Urol 2006;175:1422

Management Options – Behavioural Treatment

Watchful waiting – Behavioural Treatment

Men with mild-to-moderate uncomplicated LUTS who are not too troubled by their symptoms are suitable for WW

• Mild (to moderate) LUTS

• After first line assessment

• Explain the condition

• Reassure your patient “it is not cancer”
• Offer periodic monitoring

Flanigan et al. J Urol 1998, 160(1);12-6

Wasson et al. NEJM 1995, 332(2);75-9
Netto et al. Urology 1999, 53(2);314-6

139
 Management Options – Behavioural Treatment

• Lifestyle advice

• Reduction in Fluid intake (not below 1500mls in a day)

• Avoidance/ Moderation of Caffeine and alcohol intake
• Urethral Milking to avoid post micturition dribbling
• Distraction techniques – breathing exercises, mental tricks
• Bladder re-training (to around 400 mls)
• Treatment of constipation

Phytotherapy – Plant Extracts

Drugs – Cucurbita pepo, Hypoxis rooperi, Pygeum
africanum, Secale cereale, serenoa repens and urtica
dioica
> 20 RCTs mentioned in the guidelines

Different concentrations and combinations of active

ingredients in different brands

Guidelines committee focus on Hexane extracted Serenoa

repens (HESR)

Take home Phytotherapy

• No general recommendation

• Option for patients with mild to moderate LUTS

who dislike conventional medical therapy

• No impact on BOO or prostate volumen

140
 Management Options – Stratified Medicine

Spectrum of complaints

Risk of progression

Presence of complications

Side effects (+costs) of

treatment

Most frequent strata

surgery
WaWa

antimuscarinics
+/- α-blocker
Male LUTS α-blocker

desmopressine 5 ARI +/- α-

blocker
PDE 5
inhibitor

John, 55 year-old business man

• LUTS since 6 months: Urgency, Frequency, Nocturia
2x, limited weakness of flow
• Severely bothered by these symptoms
• Sexually active

• IPSS 17
• Qmax 15 mL/sec, PVR 10 mL
• Urinalysis: negative
• PSA 1.15 ng/mL
• TRUS volume: 25 mL

141
John, 55 year-old business man
• LUTS since 6 months: Urgency, Frequency, Nocturia
2x, limited weakness of flow
• Severely bothered by these symptoms
• Sexually active

• IPSS 17
• Qmax 15 mL/sec, PVR 10 mL
• Urinalysis: negative
• PSA 1.15 ng/mL
• TRUS volume: 25 mL

Which treatment?
1. Watchful waiting + behavioural treatment
2. Alpha-blocker
3. 5-alpha reductase inhibitor
4. PDE-5 inhibitor
5. Antimuscarinic drug
6. Desmopressin

α Blockers
α1-blockers have little effect on urodynamically determined bladder outlet resistance (Kortmann, B.B., et al. Urology. 2003).
Treatment-associated improvement of LUTS correlates poorly with obstruction (Barendrecht, M.M., Neurourol Urodyn, 2008).

Lepor H.Rev Urol 2011;13(1):20-33

142
 Alpha 1 Adrenoreceptors – Fast Facts

✔ Improve symptoms/flow Alpha 1-blockers can reduce both storage and voiding LUTS.

Onset of symptom relief within 1–2 weeks

✔ may improve resolution of AUR

Prevent symptomatic progression

✔ in the short term α1-blocker treatment appears to be maintained over
at least four years.

✔ Low rate and severity of side effects

✔ Well studied (LoE 1a, GR A)

✗ Reduce prostate volume

✗ Reduce longer-term risk of AUR and surgery

Madersbacher et al. Eur Urol 2004;46:547–54

Alpha Blockers - Efficacy

Alfuzosin Doxazosin GITS
Terazosin TAM 0.4 Placebo
Doxazosin TAM 0.8
50%
% improvement in total symptom score

40%

30%

20%

10%

0% 2 3 5a 4 5b 6 7 8a 8b 11 12 13 14 16 17a 17b 18 19 21 22 23a 24a 23b 24b 25 26 27a 28a 27b 28b

ALF IR ALF SR ALF XL TER DOX S DOX GITS TAM 0.4 TAM 0.8

Djavan B et al. Urol 2004;64:1081

• 16 placebo controlled trials

• All a1-blockers superior to

placebo

• Symptom score improved by 30

to 45% (5 to 8 points in the
IPSS)

• Qmax improved by 15 to 30%

• No significant differences
between a1-blockers

Gravas et al., EAU Guidelines 2017

143
 Alpha Blockers – Tolerability and Safety

• Driven by distribution into LUT tissue, subtype selectivity and

pharmacokinetic
• Most frequent: asthenia, dizziness, (orthostatic) hypotension
• Vasodilatation effect low in Alfuzosin & Tamsulosin (not significant to
placebo)
• Silodosin: frequency of hypotension comparable to placebo
• Retrograde ejaculation: tamsulosin 8.5x and silodosin 32.5x
more frequent than placebo
• IFIS (intraoperative floppy iris syndrome) rare, but 40x more
frequent with tamsulosin

Practical Considerations:
Take home Phytotherapy
• A1-blockers often considered 1-st line drug - • Option for patients with mild to moderate LUTS
rapid onset, good efficacy, low rate and severity • No reduction of risk of progression
of AE´s
• No relevant impact on BOO or prostate volumen
• Ophthalmologist should be informed before
cataract surgery!

Jeff, 65 year-old retired postman

• Progressively increasing LUTS since 2 years: some
Frequency, Nocturia 2x (since 5 years), weakness of
flow++
• Moderately bothered by these symptoms
• Not sexually active

• IPSS 8
• Qmax 8 ml/sec, PVR 100 ml
• Urinalysis: negative
• PSA 2.5 ng/mL
• TRUS volume: 45 ml

144
Which treatment?
1. Watchful waiting + behavioural treatment
2. Alpha-blocker
3. 5-alpha reductase inhibitor
4. PDE-5 inhibitor
5. Antimuscarinic drug
6. Desmopressin

Conversion of testosterone to DHT

requires the enzyme 5α-reductase
• 5α-reductase exists as two isoenzymes
• Type 1 (skin & liver +++, prostate +)
• Type 2 (prostate +++)

5AR type 1
Testosterone DHT
OH OH

5AR type 2
O O
H

Andriole G et al. J Urol 2004;172:1399–1403

5 Alpha Reductase Inhibitors (5ARI)

Competitive Inhibition of 5 Alpha Reductase

• Finasteride – Type 2 (Mainly prostate)
• Dutasteride – Type 1* & 2

Slow Onset of Action (6 – 12 months)

Prostate Volume Reduction by 15 – 28%

PSA decreased by 50% after 6 months

*5 Alpha reductase Type 1 – minor expression in prostate but

predominantly in skin and liver

145
 5 Alpha Reductase Inhibitors (5ARI)

✔ Improve symptoms/flow
Prevent symptomatic progression
✔ in the short term

✔ Sustained symptomatic benefit

✔ Reduce prostate volume

✔ Maintain reductions in PV

✔ Reduce longer-term risk of AUR and surgery

✗ Onset of symptom relief within 1–2 weeks

Madersbacher et al. Eur Urol 2007;51:1522–33

RCT´s with 5ARI´s in men with LUTS & BPE

44
2014

Finasteride – PLESS Findings

Probability of Surgery (%)

15

10 Placebo 4 yr Study of
5
P<0.001 Finasteride VS
Finasteride Placebo
0
0 1 2 3 4

15

• Mean Prostate Volume 55mL

Urinary Retention (%)
Probability of Acute

10
• Over 50% rel. Risk Reduction
Placebo in surgery for BPH (55%) and
5
P<0.001 AUR (57%) (10% vs. 5%/ 7% vs. 3% absolute RR)
Finasteride • Risk Reduction higher in pts
0
0 1 2 3 4 with PSA >1.4ng/ml
Year

McConnell JD et al. NEJM 1998;338:557

146
Practical Considerations:

• ARI candidates: enlarged prostate (>40 ml), moderate to

severe LUTS and/or PSA (>1.4-1.6 ng/ml)
• Slow onset: suitable only for long-term treatment
• Consider effect on PSA!

Take home ARI

• Option for patients with mild to moderate LUTS
• Long term therapy (>6 m.)
• Needs a prostate vol. > 40 ml
• Low impact on BOO

46

Combination Treatment - MTOPS

Doxazosin + Finasteride
*Mean Reduction in Symptom Score was 7 points

> 4 points in AUA

Retention of Urine
Score*
25
Cumulative Incidence of

Placebo
20
Progression (%)

Finasteride Long-Term Combination

15 (P=0.002) Therapy – Doxazosin +
10
Doxazosin
(P<0.001)
Finasteride Significantly
More Effective Than Either
5 Combination Therapy Drug Alone in Reducing Risk
(P<0.001)
0
of Overall Clinical
0 0.5 1.0 1.5 2.0 2.5 2.5 3.5 4.0 5.0 5.5 Progression of BPH
Years
No at Risk
Renal
Recurrent UTI’s
Placebo 737 712 670 631 612 588 575 555 492 337 218 84
Doxazosin 756 735 715 698 675 660 641 627 565 387 259 93
Finasteride
Combination Therapy
768
786
737
762
699
747
675
733
659
726
634
715
617
697
599
683
530
599
379
426
257
280
105
112 Insufficiency

McConnell JD et al.NEJM 2003;349:2387

Combination Treatment - CombAT

Tamsulosin + Dutasteride
• Dutasteride + Tamsulosin
Adjusted mean change from baseline
In IPSS ±standard error
– Significant Improvements in IPSS
0
• From Month 3 (vs Dutasteride)
-1 • From Month 9 (vs Tamsulosin)
Combination (n=1575)
-2
-2.8
Dutasteride (n=1592) • Increase in Adverse events
-3 -3.4 Tamsulosin (n=1592)
-4.0 -4.2
-4 -4.5 -4.4 -4.5 -4.4 -4.3
-4.7 -4.8
-5 -4.5 -4.8
-4.8 -4.8 -4.9 -5.0 -4.9
-6 -5.4
-5.6
-6.0 -6.0 -6.2
-6.2
-7
Baseline 3 6 9 12 15 18 21 24

Study month

Roehrborn et al. J Urol 2008; 179: 616–21

147
 Limitation of med. Therapy

Long term Discontinuation of medical therapy (up to >30%)

5 Alpha Reductase Inhibitors (5ARI) –

Sexual Side Effects
Patients with adverse events (%)
5ARI Alpha-blocker Combination
CombAT (dutasteride + -tamsulosin)
Decreased libido 3 2 4
ED 7 5 9
Semen volume <1 <1 2
decrease
Retrograde <1 1 4
ejaculation
MTOPS (finasteride +- doxacosin)
Decreased libido 2.4 1.6 2.5
ED 4.5 3.6 5.1
Abnormal 1.8 1.1 3.1
ejaculation

Practical Considerations – 5ARI and a1-blocker:

• Effective in prostate volumes >30-40 ml and treatment
duration >1 year
• <1year = monotherapy a1-blocker as effective
• Combination = slightly increased AE´s
• Unclear if effect is sustained after >6 years

148
 John, 62 year-old business man
• On alpha-blocker since 7 years
• Increased Urgency & Frequency, Nocturia 2x, progressively increased
weakness of flow
• Quite bothered by these symptoms
• Sexual activity: less important

• IPSS 15
• Qmax 12 mL/sec, PVR 90 mL
• Urinalysis: negative
• PSA 1.9 ng/mL
• TRUS volume: 35 mL

Which treatment?
1. Add antimuscarinic
2. Switch to 5-alpha reductase inhibitor
3. Add PDE-5 inhibitor
4. Add 5-alpha reductase inhibitor
5. Add desmopressin

Muscarinic Receptor Antagonists - Facts

• Main neurotransmitter in the bladder (acetylcholine)

stimulates muscarinic receptors of detrusor smooth
muscle cells

• 5 muscarinic receptor subtypes (M1-M5) described,

M2 (80%) & M3 (20%) predominantly in the detrusor

• M3 receptors involved in bladder contraction in

healthy humans

54

149
Antimuscarinic drugs licensed in Europe for
OAB/ storage symptoms

Trials with antimuscarinic drugs in elderly

men with LUTS

Reduction in

• Voiding frequency
• Nocturia
• Urge incontinence
• IPSS

• More effective in
small prostates

Muscarinic Receptor Antagonists –

side effects

• Generally well tolerated (3-10% withdrawals)

• Dry mouth (<16%), Constipation (< 4%), Dizziness (< 5%)

• Careful in BOO (PVR can increase, no increased rate of

AUR) (Yokoyama et al 2009)

• No comparative data between drugs, no long-term data

• Regular monitoring of IPSS & PVR

57

150
 Combination a1-blocker & anti-muscarinic drug

• Mainly assessed as „Add-on“ to a1-blocker

• Inconsistent data/ heterogeneous study
populations & designs
• „add-on“ in insufficient monotherapy
• Safe in PVR < 150ml
• No data on safety & efficacy > 4months

Practical considerations:

• Not all antimuscarinics have been tested in elderly men

• Long-term studies in men with LUTS not available
• Only men with low baseline PVR included
• Check PVR and IPSS regular

Take home antimuscarinics

• In patients with predominantly storrage symptoms

Lately approved for OAB

Beta-3 adrenoceptors are the predominant beta receptors expressed in the smooth muscle cells of the detrusor and their stimulation is thought to induce
detrusor relaxation. The mode of action of beta-3 agonists is not fully elucidated

• Mirabegron, selective ß3 receptor agonist

• Mirabegron mediates relaxation of the detrusor muscle

during the storage phase of the micturition cycle, thus
increasing bladder storage capacity

151
 • Favourable vs Placebo
• Equivalent to Antimuscarinics

Mirabegron combination therapy

• Mirabegron 25/50 mg and Solifenacin 5/10mg was associated
with sig. better Outcome & QoL than Solifenacin and placebo
Abrams, P., et al., World J Urol, 2017

• combination therapy was associated with greater improvements

in OAB symptom score, storage subscore of the IPSS, and in the
QoL index compared to monotherapy with tamsulosin
Matsuo, T., et al., BMC Urol, 2016
• fesoterodine add-on therapy to sildosin showed a significantly
greater improvement then mirabegron add-on therapy to
silodosin in OAB and alleviating DO (53% vs. 29%)
Matsukawa, Y., et al., Neurourol Urodyn, 2019.

Mirabegron: tolerability & safety

• Contraindicated in not well

controlled hypertension (≥ 180
mmHg or diastolic blood
pressure ≥ 110 mmHg)
hypertension,
• Higher incidence of CV events!
UTI, headache nasopharyngitis

152
Alex, 50 year-old colleague
• LUTS since 4 months: Limited Urgency & Frequency,
Nocturia 1x, limited weakness of flow
• Severely bothered by these symptoms
• Sexually active, and is concerned about progressively
increasing ED

• IPSS 9
• Qmax 15 mL/sec, PVR 0 mL
• Urinalysis: negative
• PSA 0.8 ng/mL
• TRUS volume: 20 mL

Which treatment?
1. Watchful waiting + behavioural treatment
2. Alpha-blocker
3. 5-alpha reductase inhibitor
4. PDE-5 inhibitor
5. Antimuscarinic drug
6. Desmopressin

The role of PDE-5 inhibitors in LUTS

Phosphodiesterase 5 inhibitors (PDE5Is) increase intracellular cyclic guanosine monophosphate, thus reducing smooth
muscle tone of the detrusor, prostate and urethra.

• PDE -5 inhibitors – Sildenafil, Tadalafil, Avanafil and

Vardenafil

• NO stimulates synthesis of cyclic GMP which reduces

smooth muscle tone of detrusor, prostate and urethra.

• PDE-5 inhibitors prevent hydrolysis of

cyclic GMP

66

153
 The role of PDE-5 inhibitors in LUTS
• Proposed working mechanisms
• Smooth muscle relaxation in LUT (detrusor, prostate, urethra)
• Smooth muscle relaxation in vasculature  better perfusion and oxygenation of bladder and
prostate
• Direct influence on afferent sensory output of bladder

PDE-5 inhibitors in LUTS

• 16 RCT available
• Consistent, significant IPSS reduction (17-
37%)
• Storage & Voiding symptoms
• Significant QoL improvement vs. placebo
• Qmax not significant to placebo

68

Practical Considerations:
• Qmax improvement only for tadalafil in 1 study

• Longterm data are missing

• Safety and Tolerability
 flushing, gastroesophageal reflux,headache,dyspepsia,back pain,nasal congestion

• Cave: contraindications of PDE5 inhibitors

 in patients using nitrates, the potassium channel opener nicorandil,
 or the α1-blockers doxazosin and terazosin.
 unstable angina pectoris, recent myocardial infarction (<3ms) or stroke (<6ms),
 myocardial insufficiency (NYHA stage > 2), hypotension, poorly controlled bl. Press.
 significant hepatic or renal insufficiency, or if anterior ischaemic optic neuropathy

Take home PD5-Inhibitors

• Option for patients with mild to moderate LUTS
• improves erectile function
• no rel. Impact on BOO

69

154
 Combination a1-blocker & PDE5 inhibitors

Gacci M, et al. Eur Urol 2012; 61:994-1003

Combination 5-ARI & PDE5 inhibitors

Casabé, et al. J Urol 2014

Joseph, 75 year-old retired bank director

• LUTS since long time: Some Urgency & Frequency, limited
weakness of flow
• Severely bothered by the nocturia, which increased to 3
times/night over the last 6 months. Sleep deficit.
• Not sexually active

• IPSS 16
• Qmax 15 mL/sec, PVR 50 mL
• Urinalysis: negative
• PSA 3.5 ng/mL
• TRUS volume: 45 mL

155
Which treatment?
1. Watchful waiting + behavioural treatment
2. Alpha-blocker
3. 5-alpha reductase inhibitor
4. PDE-5 inhibitor
5. Antimuscarinic drug
6. Desmopressin

Vasopressin analogue - desmopressin

• AVP (antidiuretic hormone arginine vasopressin) binds to V2
receptor in renal collecting duct
• Desmopressin = synthetic analogue
• Water re-absorption , water excretion , urine volume

74

Clinical trials with desmopressin in adult men

with nocturnal polyuria

• Nocturnal diuresis (0.6-0.8 ml/sec = -40%)

• Nocturnal voids (0.8-1.3 x / = -40%)
• Extent of time to 1st void 1.6-2.1 hrs.
• Night time urine volume

• Stable over 10-12 months

75

156
Practical Considerations:

• Once daily before sleep / not associated with fluid intake

• Dose titration (0.1 mg/day up to 0.4 mg/day)
• Regular check of sodium concentration

76

Gravas et al., Eur Urol

Focus. 2022

157
 Course directors Hands on training tutors:
E. Liatsikos, Patras (GR)
J. N’Dow, Aberdeen (GB) Coordinator:
B. Somani, Southampton (GB)
Scientific Board
The Board of the European School LUS tutors
of Urology G. Bozzini, Milan (IT) EAU Congress Organiser
W. Brinkman, Utrecht (NL) Congress Consultants B.V.
Faculty B. Brzoszczyk, Bydgoszcz (PL) PO Box 30016
S. Ahyai, Graz (AT) K. Dilen, Heusden-Zolder (BE) 6803 AA Arnhem
K. Bensalah, Rennes (FR) J. Gomez Rivas, Madrid (ES)
T +31 (0)26 389 1751
B. Burgu, Ankara (TR) F. Greco, Bergamo (IT)
C. Cracco, Turin (IT) M. Jarzemski, Bydgoszcz (PL)
eurep@uroweb.org
L. De Kort, Utrecht (NL) L. Osório, Porto (PT)
T. Greenwell, London (GB) A. Papatsoris, Athens (GR)
G. Karsenty, Marseille (FR) B. Rai, Newcastle (GB)
N. Kitrey, Ramat Gan (IL) D. Rengifo Abbad, Majadahonda (ES)
J.I. Martinez Salamanca (ES) T. Ribeiro de Oliveira, Lisbon (PT)
A. Merseburger, Lübeck (DE) J.B. Roche, Bordeaux (FR)
C. Mir Maresma, Valencia (ES) S. Stomps, Almelo (NL
N. Mottet, Saint-Étienne (FR)
J. Sedelaar, Nijmegen (NL) EST tutors European School of Urology
E. Serefoglu, Istanbul (TR) O. Durutovic, Belgrade (RS) PO Box 30016
K-D. Sievert, Detmold (DE) C. Houwert, Amsterdam (NL) 6803 AA Arnhem
A. Skolarikos, Athens (GR) P. Kronenberg, Lisbon (PT)
The Netherlands
A.F. Spinoit, Ghent (BE) S. Pereira, Lisbon (PT)
Z. Tandoğdu, London (GB) A. Pietropaolo, Southampton (GB)
T +31 (0)26 389 0680
J. Walz, Marseille (FR) I. Tjiam, The Hague (NL) esu@uroweb.org
E. Xylinas, Paris (FR) www.uroweb.org
TUT tutors
R. Brito Ramos, Lisbon (PT)
L. Dragos, Cambridge (GB)
M. Goossens, Aalst (BE)
P. Kallidonis, Patras (GR)
I. Kartalas Goumas, Vigevano (IT)
D. Oliveira Reis, Lisbon (PT)
B. Schoensee, Berlin (DE)
T. E. Sener, Ankara (TR)
A. Sousa Castro, Lisbon (PT)

SNM tutors
M. Culha, Istanbul (TR)
C. Ochoa Vargas, Bristol (GB)
M. Perrouin Verbe, Nantes (FR)

NTS tutors
S. Haensel, Rotterdam (NL)
N. Raison, London (GB)
G. Zanovello, Verona (IT)

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