Dr. Boyke Subali, SpU RSU. A. Wahab Sjahranie - Samarinda.

Current Strategic on BPH Management – Combination

Therapy

Dr. Boyke Subali, SpURSU. A. Wahab Sjahranie - Samarinda

PrevalenceSub Tittle

2

When should BPH be considered as a disease?

Current Treatment of BPH

Prevalence of Histologic BPH Increases with Age

Roehrborn CG, et al.International Journal of Impotence Research.2008; 20: S11–S18

BPH influenced Daily activities

Garraway WM, et al. Br J Gen Pract. 1993;43(373):318-321.

Prostatic parcYes!


Bothersome symptoms?


Benign Prostate Hyperplasia (BPH)Benign prostatic hyperplasia (BPH) is a pathologic process that contributes to, but is not the sole cause of, lower urinary tract symptoms (LUTS) in aging menBenign prostatic hyperplasia is defined histologically as a disease process characterized by stromal and epithelial cell hyperplasia.Originates from transition zone

6

AUA Guideline. J Urol.2003;170:530-547Roehrborn CG. International Journal of Impotence Research.2008;20:S11–S18

Lee KL et al. J Urol 2004;172:1784–1791

BPH is characterised by non-malignant

enlargement of the prostate

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Hypertrophieddetrusormuscle

Obstructedurinary flow

Prostate

Bladder

Urethra

Normal BPH

Enlargementof the prostate

Adapted from Kirby RS et al. Benign Prostatic Hyperplasia. Health Press, Oxford, 1999 available at: http://www.glaxosmithkline.rs/vasezdravlje-bph.html

http://www.glaxosmithkline.rs/vasezdravlje-bph.html

BPH is caused by an imbalance of cell proliferation (growth) and apoptotic (death) signals – leads to increase in

number of prostate cells and prostate size

DHT-androgen receptor complex

Growth factors

Unbalanced

DHT T

5α-reductasetypes 1 and 2

Serum DHT Serum testosterone (T)

Prostatecell

Increasedcell growth

Cell death

8Adapted from Kirby RS, McConnell. Benign Prostatic Hyperplasia. Health Press Ltd, 1999

BPH, LUTS, BPE and BOOClinical, anatomical, and pathophysiological changes

BPH = Benign Prostatic Hyperplasia Histological: stromoglandular

hyperplasia May be associated with

Clinical: presence of bothersome LUTS2

Anatomical: enlargement of the gland (BPE = Benign Prostatic Enlargement)2

Pathophysiological: compression of urethra and compromise of urinary flow (BOO = Bladder Outlet Obstruction)2

Nordling J et al. In: Chatelain C et al, eds. Benign Prostatic Hyperplasia. Plymouth, UK: Health Publication Ltd; 2001:107-166.

Histological BPH

All Men>40 y

`BOOObstruction

BPEEnlargement

LUTS/Bother

BPH can cause lower urinary tract symptoms (LUTS)

Voiding symptoms, caused by an enlarged prostate Weak urinary stream Prolonged voiding Abdominal straining Hesitancy Intermittency Incomplete bladder emptying Terminal and post-void

dribbling

BPH symptoms may include:

Storage symptoms, which can result from enlarged prostate or overactive bladder (OAB) Frequency Nocturia Urgency Incontinence

LUTS are not specific to BPH – not all men with LUTS have BPH and not all men with BPH have LUTS

Associated symptoms of BPH include: Dysuria Haematuria Haematospermia

Diagnostic tests recommended by the EAU BPH guidelines

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Medical history Symptom score Physical examination (incl. DRE) PSA Creatinine measurement* Urinalysis Flow rate** Post-void residual volume**

EAU BPH guidelines. Madersbacher S et al. Eur Urol 2004; 46: 547–554AUA Practice Guidelines Committee. J Urol 2003; 170: 530–547

*Not recommended by the AUA guidelines** Considered optional in the AUA guidelines

Symptoms scoreEvaluating symptom severity is an important part of the initial assessment

Symptom severity is probably best assessed through the use of a validated symptom score

The internationale standard instrument is the International Prostate Symptom Score (IPSS)

The IPSS comprises of 8 questions: 7 questions about the severity of symptoms

These are identical to the 7 questions of the AUA Symptom Index*

1 question on global quality of life

12EAU BPH guidelines. Madersbacher S et al. Eur Urol 2004; 46: 547–554AUA Practice Guidelines Committee. J Urol 2003; 170: 530–547

*The AUA guidelines recommend use of the AUA-SI (7 questions)

IPSS questionnaire

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Over the past month, how often have you… Not at all Less than 1 time in 5

Less than half the time

About half the

time

More than half the time

Almost always

YOUR SCORE

1. …had a sensation of not emptying your bladder completely after you finish urinating?

0 1 2 3 4 5

2. …had to urinate again less than two hours after you finished urinating?

0 1 2 3 4 5

3. …stopped and started again several times when you urinated?

0 1 2 3 4 5

4. …found it difficult to postpone urination? 0 1 2 3 4 5

5. …had a weak urinary stream? 0 1 2 3 4 5

6. …had to push or strain to begin urination? 0 1 2 3 4 5

7. Over the past month, how many times did you most typically get up to urinate from the time you went to bed at night until the time you got up in the morning?

None Once Twice 3 times 4 times 5 times or more

TOTAL

8. QUALITY OF LIFE DUE TO URINARY SYMPTOMSIf you were to spend the rest of your life with your urinary condition the way it is now, how would you feel about that?

Delighted Pleased Mostly satisfied

Mixed – about equally satisfied & dissatisfied

Mostly dissatisfied

Unhappy Terrible

0 1 2 3 4 5 6

Total IPSS indicates symptom severity

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Total IPSS Symptom severity

0–7 Mild

8–19 Moderate

20 Severe

EAU BPH guidelines. Madersbacher S et al. Eur Urol 2004; 46: 547–554

Physical examinationPhysical examination during the initial assessment of a man with LUTS suggestive of BPH should include:

Focused neurological examination Digital rectal examination (DRE)

To help evaluate prostate size To help exclude the presence of prostate cancer,

as well as prostatitis and other pelvic pathologies

15EAU BPH guidelines. Madersbacher S et al. Eur Urol 2004; 46: 547–554

The clinical utility of PSA in assessing men with LUTS

suggestive of BPH

Strong relationship between serum PSA and prostate volume enables clinicians to estimate prostate size in BPH patients

Serum PSA thresholds can be used to predict the presence of a prostate >30ml or >40ml with sensitivity between 60-70% and specificity 70%.

Along with current prostate size, serum PSA provides prognostic information about:

Prostate growth Symptoms and bother deterioration Sexual dysfunction Flow rate worsening Risk for AUR and surgery

In general higher levels of serum PSA indicate faster and greater risk for progression 16

Roehrborn CG. Int J Impot Res 2008; 20: s19–26

UrinalysisAlthough benign prostatic obstruction is the most frequent cause of LUTS in men, LUTS can also be caused by urinary tract infection or bladder cancer

The absence of haematuria or pyruria on urinalysis helps to rule out these conditions

Guidelines recommend urinalysis to aid differential diagnosis


Flow rate determined by uroflowmetry

Uroflowmetry is a simple non-invasive test that can reveal abnormal voiding.Serial flows (two or more) with a voided volume exceeding 150 ml are recommended to obtain a representative flow test.

LUTS in the presence of a normal peak flow rate (Qmax= 15ml/s) are more likely to have a non-BPH-related cause, and men with Qmax <10 ml/sec are more likely to have urodynamic obstruction

Uroflowmetry is recommended by the EAU as part of the initial assessment of a man with LUTS, as well as being required prior to prostatectomy

Uroflowmetry is considered by the AUA to be an option following the initial patient evaluation


Measurement of post-void residual (PVR) volume

Measurement of PVR urine is recommended by the EAU guidelines and considered optional by the AUA

PVR volume is calculated by measurement of bladder height, width and length obtained by

transabdominal ultrasonography This is a simple, accurate and non-invasive method

Large PVR volumes (>200 mL) may indicate bladder dysfunction and predict a less favourable response to BPH treatment

EAU BPH guidelines. Madersbacher S et al. Eur Urol 2004; 46: 547–55419

Current Treatment of BPH

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Aims of treatment: EAU and AUA guidelines

The aim of therapy is to improve lower urinary tract symptoms (LUTS) and quality of life, and to prevent BPE/BPO-related complications such as urinary retention or upper urinary tract dilatation (EAU)

The patient's perception of the severity of the condition, as well as the degree to which it interferes with his lifestyle or causes embarrassment, should be the primary consideration in choosing therapy (AUA)


BPE = Benign prostatic enlargementBPO = Benign prostatic obstruction

Treatment – initial management

Initial management of men with LUTS suggestive of BPH can be categorized into:

Watchful waiting Medical therapy Surgical management Non-surgical intervention / Minimally invasive therapy


ManagementThe following are important components of WW:

Education

Reassurance

Periodic monitoring

Lifestyle modifications

Brown C et al. Curr Opin Urol 2004; 14: 7–12

Medical therapy The following medical treatments are

recommended for BPH treatment :

Alpha blockers (as monotherapy)

5 alpha-reductase inhibitors - 5ARIs (as monotherapy)

Combination therapy


Need for a new approach

Dependence on alpha-blocker monotherapy is failing a proportion of men with BPHNeed to move away from ‘one-size-fits-all’ medicine to a more personalised approachNeed for tailored solutions consistent with treatment guidelinesAppropriate treatment needed for men with moderate symptoms onwards, prostate volume ≥30 ml and PSA ≥1.5 ng/mlEmberton M et al. BJU Int 2011 Jan 25. doi: 10.1111/j.1464-410X.2010.10041.x

What is the optimal treatment for men with moderate symptoms

onwards, prostate volume ≥30 ml and PSA ≥1.5 ng/ml?

CombAT study provides insights into treatment of men with moderate symptoms onwards, prostate volume ≥30 ml and PSA ≥1.5 ng/mlEntry criteria for CombAT:

Male aged ≥50 years Diagnosis of BPH by history and DRE IPSS ≥12 (moderate-to-severe symptoms) Prostate volume ≥30 cc by TRUS Serum PSA 1.5–10.0 ng/ml Two voids at screening with Qmax >5 and

≤15 ml/sec (moderate-to-severe impairment) and minimum voided volume of ≥125 mlSiami P et al. Contemp Clin Trials 2007;28:770–

779

What can we learn from the CombAT data?

What benefit does combination therapy with dutasteride and tamsulosin have on:

Symptoms? Quality of life? Risk of long-term complications such as AUR and

BPH-related surgery?

Baseline

Study month

Ad

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ted

me

an c

han

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fro

m b

asel

ine

in I

PS

S

Superior symptom relief with combination therapy with

dutasteride and tamsulosin versus either monotherapy

Roehrborn CG et al. Eur Urol 2010;57:123–131; Barry MJ et al. J Urol 1995;154:1770–74

Tamsulosin (n = 1582)Dutasteride (n = 1592)Combination (n = 1575)

p <0.001 combination versus tamsulosin

p <0.001 combination versus dutasteride

2421181512963 27 30 33 36 39 42 45 48

0.0

-1.0

-2.0

-3.0

-4.0

-5.0

-6.0

-7.0

-8.0

-6.3-6.3-6.3-6.3-6.2-6.2-6.2-6.0-6.0

-6.4 -6.5

-5.6-5.4

-4.8-4.8

-5.4 -5.3-5.3 -5.2-5.2-5.2-5.3-5.1-5.0 -4.9-4.9-4.8

-4.5

-4.7-4.4

-4.5 -4.4 -4.4-4.3-4.1 -4.2

-4.0 -4.0-3.8 -3.8 -3.8

-4.5-4.8

-4.2-4.0

-3.4

-2.8

-6.4

Symptom improvement of at least 3 units is generally considered to be perceptible for the patient and

accepted as the minimum threshold of clinical relevance

Symptom improvement with combination therapy starts as

rapidly as tamsulosin monotherapy

Patients with LUTS consider storage symptoms to be most bothersome symptoms

All symptoms

Dysuria

Postmicturition dribble

Incomplete emptying

Straining

Hesitancy

Weak stream

Stress incontinence

Urge incontinence

Overflow or other incontinence

Urgency

Nocturia

Daytime frequency

0.00.51.01.52.02.53.03.54.0

Storagesymptoms

Häkkinen JT et al. Eur Urol 2007;51:473–478

n=1803 to 2046, depending on the symptomBother index

Combination therapy with dutasteride and tamsulosin superior to both monotherapies at 4 years:

Storage symptoms

Combination Tamsulosin Dutasteride

-2.5

-2.0

-1.5

-1.0

-0.5

0.0

-2.3

-1.4

-1.9

Adjusted mean change from baseline in IPSS storage score

*p<0.001 versus combination

*

*

Montorsi F et al. BJU Int 2011 Feb 23; DOI: 10.1111/j.1464-410X.2011.10129.x

Many men with moderate-to-severe symptoms (IPSS ≥8) have both storage and voiding symptoms:

findings from a population-based survey

Glasser DB et al. Int J Clin Pract 2007;61:1294–1300

Age (years)

Prevalence of LUTS subtypes (%)

40–49_x000d_(

n=130)

50–59_x000d_(

n=125)

60–69_x000d_(

n=115)

≥70_x000d_(n=111)

Total_x000d_(n=481)

0%

20%

40%

60%

80%

100%

32% 33% 32%20%

29%

37% 33% 35%46%

38%

19% 27% 20% 26% 23%

Voiding Mixed Storage

Storage symptoms: sum of scores on IPSS items 2, 4 and 7 was ≥4 and score on item 4 (i.e. urgency) was ≥1Voiding symptoms: sum of scores on IPSS items 1, 3, 5 and 6 was ≥5Mixed symptoms: criteria met for both storage and voiding symptoms

Combination therapy with dutasteride and tamsulosin superior to both monotherapies at

4 years:Voiding symptoms

Combination Tamsulosin Dutasteride

-4.5

-4.0

-3.5

-3.0

-2.5

-2.0

-1.5

-1.0

-0.5

0.0

-4.0

-2.4

-3.5

Adjusted mean change from baseline in IPSS voiding score


*

*

Montorsi F et al. BJU Int 2011 Feb 23; DOI: 10.1111/j.1464-410X.2011.10129.x

Symptoms: What can we conclude?

Over 4 years, combination therapy with dutasteride and tamsulosin provided significantly superior symptom improvement compared with either monotherapy for:

Total symptoms Storage symptoms Voiding symptoms

Symptom improvement starts as rapidly as tamsulosin monotherapy

The BIIA disease-specific 4-item instrument that measures the impact of LUTS on

Physical discomfort Worry about health Degree of bother Limitations of daily activities

Total scores range from 0 (no impact) to 13 (highest negative impact)

Montorsi F et al. Int J Clin Pract 2010;64:1042–1051

BII: combination therapy with dutasteride and tamsulosin superior to both

monotherapies at 4 years

0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48-2.5

-2.0

-1.5

-1.0

-0.5

0.0Adjusted mean change from baseline in BII

p≤0.008 combination versus tamsulosin

Month

p≤0.003 combination versus dutasteride


TamsulosinDutasterideCombination

-1.2

-1.8

-2.2

Mean baseline BII = 5.3

The PPSM questionnaire was developedby GSK to assess patient satisfactionwith treatment in the CombAT study

12 questions covering six areas Control of urinary symptoms Strength of urinary stream Two aspects of pain of urination Effect on usual activities Overall satisfaction Whether the respondent would ask their doctor for

this medicationPPSM total score ranges from 7 (best) to 49 (worst) Question 12: possible responses are yes, no and not

sure

Montorsi F et al. Int J Clin Pract 2010;64:1042–1051; Black L et al. Health Qual Life Outcomes 2009;7:55

PPSM total score: combination therapy with dutasteride and tamsulosin superior to both

monotherapies at 4 years

0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48-8.0

-7.0

-6.0

-5.0

-4.0

-3.0

-2.0

-1.0

0.0Adjusted mean change from baseline in PPSM total score

Month

p<0.001 combination versus dutasteride


p<0.001 combination versus tamsulosin


-4.1

-5.5

-7.0

Mean baseline PPSM total score = 25

Satisfaction with treatment (PPSM Q11): combination therapy with dutasteride and

tamsulosin superior to both monotherapies at 4 years

0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 4830%

40%

50%

60%

70%

80%

90%Percentage of patients satisfied with treatment

p<0.001 combination versus tamsulosin

Month

p≤0.002 combination versus dutasteride


0%


80%

74%

69%

PPSM Q12: Would you ask your doctor for the medication you received in the

study?

Combination Tamsulosin Dutasteride0%

20%

40%

60%

80%

100%

64%

55%58%


Percentage of patients responding ‘Yes’


* *

QoL: What can we conclude?

Combination therapy with dutasteride and tamsulosin provides significantly superior improvements in patient-reported QoL and treatment satisfaction than either monotherapy

Improved overall QoL (IPSS Q8) Reduced impact of BPH (BII) Improved treatment satisfaction (PPSM)

Superiority of combination therapy versus both monotherapies was sustained out to 4 years

16141210

86420

0 12 24 36 48Time (months)

Per

cen

t o

f p

atie

nts

CombinationDutasterideTamsulosin

291610

271623

401611

431457

491484

1021464

581347

651365

1461307

671274

841277

1911176

CombinationCumulative no. of eventsNo. at riskDutasterideCumulative no. of eventsNo. at riskTamsulosinCumulative no. of eventsNo. at risk

CombAT 4-year primary endpoint:

Time to first AUR or BPH-related surgery

Roehrborn CG et al. Eur Urol 2010;57:123–131

8 months

ConclusionsIn men with moderate symptoms onwards with prostate volume ≥30 ml and PSA ≥1.5 ng/ml, CombAT shows that over 4 years, combination therapy with dutasteride and tamsulosin

Significantly improves symptoms and QoL versus either monotherapy

Significantly reduces the risk of AUR or BPH-related surgery versus tamsulosin monotherapy

431Madersbacher S et al. Eur Urol 2004;46:547–554; 2Roehrborn CG et al. Eur Urol 2010;57:123–131; 3Montorsi F et al. Int J Clin Pract 2010; 4Emberton M et al. Int J Clin Pract 2008; 62: 18–26

Implications of CombAT study: What do these results mean

for patients?Men with BPH/LUTS may experience a substantial reduction in their quality of life

In many men, the progressive course of BPH raises the prospect of worsening symptoms, AUR and the need for surgery4

Major goals of BPH treatment include improvement of symptom scores, lowering risk of disease progression, improving patient-reported quality of life and treatment satisfaction1

In the CombAT study, combination therapy was associated with: Improvement of symptoms2 Reduced risk of BPH clinical progression2 Reduced risk of AUR or BPH-related surgery2

Improved patient-reported health outcomes3

Dr. Boyke Subali, SpU RSU. A. Wahab Sjahranie - Samarinda.

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