Manajemen Kanker Manajemen Kanker ProstatProstat

dan Kanker Buli-dan Kanker Buli-BuliBuli

Rainy UmbasRainy UmbasDepartemen UrologiDepartemen UrologiRumah Sakit Cipto Rumah Sakit Cipto Mangunkusumo Mangunkusumo

Universitas IndonesiaUniversitas Indonesia

Presentasi Penderita Keganasan UrologiPresentasi Penderita Keganasan UrologiRSCM & RSKD 1995-2009, n= 2001RSCM & RSKD 1995-2009, n= 2001

2734 36

41

52 54

67 70

8075

8389

2129

49

30

4048 50

43

53 55

39 38

24

23 27

42

28

21

0

20

40

60

80

100

1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009

Prostate Cancer Bladder Cancer

Prostate cancer patients (1995-2009), n=782 Bladder cancer patients (1995-2009), n=586

Div. of Urology, Dept. of Surgery / “Cipto Mangunkusumo Hosp”& “Dharmais” National Cancer Center

GAMBARAN KLINIK DAN GAMBARAN KLINIK DAN PENANGANAN KANKER PENANGANAN KANKER

PROSTATPROSTAT

Prostate: Small gland ..... Big Prostate: Small gland ..... Big problemproblem

Prostatitis

BPH

Prostate cancer

41

54

8983

27

7580

6770

52

3634272324

0102030405060708090

100

1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009

Prostate cancer patients (1995-2009)Div. of Urology, Dept. of Surgery / “Cipto Mangunkusumo Hospital”

& “Dharmais” National Cancer Centern= 782

• Globocan 2002: 7/100.000 ASR

Manifestasi klinis (1)Manifestasi klinis (1)

• Tanpa keluhan (dicurigai pada pemeriksaan check up tahunan, screening, atau ada keluarga yang menderita kanker prostat)

• LUTS / retensi urin• Hemospermia• Hematuri• Nyeri tulang / fraktur patologis• Gangguan neurologis

Manifestasi klinis (2)Manifestasi klinis (2)

• Kelainan prostat pada pemeriksaan colok dubur:- konsistensi keras- berbenjol-benjol- nodul- tidak simetri

• Kelainan prostat pada pemeriksaan trans-rectal ultra sonography (TRUS):- Lesi hypo echoic atau hyper echoic- Hypervascularisasi (Doppler)

Manifestasi klinis (3)Manifestasi klinis (3)Penanda tumor

• Prostate specific antigen (PSA)- cut off level untuk indikasi biopsi: > 4 ng/ml- indikasi biopsi ulang dapat digunakan PSA density (PSAD), free/total PSA (f/t PSA), atau PSA velocity (PSAv)- untuk follow up hasil pengobatan

• PCA3 : pemeriksaan urin setelah dilakukan masase prostat

Trans rectal ultra-sonography (TRUS):Trans rectal ultra-sonography (TRUS):

Dilakukan untuk mengukur volume prostat.• Bila akan memberikan pengobatan dengan 5

alpha reductase inhibitor.• Sebelum tindakan operasi atau termoterapi

Trans rectal ultra-sonography (TRUS) & Trans rectal ultra-sonography (TRUS) & biopsi:biopsi:

Indikasi biopsi prostat:

• Kelainan pada colok dubur

• PSA > 4 ng/mlAnestesi lokal atau regional/umum

Hasil pemeriksaan histopatologi:• Jenis & grade tumor (Gleason score)• Persentase pada setiap “core”

Derajat keganasan (grade)Derajat keganasan (grade)Diagnosis pasti kanker prostat berdasarkan

pemeriksaan histopatologi jaringan biopsi atau reseksi prostat.

Ditentukan jenis tumor dan dibuat klasifikasi derajat sesuai dengan:

• WHO : berdasarkan derajat diferensiasi yaitu baik, sedang, dan buruk (Mostofi)

• Sistem Gleason : berdasarkan pola arsitektur (morfologik) kelenjar prostat yang dibagi antara 1-5. Ditentukan dua kelompok yang paling menonjol dan dijumlah menjadi Gleason score (2-10).

Gleason pathologic grading systemGleason pathologic grading system

Gleason DF. In: Tannenbaum M, ed. Urologic Pathology: The Prostate.Philadelphia, Pa: Lea & Febiger; 1977: 171–197

Pain during prostate biopsyPain during prostate biopsy

How to reduced / avoid:

• Good explanation to reduced anxiety• Treat the inducing factors (prostatitis, ano-

rectal pathology)• Using analgesia in certain condition:

- very anxiety patient- biopsy > 6 core- repeat biopsy

Pain during prostate biopsyPain during prostate biopsyDouble blinded study comparing periprostatic

injection of 1% lidocaine VS Placebo• Degree of pain was scored by VAS, 0-10.• 2.5 mL periprostatic injection around the seminal

vesicel on each side was done with 22 G needle• 18 G needle, 6-12 core.

• No significant difference of complications among these two groups.(Alvarino M & Umbas R, Indon Med J 2005)

n VAS pPlacebo

1% lidocaine

30

30

5.7 ± 1.7

2.1 ± 1.3

< 0.005

Peri-prostatic injectionPeri-prostatic injection

Jones JS et al. Prostate Cancer and Prostatic Diseases (2003) 6, 53–55

Tingkat penyakit (stage)Tingkat penyakit (stage)Berdasarkan sistem TNM (AJCC 2002) yang

ditentukan secara klinis (pemeriksaan fisik dan radio-imajing) atau surgical staging pasca radikal prostatektomi

• T : klinis biasanya dapat ditentukan berdasarkan karakteristik prostat pada pemeriksaan colok dubur. Cara lain adalah dengan bantuan trans-rectal ultrasonography (TRUS) atau MRI

• N : Hanya akurat dengan cara deseksi kelenjar getah bening.

Tingkat penyakit (stage)Tingkat penyakit (stage)• M : Bone scan, MRI, Bone survey

• Surgical staging (pT & pN) berdasarkan pemeriksaan histopatologi terhadap jaringan pasca radikal prostatektomi dan/atau deseksi kgb

Early stage Prostate CancerEarly stage Prostate Cancer

Treatment option for organ confined prostate cancer (T1a-T2b, N0, M0)

• Active surveilance / Watchful Waiting (WW)• Radical prostatectomy• Radiotherapy (EBRT or Brachytherapy)• Primary Androgen deprivation therapy

(PADT)Depend on:

risk stratification, co-morbidity, performance status, & patient preference

Early stage Prostate CancerEarly stage Prostate Cancer

Aim of treatment:

• Cancer Control• Maintaining urinary control

(continence)• Recovery of sexual function (potency)

“ TRIFECTA “

TREATMENT OPTIONS EAU 2008TREATMENT OPTIONS EAU 2008

LOCALIZED (grade A recommendation):• T1b – 2b, N0, M0

– Radical prostatectomy– Radiotherapy + Adjuvant Hormonal

treatment (2-3 years)

Radical ProstatectomyRadical Prostatectomy

Is this the best

modality ?

Radical prostatectomy: Long term Radical prostatectomy: Long term resultsresults

Cancer spesific survival (CSS): n Age group Risk group 10 years

CSS5509 < 55 years Low 99%

Medium 96%High 91%

> 70 years Low 99%Medium 97%

High 94%(Siddiqui SA et al, J Urol 2006)

Radical prostatectomy: Long term Radical prostatectomy: Long term resultsresults

Cancer spesific survival (CSS): stage & GS

(Bianco FJ Jr et al, Urology 2005)

Radical prostatectomy: Adverse eventsRadical prostatectomy: Adverse eventsShort term: • Peri-operative morbidity : 1.7-28.6%• Peri-operative mortality : 0.01-0.5%(Rabbani F, 2010; Mitchell RE, 2009; Chin JL, 2010)

Long term:• Urinary leakage (incontinence) : 7-

35%• Erectile dysfunction : 23-42%• Bowel urgency : 1%

(Wilt TJ, 2008; Loughlin KR, 2010; Tal R, 2009)

Role of EBRT in early stage Prostate Role of EBRT in early stage Prostate CancerCancer• As primary treatment in pts with life

expectancy between 5-10 years or ≥ 10 years with comorbidity

• 5-years recurrence free survival : 79-91%• 5-years survival: 62-88% depend on dose, fractination, technique, and adjuvant ADT

Adverse events:- Bowel dysfunction : 9-26%- Urinary tract dysfunction : 24-28%- Erectile dysfunction : 43%

(Michalski JM, 2010; Wilt TJ, 2008)

PADT in early stage Prostate CancerPADT in early stage Prostate CancerAs primary treatment:• Advanced age• Patient refusing curative treatment• Patient unsuitable for curative treatment

due to co-morbidity(Bartsch G et al, 6th International Consultation on new

developments in prostate cancer and prostate disease 2006)

- Could be given immediately or deferred- Continuos or intermittent

Role of PADT in early stage Prostate Role of PADT in early stage Prostate CancerCancerManagement of localized prostate cancer (by order

of preference)(Bartsch G et al, 6th International Consultation on new

developments in prostate cancer and prostate disease 2006)

Risk Life expectancy< 5 years 5-10 years > 10 years

High:• T2b, 3a, 3b or• GS ≥ 4+3 = 7 or• PSA 10-20 or• Biopsy findings >50%, perineural, ductal

1. Hormonal Tx2. RT + HT3. Investigatio

nal therapy

1. RT + HT2. Hormonal Tx3. RP4. Investigatio

nal therapy

1. RT + HT2. RP3. Investigatio

nal therapy4. Hormonal Tx

As first preference

Role of PADT in early stage Prostate Role of PADT in early stage Prostate CancerCancerAs primary treatment:• non-statistically significant benefit

in localized PCa pts with poorly differentiated tumor (Lu-Yao GL et al, JAMA 2008)

• No benefit and possibly greater mortality in well- or moderately differentiated stage 2 disease (Wong Y-N et al, Eur Urol 2009)

543210

Follow Up (year)

100

80

60

40

20

0

ADT

EBRT

Figure 2: 5-year survival rate in stage 2 prostate cancer age 70 years or more treated by EBRT or Androgen deprivation therapy (p > 0.05)

Survival of Localized Prostate Cancer patients age ≥ 70 yr treated by EBRT or ADT

The androgen deprivation The androgen deprivation syndromesyndrome

• Loss of libido• Erectile impotence• Decreased energy

- Metabolic syndrome- Osteoporosis / fracture- Loss of muscle mass- Weight gain- Anaemia- Alteration in lipid

profile- Depression, personality

change

What patients expect What they also get

(Calais da Silva FEC et al, Eur Urol 2009)

TREATMENT OPTIONS EAU 2008TREATMENT OPTIONS EAU 2008LOCALLY ADVANCED (grade A recommendation):• T3-4, N0, M0

– Radiotherapy > 70 Gy for T3 with life expectancy >5-10 yr

– Hormonal treatment for T3-4 & PSA > 25 ng/ml– Combination Radiotherapy + Hormonal treatment

better than RT alone• Any T, N1, M0

– Hormonal therapy as standard treatment

ADVANCED DISEASE

Hormonal therapy as standard treatment

Hormonal treatment:Hormonal treatment:

• Bilateral orchiectomy

• Oestrogens (DES)

• LHRH agonists• LHRH antagonists• Anti-androgens

The androgen deprivation The androgen deprivation syndromesyndrome

• Loss of libido• Erectile impotence• Decreased energy

- Metabolic syndrome- Osteoporosis / fracture- Loss of muscle mass- Weight gain- Anaemia- Alteration in lipid

profile- Depression, personality

change

What patients expect What they also get

Recent evidence on IAB in advanced Recent evidence on IAB in advanced prostate cancer patientsprostate cancer patients

• Testosteron recovery:± 90% patients recovered to normal testosteron levels within 18 weeks after 1st ON treatment cessation

• Disease progression & survival:No significant differences between IAB and CAB in term of:

- median time to progression- progression free survival- overall survival

• Tolerability & QoL:- Side effects (hot flushes, gynecomastia, headaches) were significantly more in CAB- Significantly better sexual activity & emotional function were found in patients with IAB therapy(Abrahamsson P-A, Eur Urol, 2010)

IAB vs Orchydectomy

p = 0.35

IAB in advanced Prostate CancerM1 (a/b/c)

Intermittent hormonal therapy

Successful 1st ON treatment(9 months)

Failed within 1st ON treatment

1st OFF treatment

orchydectomyRe-start if PSA ± 15ng/ml

Failed

Successful 2nd ON treatment (9 months)

2nd OFF treatment

3rd ON treatment

Recent evidence on IAB in advanced Recent evidence on IAB in advanced prostate cancer patientsprostate cancer patients

• IAB seems to be as effective as continuous AB with tolerability & QoL advantages

• When to stop & ON treatment duration:- PSA < 4 ng/ml- 9 months therapy

• When to re-start: PSA ± 15 ng/ml.

(Shaw G and Oliver RTD, Surgical Oncology 2009; Abrahamsson P-A, Eur Urol 2010)

Definition of HRPC (Hormone Refractory ProstateCancer or Androgen Independent Prostate Cancer)

1. Serum castration level of Testosteron2. Three consecutive rises of PSA 2 weeks apart

resulting in two 50% increases over the nadir3. Antiandrogen withdrawal for at least 4 weeks4. PSA progression despite secondary hormonal

manipulations5. Progression of osseous or soft tissue lesions

(EAU Guidelines 2008)

Systemic non-hormonal therapy in HRPC

• Cytotoxic chemotherapy• Bone-targeted treatments• Immunotherapy• “Targeted” therapy

Maintain androgen deprivation !!(LHRH analogue or Orchydectomy bilateral)

EAU Guidelines 2008 & Nelson WG et al. Prostate Cancer 6th Int’l Consultation 2005

Hormone refractory prostate cancer (HRPC)Hormone refractory prostate cancer (HRPC)Take home message (3):

• Make sure to have an increasing PSA during treatment even after discontinuation of anti-androgen

• Testosteron level should be < 20 ng/dL (otherwise performed an orchydectomy or give additional LHRH analogue)

• Start with systemic non-hormonal therapy• Continue with LHRH analogue or perform

bilateral orchydectomy