1. Hormonal Treatment in Prostate Cancer
Sunaryo Hardjowijoto
Department Urology
Airlangga School of Medicine-Soetomo Hospital
Surabaya
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2. EPIDEMIOLOGY : USA ; 2012: About 241.740 new cases
About will die
2/3 of pts diagnozed in > 65 y old
Rare before 40
About 1 man in 6 has PCa during lifetime
2nd leading cause of cancer death
About 1 man in 36 will die of PCa
(American Cancer Society 2912)
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3. Epidemiology of Prostate Cancer in Indonesia
Prostate cancer is the third most common cancer in male in Indonesia
Ref :
Globocan 2012 (IARC)
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4. Incidence and Mortality rate of prostate cancer in Indonesia
Ref :
Globocan 2012 (IARC)
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5. Clinical Staging of Prostate Cancer
NCCN Guideline Prostate Cancer version
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6. Indonesian Urology Association Guideline (IAUI) 2011
Risiko
Usia
>80 tahun
71-80 tahun
≤ 70 tahun
Rendah:
T: 1a atau 1c dan
Gleason:2-5 dan
PSA: <10 dan
Temuan biopsi:
Unilateral <50%
Monitoring aktif
EBRT atau Brakhiterapi permanen
Terapi investigasional
Prostatektomi radikal
Sedang:
T: 1b, 2a atau
Gleason: 6, atau 3+4 atau
PSA: < 10 atau
Bilateral, <50%
EBRT, Brakhiterapi permanen atau kombinasi
EBRT, Brakhiterapi permanen
atau kombinasi
Tinggi:
T: 2b, 3a, 3b atau
Gleason: ≥ 4+3 atau
PSA: atau
Temuan biopsi: > 50% perineural, duktal
Terapi hormonal
EBRT+terapi hormonal
EBRT+terapi hormonal (2-3 thn)
Prostatektomi radikal + diseksi KGB pelvis
EBRT+ terapi hormonal (2-3 thn)
Sangat tinggi:
T: 4 atau
Gleason: ≥ 8, atau
PSA: > 20, atau
limfovaskuler, neuroendokrin
EBRT+ terapi hormonal
Sistemik terapi non hormonal (kemoterapi)
Terapi sistemik+terapi hormonal
Terapi multimodal investigasional
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Panduan Tatalaksana Kanker Prostat Localized/locally advanced Ikatan Ahli Urologi Indonesia; 2011
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7. HORMONAL THERAPHY OF Ca P
1788 :
John Hunter “The Father of Surgery” Prostate Growth Depended on Testicular Function.
1941 :
Huggins and Hodges Proved the favourable Responsiveness of MCaP to ADT.
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8. Basics of hormonal control of the prostate
Prostate cells are physiologically dependent on androgens to stimulate growth, function and proliferation.
The testes are the source of most androgens (95%) while the adrenal biosynthesis providing only 5-10% of androgens
Testosterone secretion is regulated by the hypothalamic-pituitary-gonadal axis.
Hypothalamic luteinizing hormone-releasing hormone (LHRH) stimulates the anterior pituitary gland to release luteinizing hormone (LH) and follicle-stimulating hormone (FSH).
LH stimulates the Leydig cells of the testes to secrete testosterone. Within the prostate cell, testosterone is converted to 5-α-dihydrotestosterone (DHT) by the enzyme 5-α-reductase; DHT is an androgenic stimulant about 10 times more powerful than testosterone.
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9. Role of Androgen Deprivation Therapy (ADT) in Prostate Cancer
EAU Guidelines Prostate Cancer 2014
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10. MECHANISM of ANDROGEN DEPRIVATION :
Suppressing the secretion of testicular androgen (Castration)
Surgical
Medical
Inhibiting the action of circulating Androgen  by anti Androgen
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11. HORMONAL TREATMENT of Ca P:
INDICATIONS :
Early Ca P unfit for Radical Surgery
Refuse EBRT
Symptomatic advance Ca P (as standard therapy)
T3-4
M 
PSA > 25 ng/mL
Adjuvant/Neoadjuvant for curative therapy
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12. Methods of Hormonal Treatment (Androgen Deprivation Therapy : ADT)
IMMEDIATE/DEFFERED :
Immediate :
For symptomfull patient
Delay clinical progression in symptomless patient
Deffered :
Still controversial
Most cost effective
INTERMITTENT (IAD) VS CONTINOUS
IAD : Delay the emergence of the androgen independent clone
MAB : Preservation of QoL in off treatment periode
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13. Androgen Deprivation Therapy
Bilateral Orchidectomy  Gold standard
Simple procedure
No flare up of androgen
Negative psychological effect
Testoterone castration level ≤ 20 ng/dl
Estrogene
Suppress Leydig cell
Toxic for prostat cell
Diethyl stillestrol 1 mg once daily
Cardiotoxic
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14. Androgen Deprivation Therapy
Luteinizing Hormonal-Releasing hormone (LHRH) agonists
Buserelin
Goserolin ZOLADEX
Leuprorelin
Triptorelin
Depot : 1, 2, 3 and 6 months
Initially stimulate hipophyse LHRH 
 Transient rise of LH and FSH
 Testoteron  (flare up)
 Testoteron  within 2 – 4 weeks
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15. No flare up  immediate suppression of LHRH Receptors
LHRH Antagonists
No flare up  immediate suppression of LHRH Receptors
Serious life threatening side effects
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16. Anti Androgen Steroidal : Non Steroidal : Cyproterone Acetate
NILUTAMIDE
FLUTAMIDE
BICALUTAMID
Central inhibition of hipophise
CASODEX : 150 mg
50 mg
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17. Efficacy of ZOLADEX in Prostate Cancer
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18. UroFiesta 2015

19. ZOLADEX® as adjuvant to radiotherapy in locally advanced A 10-year extensive follow-up data
EORTC 10 years :
Clinical Disease Free Survival in radiotherapy + ZOLADEX® significantly higher compared to radiotherapy alone ( 47.7% vs 22.7%)
Sebagai terapi adjuvan dari radioterapi pada locally advanced prostate cancer, ZOLADEX efektif memperbaiki Disease Free Survival.
Ini ditunjukkan oleh hasil studi dari EORTC (European Organization for Research and Treatment of Cancer) selama 10 tahun, dimana Disease Free Survival pada kelompok radioterapi + ZOLADEX (47.7% )secara signifikan lebih tinggi dibanding hanya radioterapi saja (22.7%).
Bolla M et al. Lancet Oncol 2010;11:
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20. ZOLADEX® demonstrates similar survival to orchiectomy
ZOLADEX® in advanced stage
ZOLADEX® demonstrates similar survival to orchiectomy
ZOLADEX 3.6 mg (n=148)
Orchiectomy (n=145)
ZOLADEX 3.6 mg (n=138)
100
Orchiectomy (n=144)
Patients surviving (%)
100 80 80 60 60 40 40 20 20
p=0.33 24 48 72 96
120
144
168
192 40 80
120
160
200
240
280
320
Untuk meneliti efikasi ZOLADEX pada pasien kanker prostat dengan metastasis, terdapat 2 studi yang dilakukan pada tahun 1990-an. Kaisary et al dan Vogelzang et al melakukan penelitian yang membandingkan ZOLADEX dengan orchiectomy pada pasien dengan metastasis.
Dari kedua studi ini disimpulkan bahwa ZOLADEX dan orchiectomy menghasilkan survival yang serupa. Artinya, ZOLADEX merupakan alternatif yang efektif dari orchiectomy.
Note :
Kaisary et al :
Jumlah populasi studi adalah 292 pasien kanker prostat stadium lanjut yang diacak unutk menerima ZOLADEX 3.6 mg (n=148) atau menjalani orchiectomy (n=144).1
Median follow-up adalah 104 minggu (2 tahun).
Vogelzang et al :
Jumlah populasi studi adalah 283 pasien dimana yang menerima ZOLADEX sebanyak 138 pasien, sedangkan grup orchiectomy sebanyak 145 pasien. Masa follow up minimal selama 4 tahun.
References:
1Kaisary AV, Tyrrell CJ, Peeling WB et al. Comparison of LHRH analogue (Zoladex) with orchiectomy in patients with metastatic prostatic carcinoma. Br J Urol 1991; 67:
2Vogelzang NJ, Chodak GW, Soloway MS et al. Goserelin versus orchiectomy in the treatment of advanced prostate cancer: final results of a randomized trial. Zoladex Prostate Study Group. Urology 1995; 46:
Time (weeks)
Time (weeks)
Kaisary et al (1991)
Vogelzang et al (1995)
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21. ZOLADEX ® reduces testosterone level faster and stronger than leuprolide
90%
66%
33%
ZOLADEX ®
Leuprolide
Leuprolide
ZOLADEX® lebih cepat dan lebih kuat dalam menurunkan kadar testosteron
Pada suatu penelitian head-to-head antara ZOLADEX® dan leuprolide dengan end-point kadar testosteron setelah minggu ke-6 dan ke-12, ternyata kelompok yang diterapi dengan ZOLADEX® lebih banyak yang mengalami penurunan kadar testosteron hingga >90% dari baseline.
Sejak minggu ke-6, sebanyak 80% dari grup ZOLADEX® mengalami penurunan testosteron hingga >90% dari kadar testosteron baseline. Sedangkan grup leuprolide hanya 33% yang mengalami penurunan serupa.
Setelah minggu ke-12, sebanyak 90% dari grup ZOLADEX® mengalami penurunan kadar testosteron > 90%. Namun, pada grup leuprolide hanya 66%.
Ref:
Sood R. Jain V. Urology 2006; 68 (suppl 5A):199
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22. Efficacy of CASODEX® in Prostate Cancer
Content : BICALUTAMIDE
Non steroidal anti androgen
Available in :
Tablet : 150 mg  as monotheraphy
50 mg  in part of CAB
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23. Advise effect of anti androgen:
Liver toxic
Gynecomastia
Breast pain
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24. Iversen P et al. J Urol 2000; 164: 1579-1582.
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25. UroFiesta 2015

26. Adapted form EAU guidelines 2014
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27. 115119/Jul 2015
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28. Complete Androgen Blockade significantly improves quality of life
Selain dari segi efikasi dalam meningkatkan overall survival, CAB juga dapat memperbaiki kualitas hidup pasien.
Dari evaluasi pada minggu ke-5 setelah terapi, pasien yang diberi terapi CAB secara signifikan mengalami penurunan gejala-gejala yang berkaitan dengan kanker prostat.
Pada kelompok CAB, lebih banyak pasien yang mengalami perbaikan gejala nyeri dan sering berkemih dibandingkan kelompok monoterapi.
Ref :
Yoichi Arai et al. J Cancer Res Clin Oncol :
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29. Advers Effects of ADT Loss of Libido Erectile Dysfunction
Hot-flashes (50 – 80%)
Gynaecomastia/breast pain
Fatty
Muscle wasting
Anemia (13%)
Bone Mineral Density 
Cognitive decline (DES)
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30. SUMMARY
Prostate cancer is one of the most common cancer in male population in Indonesia.
Clinical and histopathological staging is important to determine recurrence risk and treament modality.
Androgen Deprivation Treatment is the most common treatment in high risk or very high risk patients.
Complete Androgen Blockade is significantly more effective in improving overall survival than LHRHa monotherapy.
ZOLADEX ® is faster and stronger than leuprolide in supressing testosterone level.
In locally advanced prostate cancer, CASODEX® 150 mg monotherapy is as effective as castration with maintained patients’ sexual function.
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31. THANK YOU
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