Hormonal Treatment in Prostate Cancer Sunaryo Hardjowijoto Department Urology Airlangga School of Medicine-Soetomo Hospital Surabaya UroFiesta 2015 UROFIESTA 2015

EPIDEMIOLOGY : USA ; 2012: About 241.740 new cases About 28.170 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) UroFiesta 2015

Epidemiology of Prostate Cancer in Indonesia Prostate cancer is the third most common cancer in male in Indonesia Ref : Globocan 2012 (IARC) UroFiesta 2015

Incidence and Mortality rate of prostate cancer in Indonesia Ref : Globocan 2012 (IARC) UroFiesta 2015

Clinical Staging of Prostate Cancer NCCN Guideline Prostate Cancer version 1 2014 UroFiesta 2015

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: 10-20 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 UroFiesta 2015 Panduan Tatalaksana Kanker Prostat Localized/locally advanced Ikatan Ahli Urologi Indonesia; 2011 UROFIESTA 2015

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. UroFiesta 2015

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. UroFiesta 2015

Role of Androgen Deprivation Therapy (ADT) in Prostate Cancer EAU Guidelines Prostate Cancer 2014 UroFiesta 2015

MECHANISM of ANDROGEN DEPRIVATION : Suppressing the secretion of testicular androgen (Castration) Surgical Medical Inhibiting the action of circulating Androgen  by anti Androgen UroFiesta 2015

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 UroFiesta 2015

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 UroFiesta 2015

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 UroFiesta 2015

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 UroFiesta 2015

No flare up  immediate suppression of LHRH Receptors LHRH Antagonists No flare up  immediate suppression of LHRH Receptors Serious life threatening side effects UroFiesta 2015

Anti Androgen Steroidal : Non Steroidal : Cyproterone Acetate NILUTAMIDE FLUTAMIDE BICALUTAMID Central inhibition of hipophise CASODEX : 150 mg 50 mg UroFiesta 2015

Efficacy of ZOLADEX in Prostate Cancer UroFiesta 2015

UroFiesta 2015

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;11:1066-73 UroFiesta 2015 UROFIESTA 2015

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: 502-508. 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: 220-226. Time (weeks) Time (weeks) Kaisary et al (1991) Vogelzang et al (1995) UroFiesta 2015 UROFIESTA 2015

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 UroFiesta 2015 UROFIESTA 2015

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 UroFiesta 2015

Advise effect of anti androgen: Liver toxic Gynecomastia Breast pain UroFiesta 2015

Iversen P et al. J Urol 2000; 164: 1579-1582. UroFiesta 2015

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Adapted form EAU guidelines 2014 UroFiesta 2015

115119/Jul 2015 UroFiesta 2015

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 2008. 134:1385-1396 UroFiesta 2015 UROFIESTA 2015

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) UroFiesta 2015

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. UroFiesta 2015

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