Hormonal Manipulations in Early Prostate Cancer

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Hormonal Manipulations in Early Prostate Cancer

  1. Hormonal Manipulations in Early Prostate CancerDr T. RajaConsultant Medical Oncology,Apollo Speciality Hospital,Chennai
  2. Prostate Cancer Continuum Localised prostate Locally Metastatic Hormone High-grade PIN cancer advanced disease insensitive TxN0M0 T3-4 D1.5 D2 D2.5 D3Time (years) PIN, prostatic intraepithelial Neoplasia
  3. Treatment for Prostate Cancer Localised prostate Locally Metastatic Hormone High-grade PIN cancer advanced disease insensitive TxN0M0 T3-4 D1.5 D2 D2.5 D3 Time (years)Treatment options: Radical Hormonal therapy prostatectomy Chemotherapy Radiotherapy ‘Watchful waiting’ Radiotherapy Hormonal therapy ‘Watchful waiting’ PIN, prostatic intraepithelial neoplasia
  4. Testosterone suppression with ‘Zoladex’ (goserelin)Mean 18 ‘Zoladex’ (goserelin) 3.6 mg (n=42)testosterone 16 ‘Zoladex’ (goserelin) 10.8 mg (n=38)concentration(nmol/L) 14 12 10 8 6 4 Upper castrate limit 2 0 0 4 8 12 16 20 24 26 28 32 36 40 44 Time (weeks) Dijkman et al 1995
  5. Rationale for combination therapy Androgens ACTH ‘Casodex’ (bicalutamide) Adrenal glandLHRH Hypothalamus DHT X Other ‘Zoladex’ target (goserelin) tissues Pituitary gland Androgen DHT receptor Testis Prostate cell LH Circulating testosterone -ve feedback control
  6. Topics for DiscussionLAPC: Neo-adjuvant to RP Adjuvant to RP Adjuvant to RT (Long Term Data & Duration) LHRH analogue: Approved indications in Prostate Cancer
  7. ‘Zoladex’ (goserelin) Neo-adjuvant to Radical Prostatectomy Clinical down-staging and downsizing Fourcade et al 1993 Clinical down-staging and significantly Montironi et al 1999 fewer positive margins Bono et al 2001 PROSIT Significantly fewer positive margins and Meyer et al 1999 reduction in risk of PSA failure No difference in PSA progression Witjes et al 1998PSA, prostate-specific antigen
  8. Topics for DiscussionLAPC: Neo-adjuvant to RP Adjuvant to RP Adjuvant to RT (Long Term Data & Duration) LHRH analogue: Approved indications in Prostate Cancer
  9. ‘Zoladex’ (goserelin) adjuvant to radical prostatectomy the LHRH agonist that is… proven to haveSignificant improvement in Messing et al 1999, 2003overall and disease-free ECOG 7887survival Prayer-Galetti et al 2000Significant improvement indisease-free survivalECOG, Eastern Co-operative Oncology Group
  10. ECOG 7887 trial: study design Radical prostatectomy + lymph node dissection (n=98) Randomised Immediate hormonal therapy Observation until (70% ‘Zoladex’ [goserelin], progression 30% bilateral orchiectomy) (n=51) (n=47)Messing et al 1999, 2003
  11. ECOG 7887 trial: long-term survival p=0.001Patients100 87.2(%) p=0.025 80 72.4 Median follow- 60 56.9 up 10 years 49 40 All patients 20 were high risk at baseline (T1- 0 2, N+) Overall survival Cause-specific survival Radical prostatectomy + ‘Zoladex’ (goserelin) / orchiectomy (n=47) Radical prostatectomy only (n=51)Messing et al 2003
  12. Topics for DiscussionLAPC: Neo-adjuvant to RP Adjuvant to RP Adjuvant to RT (Long Term Data & Duration) LHRH analogue: Approved indications in Prostate Cancer
  13. LAPC: Adjuvant to RT RTOG 85-31 significantly reduced risk of; – local failure – distant metastasis  significantly prolonged; – disease-free survival – overall survival The long-term results:RTOG 92-02 • 24 months of ADT after total androgen suppression and RT is superior to total androgen suppression and RT alone
  14. LAPC: Adjuvant to RT (EORTC 22863)
  15. EORTC 22863 StudyStudy Open label, randomized (1:1) phase III trial 26 centres Primary endpoint:Patients • Disease Free Survival < 80 years of age Secondary endpoint: PS: 0-2 • Overall Survival Newly diagnosed • Distant MFS Stage: • Cause Specific Mortality – T1-2, WHO grade 3 • Locoregional Control – T3-4 of any gradeHistological confirmed primary adeno-carcinoma
  16. EORTC 22863 StudyEnrollment begin with 1987 to 1995
  17. PFS: Sites of Disease Progression
  18. Distant-Metastasis-Free Survival (at 10 years) Combined Rx Group RT Group 51% 30·2% (95% CI 42·3–59·1) (95% CI 23·1–37·6)HR 0·50, 95% CI (0·38–0·65); (p<0·0001)
  19. 58.1% 39.8%
  20. Overall Survival at 10 years (HR 0·56, 95% CI 0·41–0·75; p=0·0001)
  21. Prostate Cancer Mortality: 10 yrs follow-up 30.4% 10.3%
  22. Locoregional failure rate at 10 years (HR 0·21, 95% CI 0·12–0·40; p<0·0001) 23.5% 6.0%
  23. Zoladex 10.8mg – Approved Indications in Prostate Cancer In the treatment of metastatic prostate cancer where Zoladex has demonstrated comparable survival benefits to surgical castrations In the treatment of locally advanced prostate cancer, as an alternative to surgical castration where Zoladex has demonstrated comparable survival benefits to an anti-androgen As adjuvant treatment to radiotherapy in patients with high-risk localised or locally advanced prostate cancer where Zoladex has demonstrated improved disease-free survival and overall survival As neo-adjuvant treatment prior to radiotherapy in patients with high-risk localised or locally advanced prostate cancer where Zoladex has demonstrated improved disease-free survival As adjuvant treatment to radical prostatectomy in patients with locally advanced prostate cancer at high risk of disease progression where Zoladex has demonstrated improved disease- free survival Ref : Zoladex 10.8mg – Summary of Product Characteristics
  24. Leuprolide in Prostate Cancer Clinical Data  In a randomised, open-label, multi-centre comparative trial, leuprorelin in combination with flutamide has been shown to significantly improve DFS and OS when used as an adjuvant therapy to RT in 88 patients with high-risk localised (T1-T2 and PSA of at least 10 ng/mL or a Gleason score of at least 7), or locally advanced (T3- T4) prostate cancerRef : Prostap 3 Leuprorelin Acetate Depot Injection 11.25mg - Summary of Product Characteristics
  25. Leuprolide neoadjuvant / adjuvant to RT: post-RT PSA levels RT alone (n=41)PSA level 2 Leuprolide / flutamide before RT (n=43)ng/mL Leuprolide / flutamide before and after RT (n=36) 1.56 1.20 1 0.60 0.65 0.5 0.2 0 12 24 Time post-radiotherapy (months) Laverdière et al 1997
  26. Leuprorelin Acetate Depot Injection 11.25mg – Approved Indications in Prostate Cancer  Metastatic prostate cancer  Locally advanced prostate cancer, as an alternative to surgical castration.  As an adjuvant treatment to radiotherapy in patients with high-risk localised or locally advanced prostate cancer.  As an adjuvant treatment to radical prostatectomy in patients with locally advanced prostate cancer at high risk of disease progression Ref : Prostap 3 Leuprorelin Acetate Depot Injection 11.25mg - Summary of Product Characteristics
  27. Urology. 2011 Nov;78(5 Suppl):S494-8.Dreicer R, Bajorin DF, McLeod DG, Petrylak DP, Moul JW  The luteinizing hormone-releasing hormone agonists resulted in a periodic return of noncastrate testosterone levels once the receptor desensitization attenuated and the effect of androgen agonism resumed.
  28.  Therefore, the introduction of an androgen receptor antagonist (gonadotropin-releasing hormone antagonist) appeared, conceptually at least, to be a preferable alternative. The first such agent, degarelix, has proved to provide rapid testosterone suppression without the initial testosterone surge associated with luteinizing hormone-releasing hormone agonists.
  29. GnRH Antagonists – Mechanism of Action
  30. GnRH Receptor Antagonists Dagerelix Degarelix(FIRMAGON) is a gonadotrophin releasing hormone (GnRH) antagonist indicated for treatment of adult male patients with advanced hormone-dependent prostate cancer Starting Dose : 240 mg administered as two subcutaneous injections of 120 mg each Maintenance Dose ( Monthly) : 80 mg administered as one subcutaneous injection 96% of patients had T supression (T˂ 0.5ng/ml) within 3 days of starting dose and 100% after 1 month Long term treatment & maintenance dose upto 1 year has shown that 97% of patients had sustained T supression (T˂0.5ng/ml) Advantage : Since degarelix does not induce a testosterone surge it is not necessary to add an anti-androgen as surge protection at initiation of therapy Ref : Firmagon – Summary of Prescribing Information
  31. Other new agents A selective and irreversible inhibitor of CYP17, abiraterone, MDV3100, a novel small molecule that acts as an oral nonsteroidal antiandrogen agent.
  32. Current and Future Hormonal Therapy Drugs UROLOGY 78: S494–S498, 2011
  33. NCCN Guidelines Version 3.2012 ADT based on Recurrence risk Low risk: T1-T2a, Gleasons <=6, PSA <10 No treatment Intermediate risk: T2b-T2c, Gleason >=7, PSA 10-20 ADT 4-6m0s High risk: T3a, Gleasons 10, PSA >20 ADT 4-6mos Locally advancee: T3b-T4 ADT 2-3yrs
  34. Thank You for your attention

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