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Optimale HormontherapieGeorge ThalmannUrologische Universittsklinik Bern

Charles B. Huggins

1.00.80.60.40.20.00123456YearsProbability of SurvivalEstradurin versus combined androgen deprivationTreatmentcombined androgen blockaden = 455parenteral estrogen n = 455Scandinavian Prostatic Cancer Group (SPCG) Study No. 5, Scand J Urol Nephrol 36:405-413, 20020022-5347/02/1672-0535/0 The Journal of Urology Vol. 167, 535-538, February 2002 Copyright 2002 by American Urological Association, Inc Printed in U.S.A. DIETHYLSTILBESTEROL REVISITED: ADROGEN DEPRIVATION, OSTEOPOROSIS AND PROSTATE CANCER

DOUGLAS SCHERR, W. REID PITTS, JR. AND E. DARRACOTT VAUGHAN, JR.

From the Department of Urology, The New York Presbyterian Hospital-Cornell Medical Center, New York, New YorkResults: There was a statistically significant (p < 0.05) higher level of urinary N-telopeptides/ creatinine in patients on androgen deprivation therapy who were not treated with diethylstil-besterol. The estrogenic effect of diethylstilbesterol protects one from bone resorption.

CONCLUSIONS

DES provides a safe, efficacious and time-tested treatment for prostate cancer. It not only provides clinically significant androgen deprivation, but it also likely has direct antitumor activity that is not otherwise present with conventional LHRH agonist therapy.6Ablegen unter Stammdateien PCa DES + Bone

PATCH

Prostate Adenocarcinoma: TransCutaneous HormonesA randomised-controlled trial of transcutaneous oestrogen patches versus LHRH analogues in prostate cancer.RANDOMISATIONControl Arm

Investigational Arm

LHRH analogues given as per local practice indefinitelyTranscutaneous Oestrogen Patches Induction Regimen 3 patches changed twice weekly for 4 weeksMaintenance regimen 2 patches changed twice weekly indefinitelyLancet Oncol 2013; 14: 306168010060402000510 yearsAndrogensuppression onlyAndrogen suppression + anti-androgen25.4%1.8% SD 1.3 alive%5.5%6.2%0.7% SD 1.1 (logrank2p > 0.1; NS)PROSTATE CANCER

8000 men in 27 trials of anti-androgen (nilutamide, flutamide orcyproterone acetate)Meta-Analyse Hormontherapie vs maximale Hormontherapie (n=27)23.6%Lancet 2000; 355: 1491-88MetaanalyseMAB 1999SWOG 8894 / Intergroup 105Orchiectomy + FlutamideOrchiectomy + PlaceboOrchiectomy+ Flutamide

PSA normalized69% 81%0.01

Median time to progression 36 mo 49 mo0.03 (good risk pts)

Overall survival51 mo52 mo N.S. (good risk pts)p - valuePSA is not an appropriate surrogate endpoint for survival9LNCaP und C4-2 Zellen und BicalutamidePSA mRNA ExpressionPSA Protein Expression 00.250.50.7511.251.51.7520244872hOD (570 nm)10 mmol100 mmol1000 mmolControl00.250.50.7511.251.51.7520244872OD (570 nm)10 mmol100 mmol1000 mmolControlPSA mRNA ExpressionPSA Protein Expression Peternac D, Thalmann GN et al. J Urol 2006, The Prostate 2008Bicalutamide (150 mg) versus Placebo for Prostate Cancer, SPCG - 6, EPC TrialP. Iversen et al., J. Urol., 172:1871-1876, 2004Proportion survivingTime to death (years)HR 1.47; 95% Cl 1.06, 2.03Fig. 2. Kaplan-Meier curve shows overall survival in patients with localized disease receiving 150 mg bicalutamide in addition to standard care vs standard care alone.1.00.80.60.40.20.001234567Bicalutamide 150 mgPlacebo811Prudenza! Influsso pubblicit marketing!Stammdatei: PCaDatei: RX_+_-_Hormones

LHRH-Antagonisten ?Schnelleres Erreichen von Kastrationswerten

Metaanalysen suggerieren ein besseres kardiovaskulres Risikoprofil

Metaanalyse (n=5) besseres bPFS und OS

ABER:

pooled data analysis

Heterogene Populationen

Unterschiedliche Dosierungen

Grosse prospektive Studien notwendig

Schmerzhafte Injektionsstelle

T. Kimura et al., Urologic Oncology: Seminars and Original Investigations 33 (2015) 322328 Immediate n = 469Deferred * n = 465p < 0.2, immediate v. deferred

* 29 pts died from P'Ca before treatment was startedwith courtesy from Prof. D. Kirk, GlasgowTime to death from any cause - all patients, by randomisation group1007550250Percent alive0

4694651

4304302

3583493

2802604

2072075

1521366

103 857

73528

40279

231510

11 5At risk:immediate deferredYears since randomisationSofortige vs. Verzgerte Therapie:MRC Trial: locally advanced or metastatic P'Ca13Prof. D. Kirk, GlasgowV/2Immediate n = 256Deferred n = 244p < 0.0001, immediate v. deferredwith courtesy from Prof. D. Kirk, GlasgowTime to distant disease progression, or death from prostate cancer - patients entered as non metastatic (M0), by randomisation group.10075502500

2562441

2372012

2061563

1651184

125 925

86646

59387

38228

20139

12 910

72Years since randomisationPercent without relevant eventAt risk:immediate deferredSofortige vs. Verzgerte Therapie:MRC Trial: locally advanced or metastatic P'Ca14Prof. D. Kirk, GlasgowV/1Immediate vs deferred Treatment for asymptomatic P Ca patients To-4, No-2, MoNot suitable for local treatment with curative intent (EORTC trial 30891)1002 patients, median age 74 yearsT2 disease 35%, T3-4 disease 45%N pos 5%Cardiovascular comorbidity 35%PSA median 12.7 (0.1 1306)After a median follow-up 6.4 years: 50% died

Updated results with 12.9 years of median follow-up

Patients with newly diagnosed untreated asymptomatic T0-4 N0-2 M0(UICC 1982)PCanot suitable for local treatment with curative intentRDeferred* orchiectomyor depot LH-RH N=493*Treatment starts upon events of symptoms from metastases, ureteric obstruction or decrease > of WHO performance status. Not for only rise in PSA, new hot spots or asymptomatic mets

Immediate orchiectomyor depot LH-RHN=492

Trial design and objectives(years)024681012141618200102030405060708090100ONNumber of patients at risk :Treatment373492428362289226159793561396493433336250187115482560ImmediateDeferred26.2% (CI: 22.2-30.4%)37.4%(CI: 32.9-41.9%)

Overall survivalWer profitiert von sofortiger Hormontherapie?PSA > 50 ng/ml

PSADT < 12 Monate(years)024681012141618200102030405060708090100ONNumber of patients at risk :Treatment133492428362289226159793561136493433336250187115482560Immediate (P Ca)Deferred (P Ca)21.0% (CI: 17.3-24.7%)22.2% (CI: 18.4-25.9%)Deferred/immediateHR=1.17 (95%CI: 0.92-1.49) P=0.19Prostatakarzinom Mortalitt(years)024681012141618200102030405060708090100ONNumber of patients at risk :Treatment240492428362289226159793561260493433336250187115482560ImmediateDeferred37.8% (CI: 33.4-42.1%)42.5% (CI: 38.1-47.0%)HR= 1.23 (CI: 1.03, 1.47)P (difference)=0.021Andere Ursachen MortalittZeit bis zur objektiven Progression bei sofortiger oder verzgerter HormontherapieImmediate ADT first objective = ADT refractory progDeferred ADT first objective progression = Hormone SENSITIVEHR to immediate= 1.76 (CI: 1.43-2.17) P0.004AFFIRM StudyScher HI et al., N Engl J Med. 2012 Sep 27;367(13):1187-97.49

ConclusionsEnzalutamide significantly decreased the risk of radiographic progression and death and delayed the initiation of chemotherapy in men with metastatic prostate cancer.N Engl J Med 2014;371:424-33.

PREVAIL Studie

PREVAIL Studie

Moderate aber statistisch signifikante Verbesserung des allgemeinen berlebens mit sofortiger Hormontherapie

Keine signifikante Differenz bzgl. PCA Mortalitt und symptomfreies berleben.

Oestrogene knnten wieder attraktiv werden

Primre Hormontherapie kombiniert mit Strahlentherapie

Kombinierte Hormonochemotherapie auf dem Vormarsch

Gute ZweitlinienhormontherapienSchlussfolgerungenDanke fr Ihre Aufmerksamkeit

Testosterone Loss and Estradiol Administration Modify Memory in Men

Tomasz M. Beer, Lisa B. Bland, Joseph R. Bussiere, Michelle B. Neiss, Emily M. Wersinger,Mark Garzotto, Christopher W. Ryan and Jeri S. JanowskyFrom the Department of Medicine,, Division of Hematology and Medical Oncology (TMB, EMW, CWR), and Department of Behavioral Neuroscience (JRB, MBN, JSJ), Oregon Health and Science University, and Division of Urology, Oregon Health and Science University and Portland Veterans Affairs Medical Center (LBB, MG), Portland, OregonConclusions: Sex steroid loss and replacement have effects on specific cognitive processes in older men. Furthermore, estrogen has the potential to reverse the neurotoxic effects on memory Performance caused by androgen deprivation.J. Urol., 175:130-135, 2006Androgen Deprivation Side effects

M+M+AlleAlleTucci M et al. Eur Urol in presssOverall Survival