Optimale Hormontherapie George Thalmann Urologische Universitätsklinik Bern
Apr 06, 2016
PowerPoint-Prsentation
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