GnRH-Antagonisten – eine neue Therapieoption beim fortgeschrittenen Prostatakarzinom

Zusammenfassung

Die medikamentöse Kastration mit LHRH-Agonisten (luteinisierendes Hormon Releasing Hormon) gilt als Therapie der Wahl für Patienten mit fortgeschrittenem Prostatakarzinom. LHRH-Agonisten unterdrücken die Testosteronsynthese und senken die Serum-Testosteron-Spiegel auf Kastrationsniveau. Der Vorteil gegenüber der Orchiektomie ist, dass die medikamentöse Kastration reversibel ist. Ein Nachteil der LHRH-Agonisten ist, dass es nach Therapiebeginn initial zu einem vorüber­gehenden Anstieg des Serum-Testosteron-Wertes kommt. Dieser sog. Testosteron-Surge erhöht nicht nur das Risiko des unerwünsch­ten Tumorwachstums, sondern kann auch dazu ­führen, dass krankheitsbedingte Beschwerden zunehmen (Flare-Phänomen). Nicht ausgeschlossen ist eine Verschlechterung der Gesamtüber­lebenszeit betroffener Patienten. Mit den GnRH-Antagonisten, auch GnRH-Blocker genannt, steht eine neue endokrine Therapieoption zur Ver­fügung. Gegenüber den LHRH-Agonisten haben die Antagonisten den Vorteil, dass sie keinen Testosteron-Surge induzieren. Der Testosteronspiegel im Serum sinkt innerhalb weniger Tage nach Therapiebeginn deutlich und anhaltend ab – ähnlich, wie dies von der Orchiektomie bekannt ist.

Abstract

At present medical castration employing luteinis­ing hormone releasing hormone (LHRH) agonists is the standard of care for patients with advanced prostate cancer. LHRH agonists suppress the synthesis of testosterone to a castration level. In contrast to surgical castration, medical castration is reversible. However LHRH agonists induce an initial increase of the testosterone level. This so-called testosterone surge leads to tumour growth and increases the disease-specific complaints, known as flare phenomena. It may be possible that the overall survival of these patients is deteriorated. In contrast, gonado­trophin releasing hormone (GnRH) antagonists do not induce a testosterone surge and the level of testosterone decreases as rapidly as that known from a surgical castration.

Prostatakarzinom - LHRH-Agonisten - GnRH-Antagonisten - GnRH-Blocker - Testosteron-Surge - Flare-Phänomen

prostate cancer - LHRH agonists - GnRH antagonists - GnRH-blocker - testosterone surge - flare phenomena

Literatur

• 1 van Poppel H, Nilsson S. Testosterone surge: Rationale for gonadotropin-releasing hormone blockers?.  Urology. 2008;  71 1001-1006
• 2 Bubley G J. Is the flare phenomenon clinically significant?.  Urology. 2001;  58 (2 suppl 1) 5-9
• 3 Thompson I M, Zeidman E J, Rodriguez F R. Sudden death due to disease flare with luteinizing hormone-releasing hormone agonist therapy for carcinoma of the prostate.  J Urol. 1990;  144 1479-1480
• 4 Heidenreich A, Aus G, Bolla M et al. EAU guidelines on prostate cancer.  Eur Urol. 2008;  53 68-80
• 5 Ohuchi H, Noguchi K, Kinoshita Y et al. Inhibition of disease flare with diethylstilbestrol diphosphate and chlormadinone acetate administration for two weeks prior to slow-releasing leuprolide acetate in prostatic cancer patients.  Hinyokika Kiyo. 2000;  46 531-536
• 6 Appu S, Lawrentschuk N, Grills R J et al. Effectiveness of cyproterone acetate in achieving castration and preventing luteinizing hormone ­releasing hormone analogue induced testosterone surge in patients with prostate cancer.  J Urol. 2005;  174 140-142
• 7 Kuhn J M, Billebaud T, Navratil H et al. Prevention of the transient adverse effects of a gonadotropin-releasing hormone analogue (buserelin) in metastatic prostatic carcinoma by administration of an anti­androgen (nilutamide).  NEJM. 1989;  321 413-418
• 8 Eligard A. Eligard Prescribing Information. Bridgewater, NJ, Sanofi-Aventis 2006
• 9 Seidenfeld J, Samson D J, Hasselblad V et al. Single-therapy androgen suppression in men with advanced prostate cancer: a systemic review and meta-analysis.  Ann Intern Med. 2000;  132 566-577
• 10 Sasagawa I, Kubota Y, Nakada T et al. Influence of luteinizing hormone-releasing hormone analogues on serum levels of prostatic acid phosphatise and prostatic specific antigen in patients with metastatic carcinoma of the prostate.  Int Urol Nephrol. 1998;  30 745-753
• 11 Lin B J, Chen K K, Chen M T et al. The time for serum testosterone to reach castrate level after bilateral orchiectomy or oral estrogen in the management of metastatic prostatic cancer.  Urology. 1994;  43 834-837
• 12 Denmeade S R, Tombal B, Isaacs J T. Apoptotic pathways in prostate cancer. In: Mattson MP et al., Hrsg. Programmed Cell Death, Vol. II, Amsterdam: Elsevier Sciences; 2001: 23–54
• 13 McLeod D, Zinner N, Tomera K et al. A phase 3, multicenter, open-label, randomized study of abarelix versus leuprolide acetate in men with prostate cancer.  Urology. 2001;  58 756-761
• 14 Morote J, Esquena S, Abascal J M et al. Failure to maintain a suppressed level of serum testosterone during long-acting depot luteinizing hormone-releasing hormone agonist therapy in patients with advanced prostate cancer.  Urol Int. 2006;  77 135-138
• 15 Jocham D. Leuprorelin three-month depot in the treatment of advanced and metastatic prostate cancer: long-term follow-up results.  Urol Int. 1998;  60 (suppl 2) 18-24
• 16 Khan M S, O’Brien A. An evaluation of pharamacokinetics and pharmacodynamics of leuprorelin acetate 3M-depot in patients with advanced and metastatic carcinoma of the prostate.  Urol Int. 1998;  60 33-40
• 17 Fontana D, Mari M, Martinelli A et al. 3-month formulation of goserelin acetate in advanced prostate cancer: results from an Italian, open, multicenter trial.  Urol Int. 2003;  70 316-320
• 18 Anderson J, Abrahamsson P -A, Crawford D et al. Management of advanced prostate cancer: can we improve on androgen deprivation therapy?.  BJU International. 2008;  101 1497-1501
• 19 Morote J, Planas J, Raventos C X et al. Redefining clinically significant castration levels in patients with prostate cancer receiving continuous androgen deprivation therapy.  J Urol. 2007;  178 1290-1295
• 20 Tomera K, Gleason D, Gittelman M et al. The gonadotropin-releasing hormone antagonist Abarelix depot versus luteinizing hormone releasing hormone agonists leuprolide or goserelin: initial results of ­endocrinological and biochemical efficacies in patients with prostate cancer.  J Urol. 2001;  165 1585-1589
• 21 Trachtenberg J, Gittelman M, Steidle C et al. A phase 3, multicenter, open label, randomized study of Abarelix versus leuprolide plus daily antiandrogen in men with prostate cancer.  J Urol. 2002;  167 1670-1674
• 22 Gittelmann M, Pommerville P, de la Rosette J et al. Degarelix: a gonadotropin-releasing hormone receptor (GnRH) blocker. Tested in two one-year multicenter, randomized, does-finding studies in prostate cancer patients.  Proc ASCO, JCO. 2006;  24 (suppl) 14516 a-14516a
• 23 Klotz L, Boccon-Gibod L, Shore N D et al. The efficacy and safety of ­dega­relix: a 12-month, comparative, randomized, open-label, parallel-group phase III study in patients with prostate cancer.  BJU inter­national. 2008;  102 1531-1538