Hormontherapie des Prostatakarzinoms - Übersicht und aktueller Stand

Zusammenfassung

Das Prostatakarzinom (PC) ist in der westlichen Welt der häufigste bösartige Tumor des Mannes. Durch die Einführung des PSA-Screenings wird das es zunehmend in potenziell kurablen Tumorstadien diagnostiziert. Dennoch kommt es nach kurativer Therapie innerhalb von 15 Jahren in bis zu 50 % zu einem erneuten Anstieg des PSA-Wertes und im Median nach weiteren 8 Jahren in 34 % zu einer Metastasenbildung. Beim systemischen Rezidiv ist die Hormontherapie die wichtigste palliative Maßnahme. Sie wird ebenfalls als Primärtherapie und in Kombination mit anderen Therapieformen eingesetzt. Die verschiedenen Methoden der Kastration (chirurgisch, medikamentös) sind vom Gesamtüberleben her vergleichbar. Die heutzutage für die medikamentöse Kastration eingesetzten LH-RH-Agonisten haben typische Nebenwirkungen in Form von Impotenz (69 %), Hitzewallungen (56,5 %), Gynäkomastie (24,9 %) und Osteoporose. Initial führen LH RH-Agonisten zu einem passageren Serum-Testosteronanstieg (Flare-Phänomen). Dies kann durch LH-RH-Antagonisten vermieden werden, die in Europa noch nicht zugelassen ist. Eine weitere Medikamentengruppe sind die Antiandrogene, die ein günstigeres Nebenwirkungsprofil als die Formen der Kastration besitzen. Das Antiandrogen Bicalutamid führt beim lokal fortgeschrittenen PC, adjuvant zur Radiatio verabreicht, zu einer Überlebensverlängerung, nicht aber bei der Gabe nach radikaler Prostatektomie oder bei Versagen einer „Watchful-waiting”-Strategie. Beim metastasierten PC sind Antiandrogene der Kastration im Gesamtüberleben statistisch signifikant unterlegen. Die Bedeutung der maximalen Androgenblockade (Kombination aus Kastration und Antiandrogen) wird anhaltend kontrovers diskutiert. Sie bietet beim metastasierten PC einen geringen Überlebensvorteil von wenigen Monaten bei deutlicher Zunahme der Nebenwirkungen.

Summary

Prostatic cancer (PC) heads the list of malignant tumors in the male. Resulting from the introduction of prostatic-specific antigen (PSA) screening there has been a shift towards potentially curable tumor stages. However, after curative treatment a rise in PSA has been noted in up to 50 % of cases within 15 years. Metastases are then reported in up to 34 % within the subsequent eight years. Hormonal therapy represents the most important palliative measure in metastatic PC and is also used in primary, adjuvant and neo-adjuvant hormonal treatment. The different methods of castration (orchidectomy, medical castration) are equivalent in respect of overall survival. The side effects of agonists of luteinizing-hormone-releasing hormone (LHRH) are impotence (69 %), hot flushes (56.5 %), gynecomastia (24.9 %) and osteoporosis and may initially cause a transitory increase in serum testosterone (flare phenomenon). This can be counteracted by an LHRH antagonist (not available in Europe). Anti-androgens do not lead to testosterone suppression and have a more favorable profile of side effects. Bicalutamide significantly improves overall survival rate in patients receiving radiotherapy. However, overall survival rate is not improved in patients after radical prostatectomy or under watchful waiting. Bicalutamide alone is less efficacious than castration in patients with metastases. The use of maximal androgen blockade (combination of castration and anti-androgen) remains controversial. It seems to produce a modest overall and cancer-specific increase in survival rate but is associated with increased adverse events and a reduced quality of life.

Schlüsselwörter

Prostatakarzinom - Hormontherapie - Kastration - maximale Androgenblockade - Flare - Phänomen

Key words

prostate cancer - hormone therapy - castration - maximal androgen blockade - flare phenomenon

Literatur

• 1 Bolla M, Collette L, Blank L. et al . Long-term results with immediate androgen suppression and external irradiation in patients with locally advanced prostate cancer (an EORTC study): a phase III randomised trial.  Lancet. 2002;  360 103-106
• 2 Bubley G J. Is the flare phenomenon clinically significant?.  Urology. 2001;  58 5-9
• 3 Byar D P, Corle D K. Hormone therapy for prostate cancer: results of the Veterans Administration Cooperative Urological Research Group studies.  NCI Monogr. 1988;  7 165-170
• 4 Catalona W J, Smith D S, Ratliff T L. et al . Measurement of prostate-specific antigen in serum as a screening test for prostate cancer.  N Engl J Med. 1991;  324 1156-1161
• 5 Culig Z, Hobisch A, Bartsch G. et al . Androgen receptor - an update of mechanisms of action in prostate cancer.  Urol Res. 2000;  28 211-219
• 6 Denis L J, Carnelro de Moura J L, Bono A. et al . Goserelin acetate and flutamide versus bilateral orchiectomy: a phase III EORTC trial (30853): EORTC GU Group and EORTC Data Center.  Urology. 1993;  42 119-129
• 7 Eisenberger M A, Blumenstein B A, Crawford E D. et al . Bilateral orchiectomy with or without flutamide for metastatic prostate cancer.  N Engl J Med. 1998;  339 1036-1042
• 8 Grossfeld G D, Chang J J, Broering J M. et al . Under staging and under grading in a contemporary series of patients undergoing radical prostatectomy: results from the Cancer of the Prostate Strategic Urologic Research Endeavor database.  J Urol. 2001;  165 851-856
• 9 Huggins C B, Hodges C V. Studies on prostate cancer: The effects of castration, of estrogen and androgen injection on serum phosphatases in metastatic carcinoma of the prostate.  Cancer Res. 1941;  1 293-297
• 10 Hunter J. The works of John Hunter F. R. S. With Notes. London: Longman Edited by J. F. Palmer 1837
• 11 Iversen P. Quality of life issues relating to endocrine treatment options.  Eur Urol. 1999;  (Suppl 2) 36 20-26
• 12 Iversen P, Tyrrell C J, Kaisary A V. et al . Casodex (bicalutamide) 150 mg monotherapy compared with castration in patients with previously untreated nonmetastatic prostate cancer: results from two multicenter randomized trials at a median follow-up of 4 years.  Urology. 1998;  51 389-396
• 13 Iversen P, Tyrrell C J, Kaisary A V. et al . Bicalutamide monotherapy compared with castration in patients with nonmetastatic locally advanced prostate cancer: 6.3 years of followup.  J Urol. 2000;  164 1579-1582
• 14 Klotz L, McNeill I, Fleshner N. A phase 1 - 2 trial of diethylstilbestrol plus low dose warfarin in advanced prostate carcinoma.  J Urol. 1999;  161 169-172
• 15 Krebs in Deutschland. 5. überarbeitete, aktualisierte Ausgabe Gesellschaft der epidemiologischen Krebsregister in Deutschland e. V. und das RKI. Saarbrücken 2006
• 16 Mc Ieod D G, Iversen P, See W A. et al . Bicalutamide 150 mg plus standard care vs standard care alone for early prostate cancer.  BJU Int. 2006;  97 247-254
• 17 Miyamoto H, Yeh S, Lardy H. et al . Delta5-androstenediol is a natural hormone with androgenic activity in human prostate cancer cells.  Proc Natl Acad Sci U S A. 1998;  95 11083-11088
• 18 Moffat L E. Comparison of Zoladex, diethylstilbestrol and cyproterone acetate treatment in advanced prostate cancer.  Eur Urol. 1990;  18 (Suppl 3) 26-27
• 19 Nyman C R, Andersen J T, Lodding P. et al . The patient’s choice of androgen-deprivation therapy in locally advanced prostate cancer: bicalutamide, a gonadotrophin-releasing hormone analogue or orchidectomy.  BJU Int. 2005;  96 1014-1018
• 20 Paquette E L, Sun L, Paquette L R. et al . Improved prostate cancer-specific survival and other disease parameters: impact of prostate-specific antigen testing.  Urology. 2002;  60 756-759
• 21 Pelikan E. Gerichtlich-medicinische Untersuchungen uber Das Skopzenthum in Russland, nebst historischen Notizen. Giessen: Ricker 1876
• 22 Potosky A L, Knopf K, Clegg L X. et al . Quality-of-life outcomes after primary androgen deprivation therapy: results from the Prostate Cancer Outcomes Study.  J Clin Oncol. 2001;  19 3750-3757
• 23 Pound C R, Partin A W, Eisenberger M A. et al . Natural history of progression after PSA elevation following radical prostatectomy.  JAMA. 1999;  281 1591-1597
• 24 Prostate Cancer Trialists’ Collaborative Group . Maximum androgen blockade in advanced prostate cancer: an overview of the randomised trials.  Lancet. 2000;  355 1491-1498
• 25 Radlmaier A, Bormacher K, Neumann F. Hot flushes: mechanism and prevention.  Prog Clin Biol Res. 1990;  359 131-140
• 26 Riba L W. Subcapsular castration for carcinoma of prostate.  J Urol. 1942;  48 384-387
• 27 Rohde V, Wellmann A, Fogt F. et al . Economical data and advanced prostate carcinoma: do we need new guidelines for decision making?.  Oncol Rep. 2002;  9 1185-1188
• 28 Scherr D S, Pitts W R. The nonsteroidal effects of diethylstilbestrol: the rationale for androgen deprivation therapy without estrogen deprivation in the treatment of prostate cancer.  J Urol. 2003;  170 1703-1708
• 29 Schroder F H, Collette L, Reijke T M. et al . Prostate cancer treated by anti - androgens? is sexual function preserved: EORTC Genitourinary Group. European Organization for Research and Treatment of Cancer.  Br J Cancer. 2000;  82 283-290
• 30 Seidenfeld de J, Samson D J, Hasselblad V. et al . Single-therapy androgen suppression in men with advanced prostate cancer: a systematic review and meta - analysis.  Ann Intern Med. 2000;  132 566-577
• 31 The Veterans Administration Co-operative Urological Research Group . Treatment and survival of patients with cancer of the prostate.  Surg Gynecol Obstet. 1967;  124 1011-1017
• 32 Trachtenberg J, Gittleman 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
• 33 Tsai M J, O’Malley B W. Molecular mechanisms of action of steroid/thyroid receptor superfamily members.  Annu Rev Biochem. 1994;  63 451-486
• 34 Tyrrell C J, Kaisary A V, Iversen P. et al . A randomised comparison of ‚Casodex’ (bicalutamide) 150 mg monotherapy versus castration in the treatment of metastatic and locally advanced prostate cancer.  Eur Urol. 1998;  33 447-456
• 35 Wang M C, Valenzuela L A, Murphy G P. et al . Purification of a human prostate specific antigen.  Invest Urol. 1979;  17 159-163
• 36 Weckermann D, Harzmann R. Hormone therapy in prostate cancer: LHRH antagonists versus LHRH analogues.  Eur Urol. 2004;  46 279-283
• 37 White W J. Surgical of the hypertrophied prostate.  Ann Surg. 1893;  17 70-75
• 38 Widmark A, Fossa S D, Lundmo P. et al . Does prophylactic breast irradiation prevent antiandrogen-induced gynecomastia? Evaluation of 253 patients in the randomized Scandinavian trial SPCG-7/SFUO-3.  Urology. 2003;  61 145-151
• 39 Wirth M P, See W A, Mcleod D G. et al . Bicalutamide 150 mg in addition to standard care in patients with localized or locally advanced prostate cancer: results from the second analysis of the early prostate cancer program at median followup of 5.4 years.  J Urol. 2004;  172 1865-1870
• 40 Zhang X Z, Donovan M P, Williams B T. et al . Comparison of subcapsular and total orchiectomy for treatment of metastatic prostate cancer.  Urology. 1996;  47 402-404