Die Behandlung des hormonrefraktären Prostatakarzinoms - neue Standards, neue Trends

Zusammenfassung

Das hormonrefraktäre Prostatakarzinom (HRPCA) tritt mit zunehmender Inzidenz auf und stellt für Urologen eine therapeutische Herausforderung dar. Das bessere Verständnis über tumorbiologische Mechanismen des hormonrefraktären Stadiums hat inzwischen zu hoffnungsvollen therapeutischen Entwicklungen im Bereich der Hormon- und Chemotherapie geführt. So konnte jüngst in zwei randomisierten Phase-III-Studien zur Chemotherapie mit Docetaxel eine Verlängerung des Überlebens und ein positiver Einfluss auf Schmerzen und Lebensqualität gezeigt werden, so dass hierdurch ein neuer Therapiestandard etabliert wurde. Ebenso scheint sich auch die Bisphosphonattherapie bei einzelnen Patienten positiv auszuwirken. Auf dem Sektor der modernen, molekularen Therapieansätze („Molecular Targeted Therapy”) zeigen erste Studien mit Substanzen, wie z. B. Tyrosinkinase-Inhibitoren, Antisense-Oligonukleotiden, Angiogeneseinhibitoren und Endothelin-Rezeptor-Antagonisten viel versprechende Ergebnisse in der Behandlung der Patienten mit hormonrefraktärem Prostatakarzinom.

Abstract

Hormone-refractory prostate cancer is diagnosed with increasing incidence and has become a growing challenge for urologists. The improved understanding of the tumor biological mechanisms of the hormone-refractory state has led to innovative therapeutic developments in the field of hormonal and cytotoxic therapies. Recently, two large randomized Phase III trials with docetaxel-based chemotherapy were able to show prolonged survival and a positive influence on pain and quality of life, establishing a new standard of care for these patients. Moreover, bisphosphonates seem to have positive influence on selected patients. In the growing field of molecular targeted therapy, first trials with compounds, such as tyrosine kinase inhibitors, anti-sense oligonucleotides, angiogenesis inhibitors and endothelin receptor antagonists, show promising results in the treatment of patients with hormone-refractory prostate cancer.

Schlüsselwörter

Prostatakarzinom - Chemotherapie - Bisphosphonate - molekulare Therapie - Hormontherapie

Key words

Prostate cancer - chemotherapy - bisphosphonates - molecular targeted therapy - hormone therapy

Literatur

• 1 Agus D B, Scher H I, Higgins B. et al . Response of prostate cancer to anti-Her-2/neu antibody in androgen-dependent and -independent human xenograft models.  Cancer Res. 1999;  59 4761-4764
• 2 Bartsch G, Klocker H, Logothetis C. Established Treatments of HRPC-Cytotoxic Therapy. In: Denis L, Bartsch G, Khoury S, Murai M, Partin A (eds.). Prostate Cancer - 3rd International Consultation on Prostate Cancer - Paris. Health Publications 2003 5B: 169-175
• 3 Canil C M, Tannock I F. Should bisphosphonates be used routinely in patients with prostate cancer metastatic to bone?.  J Natl Cancer Inst. 2002;  94 1422-1423
• 4 Carducci M A, Nelson J B, Bowling M K. et al . Atrasentan, an endothelin-receptor antagonist for refractory adenocarcinomas: safety and pharmacokinetics.  J Clin Oncol. 2002;  20 2171-2180
• 5 Carter B S, Epstein J I, Isaacs W B. Ras gene mutations in human prostate cancer.  Cancer Res. 1990;  50 6830-6882
• 6 Casciano R, Petrylak D, Neugut A I. et al . Systematic Review of Chemotherapy Efficacy from Controlled Trials in Hormone-Refractory Prostate Cancer (HRPC) Patients.  Proc Am Soc Clin Oncol. 2001;  Suppl #2428
• 7 Corey E, Brown L G, Quinn J E. et al . Zoledronic acid exhibits inhibitory effects on osteoblastic and osteolytic metastases of prostate cancer.  Clin Cancer Res. 2003;  9 295-306
• 8 Culig Z, Hobisch A, Cronauer M V. et al . Androgen receptor activation in prostatic tumor cell lines by insulin-like growth factor-I, keratinocyte growth factor, and epidermal growth factor.  Cancer Res. 1994;  54 5474-5478
• 9 Di Lorenzo G, Tortora G, D'Armiento F P. et al . Expression of epidermal growth factor receptor correlates with disease relapse and progresion to androgen-independence in human prostate cancer.  Clin Cancer Res. 2002;  8 3438-3444
• 10 Fowler Jr J E, Pandey P, Seaver L E, Feliz T P. Prostate specific antigen after gonadal androgen withdrawal and deferred flutamide treatment.  J Urol. 1995;  154 448-453
• 11 Gottlieb B, Beitel L K, Wu J H, Trifiro M. The androgen receptor gene mutations database (ARDB): 2004 update.  Hum Mutat. 2004;  23 527-533
• 12 Heidenreich A, Hofmann R, Engelmann U H. The use of bisphosphonate for the palliative treatment of painful bone metastasis due to hormone refractory prostate cancer.  J Urol. 2001;  165 136-140
• 13 Heldin C H, Westermark B. Mechanism of action and in vivo role of platelet-derived growth factor.  Physiol Rev. 1999;  79 1283-1316
• 14 Huggins C, Hodges C V. Studies on prostatic cancer: I. The effect of castration, of estrogen and of androgen injection on serum phosphatases in metastatic carcinoma of the prostate.  Cancer Res. 1941;  1 293-297
• 15 Kantoff P W, Halabi S, Conaway M. et al . Hydrocortisone with or without mitoxantrone in men with hormone-refractory prostate cancer: results of the cancer and leukemia group B 9182 study.  J Clin Oncol. 1999;  17 2506-2513
• 16 Kelly W K. Endocrine withdrawal syndrome and its relevance to the management of hormone refractory prostate cancer.  Eur Urol. 1998;  34 Suppl 3 18-23
• 17 Lee C. Cellular interactions in prostate cancer.  Br J Urol. 1997;  79 Suppl 1 21-27
• 18 Leung S, Miyake H, Zellweger T, Tolcher A, Gleave M E. Synergistic chemosensitization and inhibition of progression to androgen independence by antisense Bcl-2 oligodeoxynucleotide and paclitaxel in the LNCaP prostate tumor model.  Int J Cancer. 2001;  91 846-850
• 19 Mathew P, Thall P F, Jones D. et al . Platelet-derived growth factor receptor inhibitor imatinib mesylate and docetaxel: a modular phase I trial in androgen-independent prostate cancer.  J Clin Oncol. 2004;  22 3323-3329
• 20 McDonnell T J, Troncoso P, Brisbay S M. et al . Expression of the protooncogene bcl-2 in the prostate and its association with emergence of androgen-independent prostate cancer.  Cancer Res. 1992;  52 6940-6944
• 21 Morris M J, Reuter V E, Kelly W K. et al . HER-2 profiling and targeting in prostate carcinoma.  Cancer. 2002;  94 980-986
• 22 Nelson J B, Hedican S P, George D J. et al . Identification of endothelin-1 in the pathophysiology of metastatic adenocarcinoma of the prostate.  Nat Med. 1995;  1 944-949
• 23 Pavlakis N, Stockler M. Bisphosphonates for breast cancer.  Cochrane Database Syst Rev. 2002;  CD003474
• 24 Petrylak D P, Tangen C, Hussain M. et al . Docetaxel and estramustine compared with mitoxantrone and prednisone for advanced refractory prostate cancer.  New Engl J Med. 2004;  351 1513-1520
• 25 Putz T, Culig Z, Eder I E. et al . Epidermal growth factor (EGF) receptor blockade inhibits the action of EGF, insulin-like growth factor I, and a protein kinase A activator on the mitogen-activated protein kinase pathway in prostate cancer cell lines.  Cancer Res. 1999;  59 227-233
• 26 Reiner W G, Scott W W, Eggleston J C, Walsh P C. Long-term survival after hormonal therapy for stage D prostatic cancer.  J Urol. 1979;  122 183-184
• 27 Saad F, Gleason D M, Murray R. et al . A randomized, placebo-controlled trial of zoledronic acid in patients with hormone-refractory metastatic prostate carcinoma.  J Natl Cancer Inst. 2002;  94 1458-1468
• 28 Scher H I, Sarkis A, Reuter V. et al . Changing pattern of expression of the epidermal growth factor receptor and transforming growth factor alpha in the progression of prostatic neoplasms.  Clin Cancer Res. 1995;  1 545-550
• 29 Shi Y, Brands F H, Chatterjee S. et al . Her-2/neu expression in prostate cancer: high level of expression associated with exposure to hormone therapy and androgen independent disease.  J Urol. 2001;  166 1514-1519
• 30 Sirotnak F M, Zakowski M F, Miller V A, Scher H I, Kris M G. Efficacy of cytotoxic agents against human tumor xenografts is markedly enhanced by coadministration of ZD1839 (Iressa), an inhibitor of EGFR tyrosine kinase.  Clin Cancer Res. 2000;  6 4885-4892
• 31 Slamon D J, Leyland-Jones B, Shak S. et al . Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2.  N Engl J Med. 2001;  344 783-792
• 32 Small E J, Bok R, Reese D M, Sudilovsky D, Frohlich M. Docetaxel, estramustine, plus trastuzumab in patients with metastatic androgen-independent prostate cancer.  Semin Oncol. 2001;  28 71-76
• 33 Smith M R. Bisphosphonates to prevent osteoporosis in men receiving androgen deprivation therapy for prostate cancer.  Drugs Aging. 2003;  20 175-183
• 34 Tannock I, de Wit R, Berry W. et al . Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer.  New Engl J Med. 2004;  351 1502-1512
• 35 Tannock I F, Osoba D, Stockler M R. et al . Chemotherapy with mitoxantrone plus prednisone or prednisone alone for symptomatic hormone-resistant prostate cancer: a Canadian randomized trial with palliative end points.  J Clin Oncol. 1996;  14 1756-1764
• 36 Taplin M E, Rajeshkumar B, Halabi S. et al . Androgen receptor mutations in androgen-independent prostate cancer: Cancer and Leukemia Group B Study 9663.  J Clin Oncol. 2003;  21 2673-2678
• 37 Tolcher A W, Kuhn J, Schwartz G. et al . A phase I pharmacokinetic and biological correlative study of oblimersen sodium (genasense, g3139), an antisense oligonucleotide to the bcl-2 mRNA, and of docetaxel in patients with hormone-refractory prostate cancer.  Clin Cancer Res. 2004;  10 5048-5057
• 38 Trump D, Wilding G, Small E J, Soulie P. A pilot trials of ZD1839 (‘IRESSA’), an orally active, selective epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), in combination with docetaxel and estramustine in patients with hormone-refractory prostate cancer (HRPC).  J Urol. 2003;  169 244
• 39 Uehara H, Kim S J, Karashima T. et al . Effects of blocking platelet-derived growth factor-receptor signaling in a mouse model of experimental prostate cancer bone metastases.  J Natl Cancer Inst. 2003;  95 458-470
• 40 Yagoda A, Petrylak D. Cytotoxic chemotherapy for advanced hormone-resistant prostate cancer.  Cancer. 1993;  71 1098-1109