Skip to main content
SpringerLink
Log in

Wechsel des LHRH-Analogons beim progredienten kastrationsresistenten Prostatakarzinom

Change of the LHRH analogue in progressive castration-refractory prostate cancer

  • Originalien
  • Published:
Der Urologe Aims and scope Submit manuscript

Zusammenfassung

Hintergrund

Standardtherapie des metastasierten Prostatakarzinoms (PCA) ist die medikamentöse oder chirurgische Kastration – 2–12% der Patienten erreichen dieses Ziel nach medikamentöser Kastration jedoch nicht. Wir untersuchten, ob ein Wechsel des primären LHRH-Analogons (Luteinisierungs-Hormon-Releasing-Hormon) auf Triptorelinpamoat (TP) zu einem erneuten therapeutischen Ansprechen führen kann.

Patienten und Methodik

Retrospektiv wurden 36 Patienten mit einem PSA-Progress von ≥50% gegenüber dem Nadir nach kompletter Androgendeprivation (ADT) und sekundärem Antiandrogenentzug analysiert. Alle Patienten zeigten nach bildgebender Standarddiagnostik keine oder nur minimale Metastasen und waren symptomfrei. Es wurden prätherapeutisch die Parameter PSA (prostataspezifisches Antigen), PSA-Verdopplungszeit (PSA-DT), PSA-Velocity (PSA-V) sowie die Testosteronserumkonzentration (TK) bestimmt und mit der beobachteten Ansprechrate korreliert. Alle Patienten wurden mit TP, 11,5 mg in 3-monatlichen Intervallen bis zum Progress therapiert.

Ergebnisse

Das mittlere Patientenalter lag bei 69,2 (52–79) Jahren, der mittlere PSA-Wert bei 23,4 (8,7–53,1) ng/ml, Die mittlere PSA-DT betrug 9,2 (2,9–15,4) Monate. Die mittlere Testosteronkonzentration betrug 38,67 (21–76) ng/dl. Die mittlere Zeit der ADT bis zur dokumentierten PSA-Progression betrug 42,4 (13–76) Monate, die mediane Zeit lag bei 46,8 (16–82) Monaten. Eine PSA-Reduktion ≥ 50% wurde bei 9/36 (25%) Patienten nachgewiesen. Jeweils 3/36 (13,9%) Patienten zeigten stabile PSA-Werte bzw. eine reduzierte PSA-DT (6,2→9,8 Monate). Das mittlere progressionsfreie Intervall (PFI) lag bei 21,4 (7–53) Wochen. Bei PSA-Ansprechen betrug das mittlere PFI 53,2 (26–64) Wochen, bei stabilem PSA-Verlauf 28 (17–35) Wochen. Patienten mit signifikanter PSA-Regression wiesen signifikant höhere TK auf als Patienten ohne PSA-Antwort (48,3 (29–76) ng/dl vs. 32,6 (21–62) ng/dl, p=0,02). Das mittlere Nachbeobachtungsintervall beträgt 31,4 (27–39) Monate. Die Gesamtüberlebensrate 80,5%, die tumorspezifische Überlebensrate beträgt 88,9%.

Zusammenfassung

Die sekundäre LHRH-Gabe führt bei kastrationsresistenten Prostatakarzinomen (KRPCA) und begleitender T-Konzentration im hohen Kastrationsniveau zu einem vorübergehenden therapeutischen Ansprechen und kann in das Therapiekonzept bei vermeintlicher „Kastrationsresistenz“ berücksichtigt werden. Unsere Daten verdeutlichen die Bedeutung der Bestimmung der T-Konzentration unter LHRH-Therapie. Auch wenn das progressionsfreie Intervall kurz ist, erlaubt es die Fortesetzung einer nebenwirkungsarmen Therapie in einer reinen palliativen Situation.

Abstract

Introduction

Medicinal or surgical castration remains the treatment of choice in metastatic, hormone-naive prostate cancer; however, 2-12% of patients never reach the target serum levels for medicinal castration. We analyzed the therapeutic efficacy of triptorelin pamoate (TP) as salvage treatment due to its higher potency than endogenous luteinizing hormone-releasing hormone (LHRH). The amino acid sequence of TP is identical to that of endogenous LHRH except for position 6 where L-glycine is replaced by D-tryptophane rendering the synthetic moiety less susceptible to cleavage by proteolytic enzymes.

Patients and Methods

In this study 36 patients with prostate-specific antigen (PSA) progression following first line complete androgen blockade and antiandrogen (ADT) withdrawal were retrospectively analyzed. All patients demonstrated no or minimal metastatic disease. The PSA levels, PSA doubling time (PSADT), PSA velocity (PSAV) and testosterone serum concentrations were correlated with the therapeutic response. All patients received TP at a dose of 11.5 mg at 3-month intervals until documented progression.

Results

The mean patient age was 69.2 years (range 52-79 years), the mean PSA level was 23.4 ng/ml (8.7-53.1 ng/ml) and the mean PSADT was 9.2 months (2.9–15.4 months). Mean testosterone serum concentration was 38.67 ng/dl (21–76 ng/dl), the mean time between start of ADT and progression was 42.4 months (13–76 months) and the median time was 46.8 months (16–82 months). A PSA decrease of ≥50% was reached in 9 out of 36 (25%) patients, 3 out of 36 (13.9%) patients each demonstrated stable PSA levels and a prolongation of PSADT from 6.2 to 9.8 months. Mean progression-free survival (PFS) was 21.4 weeks (7-53 weeks). PSA-responders exhibited a PFS of 53.2 weeks (26–64 weeks) as compared to 28 weeks (17–35 weeks) in nonresponders. PSA responders demonstrated significantly higher testosterone serum concentrations of 48.3 ng/dl (29–76 ng/dl) as compared to nonresponders with 32.6 ng/dl (21–62 ng/dl, p=0.02). Mean follow-up was 31.4 months (27–39 months), overall survival was 80.5% and cancer-specific survival was 88.9%.

Conclusion

Changing the LHRH analogue in castration-refractory prostate cancer (CRPC) with testosterone serum concentrations at or above the castration level results in a temporary PSA response. This treatment option might be included in the therapeutic algorithm of CRPC. Although the PFS is short it allows the continuation of a treatment option with minimal side effects in a mere palliative situation. The data underline the need for continuous monitoring of testosterone during treatment with LHRH analogues.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Literatur

  1. Heidenreich A, Bellmunt J, Bolla M et al (2011) EAU Guidelines on prostate cancer. Part I: screening, diagnosis and treatment of clinically localized disease. Eur Urol 59:61–71

    Article  PubMed  Google Scholar 

  2. Mottet N, Bellmunt J, Bolla M et al (2011) EAU guidelines on prostate cancer. Part II: treatment of advanced, relapsing, and castration-resistant prostate cancer. Eur Urol 59:572–583

    Article  PubMed  Google Scholar 

  3. Sarosdy MF, Schellhammer PF, Soloway MS et al (1999) Endocrine effects, efficacy and tolerability of a 10.8- mg depot formulation of goserelin acetate administered every 13 weeks to patients with advanced prostate cancer. BJU Int 83(7):801–806

    Article  PubMed  CAS  Google Scholar 

  4. Oefelein MG, Cornum R (2000) Failure to achieve castrate levels of testosterone during luteinizing hormone releasing hormone agonist therapy: the case for monitoring serum testosterone and a treatment decision algorithm. J Urol 164(3 Pt 1):726–729

    Article  PubMed  CAS  Google Scholar 

  5. McLeod D, Zinner N, Tomera K et al (2001) Abarelix Study Group. A phase 3, multicenter, open-label, randomized study of abarelix versus leuprolide acetate in men with prostate cancer. Urology 58(5):756–761

    Article  PubMed  CAS  Google Scholar 

  6. Morote J, Orsola A, Planas J et al (2007) Redefining clinically significant castration levels in patients with prostate cancer receiving continuous androgen deprivation therapy. J Urol 178(4 Pt 1):1290–1295

    Article  PubMed  CAS  Google Scholar 

  7. Schulman CC, Irani J, Morote J et al (2010) Testosterone measurement in patients with prostate cancer. Eur Urol 58(1):65–74

    Article  PubMed  CAS  Google Scholar 

  8. Smith MR, Kabbinavar F, Saad F et al (2005) Natural history of rising serum prostate-specific antigen in men castrate nonmetastatic prostate cancer. J Clin Oncol 23:2918–2925

    Article  PubMed  Google Scholar 

  9. Heyns CF, Simonin MP, Grosgurin P et al (2003) Comparative efficacy of triptorelin pamoate and leuprolide acetate in men with advanced prostate cancer. BJU Int 92(3):226–231

    Article  PubMed  CAS  Google Scholar 

  10. Zhang L, Loblaw A, Klotz L (2006) Modeling prostate specific antigen kinetics in patients on active surveillance. J Urol 176:1392–1397

    Article  PubMed  Google Scholar 

  11. Scher HI, Halabi S, Tannock I et al (2008) Design and end points of clinical trials for patients with progressive prostate cancer and castrate levels of testosterone: recommendations of the Prostate Cancer Clinical Trials Working Group. J Clin Oncol 26(7):1148–1159

    Article  PubMed  Google Scholar 

  12. Studer UE, Whelan P, Albrecht W et al (2006) Immediate or deferred androgen deprivation for patients with prostate cancer not suitable for local treatment with curative intent: european Organisation for Research and Treatment of Cancer (EORTC) Trial 30891. J Clin Oncol 24(12):1868–1876

    Article  PubMed  Google Scholar 

  13. Small EJ, Ryan CJ (2006) The case for secondary hormonal therapies in the chemotherapy age. J Urol 176(6 Pt 2):66–71

    Article  Google Scholar 

  14. Koutsilieris M, Dimopoulos T, Milathianakis C et al (2007) Combination of somatostatin analogues and dexamethasone (anti-survival-factor concept) with luteinizing hormone-releasing hormone in androgen ablation-refractory prostate cancer with bone metastasis. BJU Int 100(Suppl 2):60–62

    Article  PubMed  CAS  Google Scholar 

  15. Serrate C, Loriot Y, De La Motte Rouge T et al (2009) Diethylstilbestrol (DES) retains activity and is a reasonable option in patients previously treated with docetaxel for castration-resistant prostate cancer. Ann Oncol 20(5):965

    Article  PubMed  CAS  Google Scholar 

  16. Tunn UW (2011) A 6-month depot formulation of leuprolide acetate is safe and effective in daily clinical practice: a non-interventional prospective study in 1,273 patients. BMC Urol 11:15

    Article  PubMed  CAS  Google Scholar 

  17. Rosette J de la, Davis R 3rd, Frankel D, Kold Olesen T (2011) Efficacy and safety of androgen deprivation therapy after switching from monthly leuprolide to monthly degarelix in patients with prostate cancer. Int J Clin Pract 65(5):559–566

    Article  PubMed  Google Scholar 

  18. Crawford ED, Tombal B, Miller K et al (2011) A phase III extension trial with a 1-arm crossover from leuprolide to degarelix: comparison of gonadotropin-releasing hormone agonist and antagonist effect on prostate cancer. J Urol 186(3):889–897

    Article  PubMed  CAS  Google Scholar 

  19. Raddin RS, Walko CM, Whang YE (2011) Response to degarelix after resistance to luteinizing hormone-releasing hormone agonist therapy for metastatic prostate cancer. Anticancer Drugs 22(3):299–302

    Article  PubMed  CAS  Google Scholar 

  20. Radu A, Pichon C, Camparo P et al (2010) Expression of follicle stimulating hormone receptor in tumor blood vessels. N Engl J Med 363:1621–1630

    Article  PubMed  CAS  Google Scholar 

  21. Porcara AB, Migliorini F, Petrozziello A et al (2011) Investigative clinical study on prostate cancer part IV: follicle-stimulating hormone and the pituitary-testicular-prostate axis at the time of initial diagnosis and subsequent cluster selection of the patient population. Urol Int (Epub ahead of print)

  22. Tombal B, Berges R (2008) Optimal control of testosterone: a clinical case-based approach of modern androgen-deprivation therapy. Eur Urol (Suppl 7):15–28

    Google Scholar 

  23. Gomella LG (2009) Effective testosterone suppression for prostate cancer: is there a best castration therapy? Rev Urol 11:52–60

    PubMed  Google Scholar 

  24. Pickles T, Tyldesly S (2011) Testosterone breakthrough during LHRH agonist androgen deprivation with curative radiation: impact on PSA kinetics and subsequent biochemical outcomes. 26th Annual Congress of the European Association of Urology, Vienna, Austria

  25. Perachino M, Cavalli V, Bravi F (2010) Testosterone levels in patients with metastatic prostate cancer treated with luteinizing hormone-releasing hormone therapy: prognostic significance? BJU Int 105:648–651

    Article  PubMed  CAS  Google Scholar 

  26. Taplin ME, Regan MM, Ko YJ et al (2009) Phase II study of androgen synthesis inhibition with ketoconazole, hydrocortisone, and dutasteride in asymptomatic castration-resistant prostate cancer. Clin Cancer Res 15(22):7099–7105

    Article  PubMed  CAS  Google Scholar 

  27. Bono JS de, Logothetis CJ, Molina A et al (2011) Abiraterone and increased survival in metastatic prostate cancer. N Engl J Med 364(21):1995–2005

    Article  PubMed  Google Scholar 

  28. Scher HI, Beer TM, Higano CS et al (2010) Prostate Cancer Foundation/Department of Defense Prostate Cancer Clinical Trials Consortium. Antitumour activity of MDV3100 in castration-resistant prostate cancer: a phase 1–2 study. Lancet 375(9724):1437–1446

    Article  PubMed  CAS  Google Scholar 

  29. Lee DJ, Cha EK, Dubin JM et al (2011) Novel therapeutics for the management of castration-resistant prostate cancer (CRPC). BJU Int 109(7):968–985, doi: 10.1111/j.1464-410X.2011.10643.x

    Article  PubMed  Google Scholar 

Download references

Interessenkonflikt

Keine Angaben

Author information

Authors and Affiliations

  1. Klinik und Poliklinik für Urologie, Universitätsklinikum Aachen, Pauwelsstraße 30, 52074, Aachen, Deutschland

    A. Heidenreich, D. Porres, R. Epplen, T. van Erps & D. Pfister

Authors
  1. A. Heidenreich
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. D. Porres
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. R. Epplen
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. T. van Erps
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. D. Pfister
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to A. Heidenreich.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Heidenreich, A., Porres, D., Epplen, R. et al. Wechsel des LHRH-Analogons beim progredienten kastrationsresistenten Prostatakarzinom. Urologe 51, 1282–1287 (2012). https://doi.org/10.1007/s00120-012-2948-9

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00120-012-2948-9

Schlüsselwörter

Keywords

Search

Navigation