Medical Oncology

, Volume 27, Issue 2, pp 363–367

Clinical outcome of patients with docetaxel-resistant hormone-refractory prostate cancer treated with second-line cyclophosphamide-based metronomic chemotherapy

  • Thomas Nelius
  • Tobias Klatte
  • Werner de Riese
  • Allan Haynes
  • Stephanie Filleur
Original Paper

Abstract

For patients with docetaxel-resistant hormone-refractory prostate cancer (HRPC) no standard chemotherapeutic treatment exists. In this study, we evaluate the efficacy of cyclophosphamide (CP)-based metronomic chemotherapy in this patient population. Patients with metastatic HRPC with disease progression under docetaxel-based chemotherapy were eligible. The primary endpoint was prostate-specific antigen (PSA) response. Secondary endpoints were survival and toxicity. Low-dose CP (50 mg/d) and dexamethasone (1 mg/d) were administered orally in a metronomic manner. Treatment was continued until disease progression or intolerable side effects occurred. Seventeen patients were enrolled in this study. The median follow-up was 12 weeks (range: 4–60). Median age was 68 years (range: 42–85). Median PSA at study entry was 134 ng/ml (range: 46.0–6554). Nine patients had a PSA response (median 44.4%), four patients ≥50% and five patients <50%. Eight patients had a PSA progression. Overall survival was 24 months. Five patients reported a decrease in bone pain after 4 weeks' treatment. No grade 3 and 4 toxicities were noted. In this study, low-dose metronomically administered CP demonstrated efficacy as a second-line treatment in patients with docetaxel-resistant HRPC. The treatment was well tolerated and almost without toxicity. Further advantages of low-dose CP were its convenient oral administration, dosing schedule, low cost, and low-toxicity profile. These attributes in combination with immunoregulatory and antiangiogenic potentials make CP also a prime candidate for combination with other treatment regimens.

Keywords

Metronomic chemotherapy Cyclophosphamide Docetaxel Hormone-refractory prostate cancer Angiogenesis 

Abbreviations

HRPC

Hormone-refractory prostate cancer

CP

Cyclophosphamide

PSA

Prostate-specific antigen

ECOG

Eastern Cooperative Oncology Group

NCI CTC

National Cancer Institute Common Toxicity Criteria

TSP1

Thrombospondin-1

References

  1. 1.
    Yagoda A, Petrylak D. Cytotoxic chemotherapy for advanced hormone-resistant prostate cancer. Cancer. 1993;71:1098–109. doi:10.1002/1097-0142(19930201)71:3+<1098::AID-CNCR2820711432>3.0.CO;2-G.CrossRefPubMedGoogle Scholar
  2. 2.
    Oudard S, Banu E, Beuzeboc P, et al. Multicenter randomized phase II study of two schedules of docetaxel, estramustine, and prednisone versus mitoxantrone plus prednisone in patients with metastatic hormone-refractory prostate cancer. J Clin Oncol. 2005;23:3343–51. doi:10.1200/JCO.2005.12.187.CrossRefPubMedGoogle Scholar
  3. 3.
    Petrylak DP, Tangen CM, Hussain MH, et al. Docetaxel and estramustine compared with mitoxantrone and prednisone for advanced refractory prostate cancer. N Engl J Med. 2004;351:1513–20. doi:10.1056/NEJMoa041318.CrossRefPubMedGoogle Scholar
  4. 4.
    Tannock IF, de Wit R, Berry WR, et al. Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. N Engl J Med. 2004;351:1502–12. doi:10.1056/NEJMoa040720.CrossRefPubMedGoogle Scholar
  5. 5.
    Nelius T, Klatte T, Yap R, et al. A randomized study of docetaxel and dexamethasone with - or high-dose estramustine for patients with advanced hormone-refractory prostate cancer. BJU Int. 2006;98:580–5. doi:10.1111/j.1464-410X.2006.06324.x.CrossRefPubMedGoogle Scholar
  6. 6.
    Nelius T, Reiher F, Lindenmeir T, et al. Characterization of prognostic factors and efficacy in a phase-II study with docetaxel and estramustine for advanced hormone refractory prostate cancer. Onkologie. 2005;28:573–8. doi:10.1159/000088297.CrossRefPubMedGoogle Scholar
  7. 7.
    Chowdhury S, Burbridge S, Harper PG. Chemotherapy for the treatment of hormone-refractory prostate cancer. Int J Clin Pract. 2007;61:2064–70. doi:10.1111/j.1742-1241.2007.01551.x.CrossRefPubMedGoogle Scholar
  8. 8.
    Nicolini A, Mancini P, Ferrari P, et al. Oral -dose cyclophosphamide in metastatic hormone refractory prostate cancer (MHRPC). Biomed Pharmacother. 2004;58:447–50.PubMedGoogle Scholar
  9. 9.
    Lord R, Nair S, Schache A, et al. Low dose metronomic oral cyclophosphamide for hormone resistant prostate cancer: a phase II study. J Urol. 2007;177:2136–40. doi:10.1016/j.juro.2007.01.143. discussion 2140.CrossRefPubMedGoogle Scholar
  10. 10.
    Lutsiak ME, Semnani RT, De Pascalis R, et al. Inhibition of CD4(+)25 + T regulatory cell function implicated in enhanced immune response by -dose cyclophosphamide. Blood. 2005;105:2862–8. doi:10.1182/blood-2004-06-2410.CrossRefPubMedGoogle Scholar
  11. 11.
    Damber JE, Vallbo C, Albertsson P, et al. The anti-tumour effect of -dose continuous chemotherapy may partly be mediated by thrombospondin. Cancer Chemother Pharmacol. 2006;58:354–60. doi:10.1007/s00280-005-0163-8.CrossRefPubMedGoogle Scholar
  12. 12.
    Hanahan D, Bergers G, Bergsland E. Less is more, regularly: metronomic dosing of cytotoxic drugs can target tumor angiogenesis in mice. J Clin Invest. 2000;105:1045–7. doi:10.1172/JCI9872.CrossRefPubMedGoogle Scholar
  13. 13.
    Browder T, Butterfield CE, Kraling BM, et al. Antiangiogenic scheduling of chemotherapy improves efficacy against experimental drug-resistant cancer. Cancer Res. 2000;60:1878–86.PubMedGoogle Scholar
  14. 14.
    Man S, Bocci G, Francia G, et al. Antitumor effects in mice of low-dose (metronomic) cyclophosphamide administered continuously through the drinking water. Cancer Res. 2002;62:2731–5.PubMedGoogle Scholar
  15. 15.
    Shaked Y, Emmenegger U, Francia G, et al. Low-dose metronomic combined with intermittent bolus-dose cyclophosphamide is an effective long-term chemotherapy treatment strategy. Cancer Res. 2005;65:7045–51. doi:10.1158/0008-5472.CAN-05-0765.CrossRefPubMedGoogle Scholar
  16. 16.
    Bubley GJ, Carducci M, Dahut W, et al. Eligibility and response guidelines for phase II clinical trials in androgen-independent prostate cancer: recommendations from the Prostate-Specific Antigen Working Group. J Clin Oncol. 1999;17:3461–7.PubMedGoogle Scholar
  17. 17.
    Beekman KW, Fleming MT, Scher HI, et al. Second-line chemotherapy for prostate cancer: patient characteristics and survival. Clin Prostate Cancer. 2005;4:86–90.PubMedGoogle Scholar
  18. 18.
    Hellerstedt B, Pienta KJ, Redman BG, et al. Phase II trial of oral cyclophosphamide, prednisone, and diethylstilbestrol for androgen-independent prostate carcinoma. Cancer. 2003;98:1603–10. doi:10.1002/cncr.11686.CrossRefPubMedGoogle Scholar
  19. 19.
    Brandes LJ, Bracken SP, Ramsey EW. N, N-diethyl-2-[4-(phenylmethyl)phenoxy]ethanamine in combination with cyclophosphamide: an active, -toxicity regimen for metastatic hormonally unresponsive prostate cancer. J Clin Oncol. 1995;13:1398–403.PubMedGoogle Scholar
  20. 20.
    Muss HB, Howard V, Richards F 2nd, et al. Cyclophosphamide versus cyclophosphamide, methotrexate, and 5-fluorouracil in advanced prostatic cancer: a randomized trial. Cancer. 1981;47:1949–53. doi:10.1002/1097-0142(19810415)47:8<1949::AID-CNCR2820470806>3.0.CO;2-3.CrossRefPubMedGoogle Scholar
  21. 21.
    Bracarda S, Tonato M, Rosi P, et al. Oral estramustine and cyclophosphamide in patients with metastatic hormone refractory prostate carcinoma: a phase II study. Cancer. 2000;88:1438–44. doi:10.1002/(SICI)1097-0142(20000315)88:6<1438::AID-CNCR23>3.0.CO;2-O.CrossRefPubMedGoogle Scholar
  22. 22.
    Glode LM, Barqawi A, Crighton F, et al. Metronomic therapy with cyclophosphamide and dexamethasone for prostate carcinoma. Cancer. 2003;98:1643–8. doi:10.1002/cncr.11713.CrossRefPubMedGoogle Scholar
  23. 23.
    Nishimura K, Nonomura N, Ono Y, et al. Oral combination of cyclophosphamide, uracil plus tegafur and estramustine for hormone-refractory prostate cancer. Oncology. 2001;60:49–54. doi:10.1159/000055296.CrossRefPubMedGoogle Scholar
  24. 24.
    Albertsson P, Lennernas B, Norrby K. Chemotherapy and antiangiogenesis: drug-specific effects on microvessel sprouting. Apmis. 2003;111:995–1003. doi:10.1111/j.1600-0463.2003.apm1111102.x.CrossRefPubMedGoogle Scholar
  25. 25.
    Nicholson B, Theodorescu D. Angiogenesis and prostate cancer tumor growth. J Cell Biochem. 2004;91:125–50. doi:10.1002/jcb.10772.CrossRefPubMedGoogle Scholar
  26. 26.
    Hamano Y, Sugimoto H, Soubasakos MA, et al. Thrombospondin-1 associated with tumor microenvironment contributes to -dose cyclophosphamide-mediated endothelial cell apoptosis and tumor growth suppression. Cancer Res. 2004;64:1570–4. doi:10.1158/0008-5472.CAN-03-3126.CrossRefPubMedGoogle Scholar

Copyright information

© Humana Press Inc. 2009

Authors and Affiliations

  • Thomas Nelius
    • 1
    • 2
  • Tobias Klatte
    • 3
  • Werner de Riese
    • 1
  • Allan Haynes
    • 1
  • Stephanie Filleur
    • 1
  1. 1.Department of UrologyTexas Tech University Health Sciences CenterLubbockUSA
  2. 2.Department of UrologyOtto-von-Guericke-University MagdeburgMagdeburgGermany
  3. 3.Department of UrologyDavid Geffen School of Medicine at UCLALos AngelesUSA

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