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

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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.

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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. 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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  25. Nicholson B, Theodorescu D. Angiogenesis and prostate cancer tumor growth. J Cell Biochem. 2004;91:125–50. doi:10.1002/jcb.10772.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

The authors thank our colleagues in the department of oncology and urology for referring patients for this study. We are also indebted to our patients with prostate cancer for their continued participation in clinical trials. We also thank the research nurses and data managers for their assistance in the conduct of this study.

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Authors and Affiliations

  1. Department of Urology, Texas Tech University Health Sciences Center, 3601 4th Street, Stop 7260, Lubbock, TX, 79430-7260, USA

    Thomas Nelius, Werner de Riese, Allan Haynes & Stephanie Filleur

  2. Department of Urology, Otto-von-Guericke-University Magdeburg, 39120, Magdeburg, Germany

    Thomas Nelius

  3. Department of Urology, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA

    Tobias Klatte

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  1. Thomas Nelius
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  2. Tobias Klatte
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Correspondence to Thomas Nelius.

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Nelius, T., Klatte, T., de Riese, W. et al. Clinical outcome of patients with docetaxel-resistant hormone-refractory prostate cancer treated with second-line cyclophosphamide-based metronomic chemotherapy. Med Oncol 27, 363–367 (2010). https://doi.org/10.1007/s12032-009-9218-8

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