Skip to main content
SpringerLink
Log in

Metronomic cyclophosphamide therapy in hormone-naive patients with non-metastatic biochemical recurrent prostate cancer: a phase II trial

  • Original Paper
  • Published:
Medical Oncology Aims and scope Submit manuscript

Abstract

After curative local therapy, biochemical recurrence is a mode of relapse among patient with prostate cancer (PC). Deferring androgen deprivation therapy (ADT) or offering non-hormonal therapies may be an appropriate option for these non-symptomatic patients with no proven metastases. Metronomic cyclophosphamide (MC) has shown activity in metastatic PC setting and was chosen to be assessed in biochemical relapse. This prospective single-arm open-label phase II study was conducted to evaluate MC regimen in patients with biochemical recurrent PC. MC was planned to be administered orally at a daily dose of 50 mg for 6 months. Primary endpoint was PSA response. Thirty-eight patients were included and treated. Median follow-up was 45.5 months (range 17–100). Among them, 14 patients (37 %) achieved PSA stabilisation and 22 patients (58 %) experienced PSA progression. Response rate was 5 % with one complete response (2.6 %), and 1 partial response with PSA decrease >50 % (2.6 %). The median time until androgen deprivation therapy initiation was around 15 months. The treatment was well tolerated. Neither grade 3–4 toxicity nor serious adverse events were observed. This first prospective clinical trial with MC therapy in patients with non-metastatic biochemical recurrence of PC displayed modest efficacy when measured with PSA response rate, without significant toxicity. It might offer a new safe and non-expensive option to delay initiation of ADT. These results would need to be confirmed with larger prospective randomised trials.

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

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Jemal A, Siegel R, Xu J, Ward E. Cancer statistics, 2010. CA Cancer J Clin. 2010;60(5):277–300.

    Article  PubMed  Google Scholar 

  2. La Vecchia C, Bosetti C, Lucchini F, Bertuccio P, Negri E, Boyle P, et al. Cancer mortality in Europe, 2000–2004, and an overview of trends since 1975. Ann Oncol. 2010;21(6):1323–60.

    Article  PubMed  Google Scholar 

  3. Khan MA, Han M, Partin AW, Epstein JI, Walsh PC. Long-term cancer control of radical prostatectomy in men younger than 50 years of age: update 2003. Urology. 2003;62(1):86–91 (discussion-2).

    Article  PubMed  Google Scholar 

  4. Djavan B, Moul JW, Zlotta A, Remzi M, Ravery V. PSA progression following radical prostatectomy and radiation therapy: new standards in the new Millennium. Eur Urol. 2003;43(1):12–27.

    Article  PubMed  Google Scholar 

  5. Polascik TJ, Oesterling JE, Partin AW. Prostate specific antigen: a decade of discovery–what we have learned and where we are going. J Urol. 1999;162(2):293–306.

    Article  CAS  PubMed  Google Scholar 

  6. Moul JW. Prostate specific antigen only progression of prostate cancer. J Urol. 2000;163(6):1632–42.

    Article  CAS  PubMed  Google Scholar 

  7. Pound CR, Partin AW, Eisenberger MA, Chan DW, Pearson JD, Walsh PC. Natural history of progression after PSA elevation following radical prostatectomy. JAMA. 1999;281(17):1591–7.

    Article  CAS  PubMed  Google Scholar 

  8. Roach M 3rd, Hanks G, Thames H Jr, Schellhammer P, Shipley WU, Sokol GH, et al. Defining biochemical failure following radiotherapy with or without hormonal therapy in men with clinically localized prostate cancer: recommendations of the RTOG-ASTRO Phoenix Consensus Conference. Int J Radiat Oncol Biol Phys. 2006;65(4):965–74.

    Article  PubMed  Google Scholar 

  9. Andre N, Carre M, Pasquier E. Metronomics: towards personalized chemotherapy? Nat Rev Clin Oncol. 2014;11(7):413–31.

    Article  CAS  PubMed  Google Scholar 

  10. Gnoni A, Silvestris N, Licchetta A, Santini D, Scartozzi M, Ria R, et al. Metronomic chemotherapy from rationale to clinical studies: a dream or reality? Crit Rev Oncol Hematol. 2015;95(1):46–61.

    Article  PubMed  Google Scholar 

  11. Andre N, Padovani L, Verschuur A. Metronomic chemotherapy: back to the future! Drug News Perspect. 2010;23(2):143–51.

    Article  PubMed  Google Scholar 

  12. Lien K, Georgsdottir S, Sivanathan L, Chan K, Emmenegger U. Low-dose metronomic chemotherapy: a systematic literature analysis. Eur J Cancer. 2013;49(16):3387–95.

    Article  CAS  PubMed  Google Scholar 

  13. Yashi M, Nishihara D, Mizuno T, Yuki H, Masuda A, Kambara T, et al. Metronomic oral cyclophosphamide chemotherapy possibly contributes to stabilization of disease in patients with metastatic castration-resistant prostate cancer: a prospective analysis of consecutive cases. Clin Genitourin Cancer. 2014;12(5):e197–203.

    Article  PubMed  Google Scholar 

  14. Ladoire S, Eymard JC, Zanetta S, Mignot G, Martin E, Kermarrec I, et al. Metronomic oral cyclophosphamide prednisolone chemotherapy is an effective treatment for metastatic hormone-refractory prostate cancer after docetaxel failure. Anticancer Res. 2010;30(10):4317–23.

    CAS  PubMed  Google Scholar 

  15. Lord R, Nair S, Schache A, Spicer J, Somaihah N, Khoo V, et al. Low dose metronomic oral cyclophosphamide for hormone resistant prostate cancer: a phase II study. J Urol. 2007;177(6):2136–40 (discussion 40).

    Article  CAS  PubMed  Google Scholar 

  16. Nicolini A, Mancini P, Ferrari P, Anselmi L, Tartarelli G, Bonazzi V, et al. Oral low-dose cyclophosphamide in metastatic hormone refractory prostate cancer (MHRPC). Biomed Pharmacother. 2004;58(8):447–50.

    Article  CAS  PubMed  Google Scholar 

  17. Raghavan D, Cox K, Pearson BS, Coorey GJ, Rogers J, Watt WH, et al. Oral cyclophosphamide for the management of hormone-refractory prostate cancer. Br J Urol. 1993;72(5 Pt 1):625–8.

    Article  CAS  PubMed  Google Scholar 

  18. Derosa L, Galli L, Orlandi P, Fioravanti A, Di Desidero T, Fontana A, et al. Docetaxel plus oral metronomic cyclophosphamide: a phase II study with pharmacodynamic and pharmacogenetic analyses in castration-resistant prostate cancer patients. Cancer. 2014;120(24):3923–31.

    Article  CAS  PubMed  Google Scholar 

  19. Barroso-Sousa R, da Fonseca LG, Souza KT, Chaves AC, Kann AG, de Castro G Jr, et al. Metronomic oral cyclophosphamide plus prednisone in docetaxel-pretreated patients with metastatic castration-resistant prostate cancer. Med Oncol. 2015;32(1):443.

    Article  PubMed  Google Scholar 

  20. Orlandi P, Fontana A, Fioravanti A, Di Desidero T, Galli L, Derosa L, et al. VEGF-A polymorphisms predict progression-free survival among advanced castration-resistant prostate cancer patients treated with metronomic cyclophosphamide. Br J Cancer. 2013;109(4):957–64.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Dickinson PD, Peel DN, Sundar S. Metronomic chemotherapy with cyclophosphamide and dexamethasone in patients with metastatic carcinoma of the prostate. Br J Cancer. 2012;106(8):1464–5 (author reply 6).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Meng LJ, Wang J, Fan WF, Pu XL, Liu FY, Yang M. Evaluation of oral chemotherapy with capecitabine and cyclophosphamide plus thalidomide and prednisone in prostate cancer patients. J Cancer Res Clin Oncol. 2012;138(2):333–9.

    Article  CAS  PubMed  Google Scholar 

  23. Hatano K, Nonomura N, Nishimura K, Kawashima A, Mukai M, Nagahara A, et al. Retrospective analysis of an oral combination of dexamethasone, uracil plus tegafur and cyclophosphamide for hormone-refractory prostate cancer. Jpn J Clin Oncol. 2011;41(2):253–9.

    Article  PubMed  Google Scholar 

  24. Gebbia V, Serretta V, Borsellino N, Valerio MR, Foundation G. Salvage therapy with oral metronomic cyclophosphamide and methotrexate for castration-refractory metastatic adenocarcinoma of the prostate resistant to docetaxel. Urology. 2011;78(5):1125–30.

    Article  PubMed  Google Scholar 

  25. Jellvert A, Lissbrant IF, Edgren M, Ovferholm E, Braide K, Olvenmark AM, et al. Effective oral combination metronomic chemotherapy with low toxicity for the management of castration-resistant prostate cancer. Exp Ther Med. 2011;2(4):579–84.

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Fontana A, Galli L, Fioravanti A, Orlandi P, Galli C, Landi L, et al. Clinical and pharmacodynamic evaluation of metronomic cyclophosphamide, celecoxib, and dexamethasone in advanced hormone-refractory prostate cancer. Clin Cancer Res. 2009;15(15):4954–62.

    Article  CAS  PubMed  Google Scholar 

  27. Nelius T, Klatte T, de Riese W, Haynes A, Filleur S. Clinical outcome of patients with docetaxel-resistant hormone-refractory prostate cancer treated with second-line cyclophosphamide-based metronomic chemotherapy. Med Oncol. 2010;27(2):363–7.

    Article  CAS  PubMed  Google Scholar 

  28. Di Lorenzo G, Autorino R, De Laurentiis M, Forestieri V, Romano C, Prudente A, et al. Thalidomide in combination with oral daily cyclophosphamide in patients with pretreated hormone refractory prostate cancer: a phase I clinical trial. Cancer Biol Ther. 2007;6(3):313–7.

    Article  PubMed  Google Scholar 

  29. Hellerstedt B, Pienta KJ, Redman BG, Esper P, Dunn R, Fardig J, et al. Phase II trial of oral cyclophosphamide, prednisone, and diethylstilbestrol for androgen-independent prostate carcinoma. Cancer. 2003;98(8):1603–10.

    Article  CAS  PubMed  Google Scholar 

  30. Glode LM, Barqawi A, Crighton F, Crawford ED, Kerbel R. Metronomic therapy with cyclophosphamide and dexamethasone for prostate carcinoma. Cancer. 2003;98(8):1643–8.

    Article  CAS  PubMed  Google Scholar 

  31. Nishimura K, Nonomura N, Ono Y, Nozawa M, Fukui T, Harada Y, et al. Oral combination of cyclophosphamide, uracil plus tegafur and estramustine for hormone-refractory prostate cancer. Oncology. 2001;60(1):49–54.

    Article  CAS  PubMed  Google Scholar 

  32. Bracarda S, Tonato M, Rosi P, De Angelis V, Mearini E, Cesaroni S, et al. Oral estramustine and cyclophosphamide in patients with metastatic hormone refractory prostate carcinoma: a phase II study. Cancer. 2000;88(6):1438–44.

    Article  CAS  PubMed  Google Scholar 

  33. Maulard-Durdux C, Dufour B, Hennequin C, Chretien Y, Delanian S, Housset M. Phase II study of the oral cyclophosphamide and oral etoposide combination in hormone-refractory prostate carcinoma patients. Cancer. 1996;77(6):1144–8.

    Article  CAS  PubMed  Google Scholar 

  34. Wozniak AJ, Blumenstein BA, Crawford ED, Boileau M, Rivkin SE, Fletcher WS. Cyclophosphamide, methotrexate, and 5-fluorouracil in the treatment of metastatic prostate cancer. A Southwest Oncology Group study. Cancer. 1993;71(12):3975–8.

    Article  CAS  PubMed  Google Scholar 

  35. http://www.mskcc.org/nomograms/prostate/psa-doubling-time.

  36. http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/ctcaev3.pdf.

  37. Duchesne GM, Woo HH, Bassett JK, Bowe SJ, D’Este C, Frydenberg M, et al. Timing of androgen-deprivation therapy in patients with prostate cancer with a rising PSA (TROG 03.06 and VCOG PR 01-03 [TOAD]): a randomised, multicentre, non-blinded, phase 3 trial. Lancet Oncol. 2016;17(6):727–37.

    Article  CAS  PubMed  Google Scholar 

  38. Xabier Garcia-Albeniz JMC, Paciorek AT, Logan RW, Kenfield SA, Cooperberg MR, Caroll P, Hernan M. Immediate versus deferred initiation of androgen deprivation therapy in prostate cancer patients with PSA-only relapse. J Clin Oncol 32:5s, 2014 (suppl; abstr 5003). In: 2014 ASCO Annual Meeting. 2014; Oral Abstract Session, Genitourinary (Prostate) Cancer(5003).

  39. Crook JM, O’Callaghan CJ, Duncan G, Dearnaley DP, Higano CS, Horwitz EM, et al. Intermittent androgen suppression for rising PSA level after radiotherapy. N Engl J Med. 2012;367(10):895–903.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Andres E, Eschwege P, Lang H, Moreau JL, Peiffert D, Thiery-Vuillemin A, et al. Metabolic impact of androgen deprivation therapy for prostate cancer. Prog Urol. 2012;22(Suppl 2):S39–47.

    Article  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Medical Oncology, CHRU Minjoz, Besançon, France

    Fabien Calcagno, Guillaume Mouillet, Olivier Adotevi, Tristan Maurina, Thierry Nguyen, Philippe Montcuquet, E. Curtit, Xavier Pivot, Christophe Borg & Antoine Thiery-Vuillemin

  2. INSERM, UMR1098, Besançon, France

    Olivier Adotevi, E. Curtit, F. Kleinclauss, Xavier Pivot, Christophe Borg & Antoine Thiery-Vuillemin

  3. UMR1098, SFR IBCT, University of Franche-Comté, Besançon, France

    Fabien Calcagno, Olivier Adotevi, E. Curtit, F. Kleinclauss, Xavier Pivot, Christophe Borg & Antoine Thiery-Vuillemin

  4. Clinical Investigation Center, Inserm CIC1431, Besançon, France

    Fabien Calcagno & Christophe Borg

  5. Department of Urology, CHRU Minjoz, Besançon, France

    F. Kleinclauss

Authors
  1. Fabien Calcagno
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Guillaume Mouillet
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Olivier Adotevi
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Tristan Maurina
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Thierry Nguyen
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Philippe Montcuquet
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. E. Curtit
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. F. Kleinclauss
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Xavier Pivot
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Christophe Borg
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Antoine Thiery-Vuillemin
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Fabien Calcagno.

Ethics declarations

Conflict of interest

Dr. Calcagno has nothing to disclose. Dr. Mouillet reports non-financial support from JANSSEN, personal fees from ASTELLAS, personal fees and non-financial support from Sanofi, during the conduct of the study. Pr. Adotevi has nothing to disclose. Dr. Maurina has nothing to disclose. Dr. Nguyen has nothing to disclose. Dr. Montcuquet has nothing to disclose. Dr. Curtit has nothing to disclose. Pr. Kleinclauss has nothing to disclose. Pr. Pivot has nothing to disclose. Pr. Borg reports grants from Roche, grants and personal fees from Sanofi, personal fees from Cellgen, personal fees from Lilly, outside the submitted work. Dr. Thiery-Vuillemin board membership + expert testimony = novartis, roche, ipsen, sanofi, takeda, pfizer, ferring.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (DOCX 782 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Calcagno, F., Mouillet, G., Adotevi, O. et al. Metronomic cyclophosphamide therapy in hormone-naive patients with non-metastatic biochemical recurrent prostate cancer: a phase II trial. Med Oncol 33, 89 (2016). https://doi.org/10.1007/s12032-016-0806-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1007/s12032-016-0806-0

Keywords

Search

Navigation