Skip to main content

Advertisement

SpringerLink
Log in

Pegylated liposomal doxorubicin and cyclophosphamide in early recurrent ovarian carcinoma: phase I dose-finding study

  • Original Article
  • Published:
Cancer Chemotherapy and Pharmacology Aims and scope Submit manuscript

Abstract

Purpose

This single-arm phase I dose-escalation study determines the optimal dose of the non-platinum treatment pegylated liposomal doxorubicin (PLD) plus cyclophosphamide (CPM) every 4 weeks in early recurrent ovarian carcinoma.

Methods

Twenty-one women with ovarian carcinoma relapsing within 12 months of first-line surgery and platinum–taxane chemotherapy received escalating doses of PLD (35–45 mg/m2) and CPM (500–600 mg/m2) every 4 weeks for at least two cycles. Primary objective was assessment of maximum-tolerated dose (MTD) over the first two cycles. Secondary objectives were to assess safety over 2 cycles, efficacy evaluated every two cycles (response evaluation criteria in solid tumours criteria) and overall survival (OS).

Results

The PLD-CPM MTD was 40/600 mg/m2 with 2/3 patients treated at 45/500 mg/m2, showing DLTs with Grade 3/4 oesophagitis, thrombopenia/neutropenia, leucopoenia, and Grade 3 stomatitis/asthenia during the first cycle of treatment. Four severe toxicities were reported by three patients during the two first cycles, namely Grade 4 anaemia, and Grade 3 stomatitis. The most common treatment-related toxicities were anaemia (71.4 %), nausea (61.9 %), neutropenia (57.1 %), asthenia (52.4 %), leucopoenia (47.6 %), stomatitis (42.9 %), skin (28.6 %) and palmar–plantar–erythrodysesthesia (19 %). No treatment-related deaths were reported. The overall response rate (complete and partial) was 31 %, and median OS was 8.2 months [95 % CI (3.3–13.2)].

Conclusions

The combination of PLD and CPM is feasible and may be considered particularly in cases where platinum-based treatment is not suitable. The recommended doses for a phase II trial are PLD 40 mg/m2 plus CPM 600 mg/m2 every 4 weeks.

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

Similar content being viewed by others

References

  1. Tretarre B, Remontet L, Menegoz F et al (2005) Ovarian cancer: incidence and mortality in France. J Gynecol Obstet Biol Reprod (Paris) 34(2):154–161

    Article  CAS  Google Scholar 

  2. du Bois A, Quinn M, Thigpen T et al (2005) 2004 consensus statements on the management of ovarian cancer: final document of the 3rd International gynecologic cancer intergroup ovarian cancer consensus conference (GCIG OCCC 2004). Ann Oncol 16(Suppl 8):viii7–viii12

    PubMed  Google Scholar 

  3. Pujade-Lauraine E, Wagner U, Aavall-Lundqvist E et al (2010) Pegylated liposomal doxorubicin and carboplatin compared with paclitaxel and carboplatin for patients with platinum-sensitive ovarian cancer in late relapse. J Clin Oncol 28(20):3323–3329

    Article  CAS  PubMed  Google Scholar 

  4. Parmar MK, Ledermann JA, Colombo N et al (2003) Paclitaxel plus platinum-based chemotherapy versus conventional platinum-based chemotherapy in women with relapsed ovarian cancer: the ICON4/AGO-OVAR-2.2 trial. Lancet 361(9375):2099–2106

    Article  CAS  PubMed  Google Scholar 

  5. Pfisterer J, Plante M, Vergote I et al (2006) Gemcitabine plus carboplatin compared with carboplatin in patients with platinum-sensitive recurrent ovarian cancer: an intergroup trial of the AGO-OVAR, the NCIC CTG, and the EORTC GCG. J Clin Oncol 24(29):4699–4707

    Article  CAS  PubMed  Google Scholar 

  6. Gordon AN, Fleagle JT, Guthrie D, Parkin DE, Gore ME, Lacave AJ (2001) Recurrent epithelial ovarian carcinoma: a randomized phase III study of pegylated liposomal doxorubicin versus topotecan. J Clin Oncol 19(14):3312–3322

    CAS  PubMed  Google Scholar 

  7. Ferrandina G, Corrado G, Licameli A et al (2010) Pegylated liposomal doxorubicin in the management of ovarian cancer. Ther Clin Risk Manag 6:463–483

    CAS  PubMed Central  PubMed  Google Scholar 

  8. Gladieff L, Ferrero A, De RG et al (2012) Carboplatin and pegylated liposomal doxorubicin versus carboplatin and paclitaxel in partially platinum-sensitive ovarian cancer patients: results from a subset analysis of the CALYPSO phase III trial. Ann Oncol 23(5):1185–1189

    Google Scholar 

  9. Markman M, Moon J, Wilczynski S et al (2010) Single agent carboplatin versus carboplatin plus pegylated liposomal doxorubicin in recurrent ovarian cancer: final survival results of a SWOG (S0200) phase 3 randomized trial. Gynecol Oncol 116(3):323–325

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  10. Power P, Stuart G, Oza A et al (2009) Efficacy of pegylated liposomal doxorubicin (PLD) plus carboplatin in ovarian cancer patients who recur within six to twelve months: a phase II study. Gynecol Oncol 114(3):410–414

    Article  CAS  PubMed  Google Scholar 

  11. Markman M, Markman J, Webster K et al (2004) Duration of response to second-line, platinum-based chemotherapy for ovarian cancer: implications for patient management and clinical trial design. J Clin Oncol 22(15):3120–3125

    Article  CAS  PubMed  Google Scholar 

  12. McGuire WP, Hoskins WJ, Brady MF et al (1996) Cyclophosphamide and cisplatin compared with paclitaxel and cisplatin in patients with stage III and stage IV ovarian cancer. N Engl J Med 334(1):1–6

    Article  CAS  PubMed  Google Scholar 

  13. Piccart MJ, Bertelsen K, James K et al (2000) Randomized intergroup trial of cisplatin-paclitaxel versus cisplatin-cyclophosphamide in women with advanced epithelial ovarian cancer: three-year results. J Natl Cancer Inst 92(9):699–708

    Article  CAS  PubMed  Google Scholar 

  14. Owainati A, Zalupski M, Shields A, Hussain M, Philip PA (1998) Phase I study of liposomal doxorubicin (doxil) and cyclophosphamide in solid tumors. J Clin Oncol 17:abs 954

    Google Scholar 

  15. Ray-Coquard I, Paraiso D, Guastalla JP et al (2007) Intensified dose of cyclophosphamide with G-CSF support versus standard dose combined with platinum in first-line treatment of advanced ovarian cancer a randomised study from the GINECO group. Br J Cancer 97(9):1200–1205

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  16. Therasse P, Arbuck SG, Eisenhauer EA et al (2000) New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst 92(3):205–216

    Article  CAS  PubMed  Google Scholar 

  17. Rustin GJ, Nelstrop AE, Bentzen SM, Bond SJ, McClean P (2000) Selection of active drugs for ovarian cancer based on CA-125 and standard response rates in phase II trials. J Clin Oncol 18(8):1733–1739

    CAS  PubMed  Google Scholar 

  18. Rose PG, Maxson JH, Fusco N, Mossbruger K, Rodriguez M (2001) Liposomal doxorubicin in ovarian, peritoneal, and tubal carcinoma: a retrospective comparative study of single-agent dosages. Gynecol Oncol 82(2):323–328

    Article  CAS  PubMed  Google Scholar 

  19. Overmoyer B, Silverman P, Holder LW, Tripathy D, Henderson IC (2005) Pegylated liposomal doxorubicin and cyclophosphamide as first-line therapy for patients with metastatic or recurrent breast cancer. Clin Breast Cancer 6(2):150–157

    Article  CAS  PubMed  Google Scholar 

  20. Trudeau ME, Clemons MJ, Provencher L et al (2009) Phase II multicenter trial of anthracycline rechallenge with pegylated liposomal doxorubicin plus cyclophosphamide for first-line therapy of metastatic breast cancer previously treated with adjuvant anthracyclines. J Clin Oncol 27(35):5906–5910

    Article  CAS  PubMed  Google Scholar 

  21. Bourgeois H, Joly F, Pujade-Lauraine E et al (2006) Phase I study of pegylated liposomal doxorubicin in combination with ifosfamide in pretreated ovarian cancer patients. Am J Clin Oncol 29(4):399–404

    Article  CAS  PubMed  Google Scholar 

  22. ten Bokkel HW, Lane SR, Ross GA (2004) Long-term survival in a phase III, randomised study of topotecan versus paclitaxel in advanced epithelial ovarian carcinoma. Ann Oncol 15(1):100–103

    Article  Google Scholar 

  23. Pujade-Lauraine E, Hilpert F, Weber B et al (2013) AURELIA: a randomized phase III trial evaluating bevacizumab (BEV) plus chemotherapy (CT) for platinum (PT)-resistant recurrent ovarian cancer (OC). J Clin Oncol 30(Suppl 18):LBA5002

    Google Scholar 

  24. Pignata S, Lauraine EP, du Bois A, Pisano C (2010) Pegylated liposomal doxorubicin combined with carboplatin: a rational treatment choice for advanced ovarian cancer. Crit Rev Oncol Hematol 73(1):23–30

    Article  PubMed  Google Scholar 

  25. du Bois A, Pfisterer J, Burchardi N et al (2007) Combination therapy with pegylated liposomal doxorubicin and carboplatin in gynecologic malignancies: a prospective phase II study of the Arbeitsgemeinschaft Gynaekologische Onkologie Studiengruppe Ovarialkarzinom (AGO-OVAR) and Kommission Uterus (AGO-K-Ut). Gynecol Oncol 107(3):518–525

    Article  PubMed  Google Scholar 

  26. Alberts DS, Liu PY, Wilczynski SP et al (2008) Randomized trial of pegylated liposomal doxorubicin (PLD) plus carboplatin versus carboplatin in platinum-sensitive (PS) patients with recurrent epithelial ovarian or peritoneal carcinoma after failure of initial platinum-based chemotherapy (Southwest Oncology Group protocol S0200). Gynecol Oncol 108(1):90–94

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  27. Poveda A, Vergote I, Tjulandin S et al (2011) Trabectedin plus pegylated liposomal doxorubicin in relapsed ovarian cancer: outcomes in the partially platinum-sensitive (platinum-free interval 6–12 months) subpopulation of OVA-301 phase III randomized trial. Ann Oncol 22(1):39–48

    Article  CAS  PubMed  Google Scholar 

  28. Gibson JM, Alzghari S, Ahn C, Trantham H, La-Beck NM (2013) The role of pegylated liposomal doxorubicin in ovarian cancer: a meta-analysis of randomized clinical trials. Oncologist 18(9):1022–1031

    Article  PubMed  Google Scholar 

  29. Handolias D, Quinn M, Foo S et al (2013) Oral cyclophosphamide in recurrent ovarian cancer. Asia Pac J Clin Oncol. doi:10.1111/ajco.12074

Download references

Acknowledgments

The authors wish to thank Christine Dupouy for data collection and management, Pippa McKelvie-Sebileau, medical writer employed by Institut Bergonié, who provided medical writing services on behalf of Institut Bergonié, and staff at the participating centres: Institut Bergonié, Bordeaux; Clinique Francheville, Périgueux; and Centre Hospitalier de la Rochelle, La Rochelle. This study was supported by grants from Schering Plough, France.

Conflict of interest

None.

Author information

Authors and Affiliations

  1. Department of Medical Oncology, Institut Bergonié, 229 Cours de l’Argonne, 33076, Bordeaux, France

    Anne Floquet

  2. Univ. Bordeaux, ISPED, Centre INSERM U897-Epidemiologie-Biostatistique, 33000, Bordeaux, France

    Adélaïde Doussau & Simone Mathoulin-Pélissier

  3. INSERM, ISPED, Centre INSERM U897-Epidemiologie-Biostatistique, CIC-EC7, 33000, Bordeaux, France

    Adélaïde Doussau & Simone Mathoulin-Pélissier

  4. Clinical and Epidemiological Research Unit, Institut Bergonié, 229 Cours de l’Argonne, 33076, Bordeaux, France

    Véronique Brouste & Simone Mathoulin-Pélissier

  5. Clinique Francheville, Périgueux, France

    Laurent Cany

  6. Centre Hospitalier de la Côte Basque, Bayonne, France

    Jean-Philippe Dutin

Authors
  1. Anne Floquet
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Adélaïde Doussau
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Véronique Brouste
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Laurent Cany
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Jean-Philippe Dutin
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Simone Mathoulin-Pélissier
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Anne Floquet.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Floquet, A., Doussau, A., Brouste, V. et al. Pegylated liposomal doxorubicin and cyclophosphamide in early recurrent ovarian carcinoma: phase I dose-finding study. Cancer Chemother Pharmacol 73, 61–68 (2014). https://doi.org/10.1007/s00280-013-2317-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00280-013-2317-4

Keywords

Search

Navigation