Skip to main content

Advertisement

SpringerLink
Log in

Postoperative dose-dense sequential versus concomitant administration of epirubicin and paclitaxel in patients with node-positive breast cancer: 5-year results of the Hellenic Cooperative Oncology Group HE 10/00 phase III Trial

  • Clinical trial
  • Published:
Breast Cancer Research and Treatment Aims and scope Submit manuscript

Abstract

To explore the impact of dose intensity (DI) in the adjuvant setting of breast cancer, a randomized phase III trial was conducted comparing postoperative dose-dense sequential chemotherapy with epirubicin, paclitaxel, and cyclophosphamide, methotrexate and fluorouracil (CMF)in high-risk breast cancer patients. From Oct 2000 to June 2005, 1,121 node-positive patients were randomized to dose-dense sequential epirubicin 110 mg/m2 and paclitaxel (Taxol®, Bristol Myers-Squibb, Princeton, NJ) 250 mg/m2 (group A), or concurrent epirubicin 83 mg/m2 and paclitaxel 187 mg/m2 (group B), both followed by three cycles of “intensified” combination chemotherapy with CMF. By protocol design total cumulative dose and duration of treatment were identical in both groups. Dose intensity of epirubicin and paclitaxel was double in the dose-dense arm. Prophylactic treatment with granulocyte colony-stimulating factor was given with the dose-dense treatments. Disease-free survival (DFS) was the primary endpoint. At a median follow-up of 76 months, 253 patients (23%) had documented disease relapse (123 vs. 130 in groups A and B, respectively) and 208 deaths (101, group A and 107, group B) had been observed. The 5-year DFS rate of 74 and 74% and OS rate of 86 and 85% were observed for group A and group B, respectively. No differences were found in DFS or OS between the two treatment groups (P = 0.78 and P = 0.45 for DFS and OS, respectively). Safety analysis results showing that both regimens were well tolerated and safe have been previously published (Fountzilas et al. Ann Oncol 2008). No DFS or OS benefit from the dose-dense sequential epirubicin and paclitaxel was detected when compared to the concurrent administration of the same drugs. No additional safety issues were raised with long-term follow-up.

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

Similar content being viewed by others

References

  1. Berry DA, Cronin KA, Plevritis SK et al (2005) Effect of screening and adjuvant therapy on mortality from breast cancer. N Engl J Med 353:1784–1792

    Article  PubMed  CAS  Google Scholar 

  2. Norton L (2001) Theoretical concepts and the emerging role of taxanes in adjuvant therapy. Oncologist 6(Suppl 3):30–35

    Article  PubMed  CAS  Google Scholar 

  3. Trudeaue M, Charbonneau F, Gelmon K et al (2005) Selection of adjuvant chemotherapy for treatment of node-positive breast cancer. Lancet Oncol 6:886–898

    Article  Google Scholar 

  4. Bonadonna G, Zambetti M, Valagussa P (1995) Sequential or alternating doxorubicin and CMF regimens in breast cancer with more than three positive nodes. Ten-year results. JAMA 273:542–547

    Article  PubMed  CAS  Google Scholar 

  5. Henderson IC, Berry DA, Demetri GD et al (2003) Improved outcomes from adding sequential paclitaxel but not from escalating doxorubicin dose in an adjuvant chemotherapy regimen for patients with node-positive primary breast cancer. J Clin Oncol 21:976–983

    Article  PubMed  CAS  Google Scholar 

  6. Hudis C, Seidman A, Baselga J et al (1999) Sequential dose-dense doxorubicin, paclitaxel, and cyclophosphamide for resectable high-risk breast cancer: feasibility and efficacy. J Clin Oncol 17:93–100

    PubMed  CAS  Google Scholar 

  7. Founzilas G, Nicolaides C, Aravantinos G et al (1998) Dose-dense adjuvant chemotherapy with epirubicin monotherapy in patients with operable breast cancer and 10 positive axillary lymph nodes. A feasibility study. Oncology 55:508–512

    Article  Google Scholar 

  8. Norton L, Simon R (1986) The Norton-Simon hypothesis revisited. Cancer Treat Res 70:163–169

    CAS  Google Scholar 

  9. Citron ML, Berry DA, Cirrincione C et al (2003) Randomized trial of dose-dense versus conventionally scheduled and sequential versus concurrent combination chemotherapy as postoperative adjuvant treatment of node-positive primary breast cancer; first report of Intergroup Trial C9741/Cancer and Leukemia Group B trial 9741. J Clin Oncol 21:1431–1439

    Article  PubMed  CAS  Google Scholar 

  10. Fountzilas G, Dafni U, Gogas H et al (2007) Postoperative dose-dense sequential chemotherapy with epirubicin, paclitaxel and CMF in patients with high-risk breast cancer: safety analysis of the Hellenic Cooperative Oncology Group randomized Phase III trial HE 10/00. Ann Oncol 19:853–860

    Article  PubMed  Google Scholar 

  11. Coombes RC, Hall E, Gibson LJ et al (2004) Intergroup Exemestane Study. A randomized trial of exemestane after two to three years of tamoxifen therapy in postmenopausal women with primary breast cancer. N Engl J Med 350:1081–1092

    Article  PubMed  CAS  Google Scholar 

  12. Fountzilas G, Skarlos D, Dafni U et al (2005) Postoperative dose-dense sequential chemotherapy with epirubicin, followed by CMF with or without paclitaxel in patients with high-risk operable breast cancer: a randomized phase III study conducted by the Hellenic Cooperative Oncology Group. Ann Oncol 16:1762–1771

    Article  PubMed  CAS  Google Scholar 

  13. Moher D (1998) CONSORT: an evolving tool to help improve the quality of reports of randomized controlled trials. JAMA 279:1489–1491

    Article  PubMed  CAS  Google Scholar 

  14. Hudis C, Fornier M, Riccio L et al (1999) 5-Year results of dose-intensive sequential adjuvant chemotherapy for women with high-risk node-positive breast cancer: a phase II study. J Clin Oncol 17:118–1126

    Google Scholar 

  15. Hryniuk W (2001) Dosage parameters in chemotherapy of breast cancer. Breast Dis 14:21–30

    PubMed  CAS  Google Scholar 

  16. Piccart-Gebhart MJ (2003) Mathematics and Oncology: a match for life? J Clin Oncol 21:1425–1428

    Article  PubMed  CAS  Google Scholar 

  17. Trudeau ME (2001) Optimizing adjuvant breast cancer chemotherapy: rationale for the MA.21 study. Oncology (Williston Park) 5(Suppl. 7):7–13

    Google Scholar 

  18. Moebus V, Jackisch Ch, Luek HJ et al (2010) Intense dose-dense sequential chemotherapy with epirubicin, paclitaxel and cyclophosphamide compared with conventionally scheduled chemotherapy in high-risk primary breast cancer: mature results of an AGO phase III study. J Clin Oncol 28:2874–2880

    Article  PubMed  CAS  Google Scholar 

  19. Hudis C, Citron M, Berry D et al (2005) Five year follow-up of INT C9741: Dose dense chemotherapy is safe and effective. Breast Cancer Res Treat 94:S20 (suppl: abstr 41)

    Google Scholar 

  20. Green MC, Buzdar AU, Smith T et al (2005) Weekly paclitaxel improves pathologic complete remission in operable breast cancer when compared with paclitaxel once every 3 weeks. J Clin Oncol 23:5983–5992

    Article  PubMed  CAS  Google Scholar 

  21. Sparano JA, Wang M, Martino S et al (2008) Weekly paclitaxel in the adjuvant treatment of breast cancer. N Engl J Med 358:1663–1671

    Article  PubMed  CAS  Google Scholar 

  22. Mamounas EP, Bryant J, Lembersky BC et al (2005) Paclitaxel after doxorubicin plus cyclophosphamide as adjuvant chemotherapy for node-positive breast cancer. Results from NSABP-B28. J Clin Oncol 23:3686–3696

    Article  PubMed  CAS  Google Scholar 

  23. Fisher B, Anderson S, Wickerham DL et al (1996) Increased intensification and total dose of cyclophosphamide in a doxorubicin-cyclophosphamide regimen for the treatment of primary breast cancer. Findings from national surgical adjuvant breast and bowel project B-22. J Clin Oncol 15:1858–1869

    Google Scholar 

  24. Fisher B, Anderson S, DeCillis A et al (1999) Further evaluation of intensified and increased total dose of cyclophosphamide for the treatment of primary breast cancer: Finding from National Surgical Adjuvant Breast and Bowel Project B-25. J Clin Oncol 17:3374–3388

    PubMed  CAS  Google Scholar 

  25. Βonilla L, Ben-Aharon I, Vidal L et al (2010) Dose-Dense chemotherapy in nonmetastatic breast cancer: a systematic review and meta-analysis of randomized controlled trials. JNCI 24:1845–1854

    Google Scholar 

  26. Venturini M, Del Mastro L, Aitini E et al (2005) Dose-dense adjuvant chemotherapy in early breast cancer patients. Results from a randomized trial. J Natl Cancer Inst 97:1724–1733

    Article  PubMed  CAS  Google Scholar 

  27. Levine MN, Pritchard KI, Bramwell VHC et al (2005) Randomized trial comparing cyclophosphamide, epirubicin and fluorouracil with cyclophosphamide, methotrexate and flouorouracil in premenopausal women with node-positive breast cancer. Update of National Cancer Institute of Canada Clinical Trial Group Trial MA5. J Clin Oncol 23:5166–5170

    Article  PubMed  CAS  Google Scholar 

  28. Bonneterre J, Roche H, Kerbrat P et al (2005) Epirubicin increases long-term survival in adjuvant chemotherapy of patients with poor-prognosis, node-positive, early breast cancer: 10 year follow-up results of the French Adjuvant Study Group 05 randomized trial. J Clin Oncol 23:2686–2693

    Article  PubMed  CAS  Google Scholar 

  29. Linden HM, Haskell CM, Green SJ et al (2007) Sequenced compared with simultaneous anthracycline and cyclophosphamide in high-risk stage I and II breast cancer: final analysis from INT-0137 (S9313). J Clin Oncol 25(6):656–661

    Article  PubMed  CAS  Google Scholar 

  30. Burnell M, Levine MN, Chapman Jw et al (2010) Cyclophosphaimide, epirubicin and fluorouracil versus dose-dense epirubicin and cyclophosphamide followed by paclitaxel versus doxorubicin and cyclophosphamide followed by paclitaxel in node-positive or high-risk node-negative breast cancer. J Clin Oncol 28:77–82

    Article  PubMed  CAS  Google Scholar 

  31. Hayes DF, Thor AD, Dressler LG et al (2007) HER2 and response to paclitaxel in node-positive breast cancer. N Engl J Med 357:1496–1506

    Article  PubMed  CAS  Google Scholar 

  32. Berry DA, Cirrincione C, Henderson IC et al (2006) Estrogen-receptor status and outcomes of modern chemotherapy for patients with node-positive breast cancer. JAMA 295:1658–1667

    Article  PubMed  CAS  Google Scholar 

  33. Gluz O, Nitz UA, Harbeck N et al (2008) Triple-negative high-risk breast cancer derives particular benefit from dose intensification of adjuvant chemotherapy: results of WSG AM-01 trial. Ann Oncol 19:861–870

    Article  PubMed  CAS  Google Scholar 

  34. Eiermann W, Pienkowski T, Crown J (2011) Phase III study of doxorubicin/cyclophosphamide with concomitant versus sequential docetaxel as adjuvant treatment in patients with human epidermal growth factor receptor 2-normal, node-positive breast cancer: BCIRG-005 trial. J Clin Oncol 29:3877–3884

    Article  PubMed  CAS  Google Scholar 

  35. Piedbois P, Serin D, Priou F et al (2007) Dose-dense adjuvant chemotherapy in node-positive breast cancer: docetaxel followed by epirubicin/cyclophosphamide (T/EC), or the reverse sequence (EC/T), every 2 weeks, versus docetaxel, epirubicin and cyclophosphamide (TEC) every 3 weeks. AERO B03 randomized phase II study. Ann Oncol 18:52–57

    Article  PubMed  CAS  Google Scholar 

  36. Gluck S (2005) Adjuvant chemotherapy for early breast cancer: optimal use of epirubicin. Oncologist 10:780–791

    Article  PubMed  CAS  Google Scholar 

  37. Praga C, Bergh J, Biss J et al (2005) Risk of acute myeloid leukemia and myelodysplastic syndrome in trials of adjuvant epirubicin for early breast cancer: correlation with doses of epirubicin and cyclophosphamide. J Clin Oncol 23:4179–4191

    Article  PubMed  CAS  Google Scholar 

  38. Burstein HJ, Parker LM, Keshaviah A et al (2005) Efficacy of pegfilgrastim and darbepoetin alfa as hematopoietic support for dose-dense every-2-week adjuvant breast cancer chemotherapy. J Clin Oncol 23:8340–8347

    Article  PubMed  CAS  Google Scholar 

  39. Smith TJ, Khatcheressian J, Lyman GH et al (2006) Update of recommendations for the use of white blood cell growth factors: an evidence-based clinical practice guideline. J Clin Oncol 24:1–19

    Article  Google Scholar 

  40. Hershman D, Neugut Al, Jacobson JS et al (2007) Acute myeloid leukemia or myelodysplastic syndrome following use of granulocyte colony-stimulating factors during breast cancer adjuvant chemotherapy. J Natl Cancer Inst 99:196–205

    Article  PubMed  CAS  Google Scholar 

  41. Chau D (2011) The End of an era: shall we move forward? JCO 3849–3851

Download references

Disclosures

None.

Author information

Authors and Affiliations

  1. 1st Department of Medicine, “Laiko” General Hospital, University of Athens, Medical School, P.O. Box 14120, Athens, 11510, Greece

    Helen Gogas & Christos Markopoulos

  2. Laboratory of Biostatistics, University of Athens School of Nursing, Athens, Greece

    Urania Dafni

  3. Department of Medical Oncology, “Papageorgiou” Hospital, Aristotle University of Thessaloniki School of Medicine, Thessaloniki, Greece

    Maria Karina, Eleni Timotheadou & George Fountzilas

  4. Department of Clinical Therapeutics, “Alexandra” Hospital, University of Athens School of Medicine, Athens, Greece

    Christos Papadimitriou & Meletios A. Dimopoulos

  5. Department of Pathology, Ioannina University Hospital, Ioannina, Greece

    Anna Batistatou

  6. Laboratory of Molecular Oncology, Hellenic Foundation for Cancer Research, Aristotle University of Thessaloniki School of Medicine, Thessaloniki, Greece

    Mattheos Bobos

  7. Department of Medicine, Division of Oncology, University Hospital, University of Patras Medical School, Patras, Greece

    Haralabos P. Kalofonos

  8. Hellenic Cooperative Oncology Group, Data Office, Section of Biostatistics, Athens, Greece

    Anastasia G. Eleftheraki

  9. 1st Department of Medical Oncology, “Metropolitan” Hospital, Athens, Greece

    Dimitrios Bafaloukos

  10. 2nd Department of Medical Oncology, “Metropolitan” Hospital, Athens, Greece

    Christos Christodoulou

  11. Department of Medical Oncology, Ioannina University Hospital, Ioannina, Greece

    Evangelos Briasoulis

  12. Department of Medical Oncology, “Hippokration” Hospital, Athens, Greece

    Pavlos Papakostas

  13. 3rd Department of Medical Oncology, “Agii Anargiri” Cancer Hospital, Athens, Greece

    Epaminontas Samantas

  14. 2nd Department of Medical Oncology, “Hygeia” Hospital, Athens, Greece

    Paris Kosmidis

  15. First Oncology Clinic, “Henry Dunant” Hospital, Athens, Greece

    George P. Stathopoulos

  16. Department of Medical Oncology, 424 General Military Hospital of Thessaloniki, Thessaloniki, Greece

    Charisios Karanikiotis

  17. 2nd Department of Internal Medicine, Oncology Section, “Hippokration” Hospital, Athens, Greece

    Dimitrios Pectasides

Authors
  1. Helen Gogas
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Urania Dafni
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Maria Karina
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Christos Papadimitriou
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Anna Batistatou
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Mattheos Bobos
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Haralabos P. Kalofonos
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Anastasia G. Eleftheraki
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Eleni Timotheadou
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Dimitrios Bafaloukos
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Christos Christodoulou
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Christos Markopoulos
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Evangelos Briasoulis
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Pavlos Papakostas
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Epaminontas Samantas
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Paris Kosmidis
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. George P. Stathopoulos
    View author publications

    You can also search for this author in PubMed Google Scholar

  18. Charisios Karanikiotis
    View author publications

    You can also search for this author in PubMed Google Scholar

  19. Dimitrios Pectasides
    View author publications

    You can also search for this author in PubMed Google Scholar

  20. Meletios A. Dimopoulos
    View author publications

    You can also search for this author in PubMed Google Scholar

  21. George Fountzilas
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Helen Gogas.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Gogas, H., Dafni, U., Karina, M. et al. Postoperative dose-dense sequential versus concomitant administration of epirubicin and paclitaxel in patients with node-positive breast cancer: 5-year results of the Hellenic Cooperative Oncology Group HE 10/00 phase III Trial. Breast Cancer Res Treat 132, 609–619 (2012). https://doi.org/10.1007/s10549-011-1913-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10549-011-1913-4

Keywords

Search

Navigation