Skip to main content

Advertisement

SpringerLink
Log in

Dose intensity in anthracycline-based chemotherapy for metastatic breast cancer: mature results of the randomised clinical trial ANZ 9311

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

Abstract

Purpose

The separate impacts of dose and dose intensity of chemotherapy for metastatic breast cancer remain uncertain. The primary objective of this trial was to compare a short, high-dose, intensive course of epirubicin and cyclophosphamide (EC) with a longer conventional dose regimen delivering the same total dose of chemotherapy.

Methods

This open label trial randomised 235 women with metastatic breast cancer to receive either high-dose epirubicin 150 mg/m2 and cyclophosphamide 1500 mg/m2 with filgrastim support every 3 weeks for 3 cycles (HDEC) or standard dose epirubicin 75 mg/m2 and cyclophosphamide 750 mg/m2 every 3 weeks for 6 cycles (SDEC). Primary outcomes were time to progression, overall survival and quality of life.

Results

In 118 patients allocated HDEC 90% of the planned dose was delivered, compared to 96% in the 117 participants allocated SDEC. There were no significant differences in the time to disease progression (5.7 vs. 5.8 months, P = 0.19) or overall survival (14.5 vs. 16.5 months, P = 0.29) between HDEC and SDEC, respectively. Patients on HDEC reported worse quality of life during therapy, but scores improved after completion to approximate those reported by patients allocated SDEC. Objective tumour response was recorded in 33 (28%) on HDEC and 42 patients (36%) on SDEC. HDEC produced more haematologic toxicity.

Conclusion

For women with metastatic breast cancer, disease progression, survival or quality of life were no better with high-dose intensity compared to standard dose EC chemotherapy.

Australian Clinical Trials Registry registration number ACTRN12605000478617.

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. International Agency for Research on Cancer (GLOBOCAN 2012) Estimated cancer incidence, prevalence and mortality worldwide in 2012. WHO 2012

  2. Australian Institute of Health and Welfare (2014) Cancer in Australia: an overview. Australian Institute of Health and Welfare & Australasian Association of Cancer Registries, Canberra

    Google Scholar 

  3. Cardoso F, Costa A, Senkus E et al (2017) 3rd ESO–ESMO International Consensus Guidelines for Advanced Breast Cancer (ABC 3). Ann Oncol 28:16–33

    Article  CAS  PubMed  Google Scholar 

  4. Skipper HE (1971) Kinetics of mammary tumor cell growth and implications for therapy. Cancer 28:1479–1499

    Article  CAS  PubMed  Google Scholar 

  5. Hryniuk W, Bush H (1984) The importance of dose intensity in chemotherapy of metastatic breast cancer. J Clin Oncol 2:1281–1288

    Article  CAS  Google Scholar 

  6. Soley B, Banu A (2012) Dose-dense chemotherapy for breast cancer. Breast J 18:261–266

    Article  CAS  Google Scholar 

  7. Tannock IF, Boyd NF, DeBoer G et al (1988) A randomized trial of two dose levels of cyclophosphamide, methotrexate, and fluorouracil chemotherapy for patients with metastatic breast cancer. J Clin Oncol 6:1377–1387

    Article  CAS  PubMed  Google Scholar 

  8. Wood WC, Budman DR, Korzun AH et al (1994) Dose and dose intensity of adjuvant chemotherapy for stage II, node-positive breast carcinoma. N Engl J Med 330:1253–1259

    Article  CAS  PubMed  Google Scholar 

  9. Marschner N, Nagel GA, Beyer JH et al (1990) High-dose epirubicin in combination with cyclophosphamide (HD-EC) in advanced breast cancer: final results of a dose finding study and phase II trial. Onkologie 13:272–278

    CAS  PubMed  Google Scholar 

  10. Brufman G, Colajori E, Ghilezan N et al (1997) Doubling epirubicin dose intensity (100 mg/m2 versus 50 mg/m2) in the FEC regimen significantly increases response rates. An international randomised phase III study in metastatic breast cancer. The Epirubicin High Dose (HEPI 010) Study Group. Ann Oncol 8:155–162

    Article  CAS  PubMed  Google Scholar 

  11. 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: findings from National Surgical Adjuvant Breast and Bowel Project B-25. J Clin Oncol 17:3374–3388

    Article  CAS  PubMed  Google Scholar 

  12. Talbot SM, Westerman DA, Grigg AP et al (1999) Phase I and subsequent phase II study of filgrastim (r-met-HuG-CSF) and dose intensified cyclophosphamide plus epirubicin in patients with non-Hodgkin’s lymphoma and advanced solid tumors. Ann Oncol 10:907–914

    Article  CAS  PubMed  Google Scholar 

  13. Levi JA, Beith JM, Snyder RD et al (1995) Phase II study of high dose epirubicin in combination with cyclophosphamide in patients with advanced breast cancer. Aust New Z J Med 25:474–478

    Article  CAS  Google Scholar 

  14. Coates A, Gebski V, Bishop JF et al (1987) Improving the quality of life during chemotherapy for advanced breast cancer. A comparison of intermittent and continuous treatment strategies. N Engl J Med 317:1490–1495

    Article  CAS  PubMed  Google Scholar 

  15. Coates A, Glasziou P, McNeil D (1990) On the receiving end–III. Measurement of quality of life during cancer chemotherapy. Ann Oncol 1:213–217

    Article  CAS  PubMed  Google Scholar 

  16. Spitzer WO, Dobson AJ, Hall J et al (1981) Measuring the quality of life of cancer patients: a concise QL-index for use by physicians. J Chronic Dis 34:585–597

    Article  CAS  PubMed  Google Scholar 

  17. Kaplan EL, Meier P (1958) Nonparametric estimation from incomplete observation. J Am Stat Assoc 53:457–481

    Article  Google Scholar 

  18. Peto R, Pike MC, Armitage P et al (1977) Design and analysis of randomized clinical trials requiring prolonged observation of each patient. II. Analysis and examples. Br J Cancer 35:1–39

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Miller AB, Hoogstraten B, Staquet M, Winkler A (1981) Reporting results of cancer treatment. Cancer 47:207–214

    Article  CAS  PubMed  Google Scholar 

  20. French Epirubicin Study Group (2000) Epirubicin-based chemotherapy in metastatic breast cancer patients: role of dose-intensity and duration of treatment. J Clin Oncol 18:3115–3124

    Article  Google Scholar 

  21. Norton L, Simon R, Brereton HD, Bogden AE (1976) Predicting the course of Gompertzian growth. Nature 264:542–545

    Article  CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  23. Castorina P, Carcò D, Guiot C, Deisboeck TS (2009) Tumor growth instability and its implications for chemotherapy. Cancer Res 69:8507–8515

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Gatenby RA, Silva AS, Gillies RJ, Frieden BR (2009) Adaptive therapy. Cancer Res 69:4894–4903

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Chia SK, Speers CH, D’Yachkova Y et al (2007) The impact of new chemotherapeutic and hormone agents on survival in a population-based cohort of women with metastatic breast cancer. Cancer 110:973–979

    Article  PubMed  Google Scholar 

  26. Bilgrami S, Feingold JM, Bona RD et al (2000) Dose-intense paclitaxel, etoposide and cyclophosphamide: a safe and active regimen for tumor cytoreduction and stem cell mobilization in metastatic breast cancer. Bone Marrow Transpl 25:123–130

    Article  CAS  Google Scholar 

  27. Ballestrero A, Montemurro F, Gonella R et al (2003) Dose-dense vinorelbine and paclitaxel with granulocyte colony-stimulating factor in metastatic breast cancer patients: anti-tumor activity and peripheral blood progenitor cell mobilization capability. Breast Cancer Res Treat 82:185–190

    Article  CAS  PubMed  Google Scholar 

  28. Winer EP, Berry DA, Woolf S et al (2004) Failure of higher-dose paclitaxel to improve outcome in patients with metastatic breast cancer: cancer and leukemia group B trial 9342. J Clin Oncol 22:2061–2068

    Article  CAS  PubMed  Google Scholar 

  29. Berry DA, Ueno NT, Johnson MM et al (2011) High-dose chemotherapy with autologous stem-cell support as adjuvant therapy in breast cancer: overview of 15 randomized trials. J Clin Oncol 29:3214–3223

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Tanner M, Isola J, Wiklund T et al (2006) Topoisomerase IIα gene amplification predicts favorable treatment response to tailored and dose-escalated anthracycline-based adjuvant chemotherapy in HER-2/neu–amplified breast cancer: Scandinavian Breast Group Trial 9401. J Clin Oncol 24:2428–2436

    Article  CAS  PubMed  Google Scholar 

  31. Bastholt L, Dalmark M, Gjedde SB et al (1996) Dose-response relationship of epirubicin in the treatment of postmenopausal patients with metastatic breast cancer: a randomized study of epirubicin at four different dose levels performed by the Danish Breast Cancer Cooperative Group. J Clin Oncol 14:1146–1155

    Article  CAS  PubMed  Google Scholar 

  32. Lalisang RI, Erdkamp FL, Rodenburg CJ et al (2011) Epirubicin and paclitaxel with G-CSF support in first line metastatic breast cancer: a randomized phase II study of dose-dense and dose-escalated chemotherapy. Breast Cancer Res Treat 128:437–445

    Article  CAS  PubMed  Google Scholar 

  33. Farquhar C, Marjoribanks J, Basser R et al (2005) High dose chemotherapy and autologous bone marrow or stem cell transplantation versus conventional chemotherapy for women with metastatic breast cancer. Cochrane Database Syst Rev. https://doi.org/10.1002/14651858.CD003142.pub2

    Article  PubMed  Google Scholar 

  34. Berry DA, Ueno NT, Johnson MM et al (2011) High-dose chemotherapy with autologous hematopoietic stem-cell transplantation in metastatic breast cancer: overview of six randomized trials. J Clin Oncol 29:3224–3231

    Article  PubMed  PubMed Central  Google Scholar 

  35. Petrelli F, Coinu A, Lonati V et al (2016) Neoadjuvant dose-dense chemotherapy for locally advanced breast cancer: a meta-analysis of published studies. Anticancer Drugs 27:702–708

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We would like to thank the 235 women who took part in this trial and their families, the investigators and trial site staff, and the central coordination staff at the BCT operations office. This trial was supported by research grant support and drug supply from Pharmacia and Upjohn and Amgen Pharmaceuticals.

Funding

This trial was sponsored by Breast Cancer Trials Ltd., supported by Pharmacia and Upjohn Australia (Grant) and Amgen Australia (grant, trial drug).The National Health and Medical Research Council of Australia Clinical Trials Centre provided randomisation and statistical support.

Author information

Authors and Affiliations

  1. Calvary Mater Newcastle Hospital, Newcastle, NSW, Australia

    Stephen. P. Ackland, N. Zdenkowski & J. F. Forbes

  2. NHMRC Clinical Trials Centre, University of Sydney, Sydney, NSW, Australia

    V. Gebski, H. Dhillon, R. J. Simes & A. S. Coates

  3. Royal Melbourne Hospital, Parkville, VIC, Australia

    M. Green

  4. Breast Cancer Trials Ltd., Newcastle, NSW, Australia

    Stephen. P. Ackland, N. Zdenkowski, A. Wilson, S. Tees & J. F. Forbes

  5. Sir Charles Gairdner Hospital, Nedlands, WA, Australia

    G. Van Hazel

  6. Royal North Shore Hospital, St Leonards, NSW, Australia

    J. Levi

  7. University of Newcastle, Newcastle, NSW, Australia

    Stephen. P. Ackland, N. Zdenkowski & J. F. Forbes

Authors
  1. Stephen. P. Ackland
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. V. Gebski
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. N. Zdenkowski
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. A. Wilson
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. M. Green
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. S. Tees
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. H. Dhillon
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. G. Van Hazel
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. J. Levi
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. R. J. Simes
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. J. F. Forbes
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. A. S. Coates
    View author publications

    You can also search for this author in PubMed Google Scholar

Consortia

for Breast Cancer Trials Ltd (formerly known as the Australia and New Zealand Breast Cancer Trials Group)

Corresponding authors

Correspondence to Stephen. P. Ackland or N. Zdenkowski.

Ethics declarations

Conflict of interest

All authors declare that they do not have a conflict of interest.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Informed consent

was obtained from all individual participants included in the study.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (DOCX 279 KB)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Ackland, S.P., Gebski, V., Zdenkowski, N. et al. Dose intensity in anthracycline-based chemotherapy for metastatic breast cancer: mature results of the randomised clinical trial ANZ 9311. Breast Cancer Res Treat 176, 357–365 (2019). https://doi.org/10.1007/s10549-019-05187-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10549-019-05187-y

Keywords

Search

Navigation