Breast Cancer Research and Treatment

, Volume 131, Issue 3, pp 939–947 | Cite as

Individually tailored treatment with epirubicin and paclitaxel with or without capecitabine as first-line chemotherapy in metastatic breast cancer: a randomized multicenter trial

  • T. HatschekEmail author
  • L. Carlsson
  • Z. Einbeigi
  • E. Lidbrink
  • B. Linderholm
  • B. Lindh
  • N. Loman
  • M. Malmberg
  • S. Rotstein
  • M. Söderberg
  • M. Sundquist
  • T. M. Walz
  • M. Hellström
  • H. Svensson
  • G. Åström
  • Y. Brandberg
  • J. Carstensen
  • M. Fernö
  • J. Bergh
Clinical trial


Anthracyclines and taxanes are active cytotoxic drugs in the treatment of early metastatic breast cancer. It is yet unclear whether addition of capecitabine to the combination of these drugs improves the treatment outcome. Patients with advanced breast cancer were randomized to first-line chemotherapy with a combination of epirubicin (Farmorubicin®) and paclitaxel (Taxol®) alone (ET) or in combination with capecitabine (Xeloda®, TEX). Starting doses for ET were epirubicin 75 mg/m2 plus paclitaxel 175 mg/m2, and for TEX epirubicin 75 mg/m2, paclitaxel 155 mg/m2, and capecitabine 825 mg/m2 BID for 14 days. Subsequently, doses were tailored related to side effects. Primary endpoint was progression-free survival (PFS); secondary endpoints were overall survival (OS), time to treatment failure (TTF), objective response (OR), safety and quality of life (QoL). 287 patients were randomized, 143 to ET and 144 to TEX. Median PFS was 10.8 months for patients treated with ET, and 12.4 months for those treated with TEX (HR 0.84, 95% CI 0.65–1.07, P = 0.16); median OS was 26.0 months for women in the ET versus 29.7 months in the TEX arm (HR 0.84, 95% CI 0.63–1.11, P = 0.22). OR was achieved in 44.8% (ET) and 54.2% (TEX), respectively (χ2 3.66, P = 0.16). TTF was significantly longer for patients treated with TEX, 6.0 months, versus 5.2 months following ET (HR 0.73, 95% CI 0.58–0.93, P = 0.009). Severe hematological side effects related to epirubicin and paclitaxel were evenly distributed between the treatment arms, mucositis, diarrhea, and Hand-Foot syndrome were significantly more frequent in the TEX arm. Toxicity-adjusted treatment with ET and TEX showed similar efficacy in terms of PFS, OS, and OR. In this trial with limited power, the addition of capecitabine to epirubicin and paclitaxel as first-line treatment did not translate into clinically relevant improvement of the outcome.


Advanced breast cancer First-line treatment Epirubicin Paclitaxel Capecitabine 



Members of the Independent Review Committee Prof. Lars Holmberg, Division of Cancer Studies, King’s College, London, UK, Assoc. Prof. Torgil Möller, Dept of Cancer Epidemiology, Lund University, Sweden, and Prof. Erik Wist, Oslo University Hospital, Oslo, Norway, for constructive discussions during the study.


Unrestricted grants from Bristol-Myers Squibb Sweden AB, Pfizer Sweden AB and Roche Sweden AB, the Research Funds at Radiumhemmet, the Swedish Cancer Society, the Swedish Breast Cancer Association (BRO) and ALF/FOU research funds at the Karolinska Institutet and Stockholm County Council.

Conflict of interest

T. Hatschek: Consulting/advisory role: Pfizer; Funding: Roche, Sanofi-aventis. L. Carlsson: None. Z. Einbeigi: None. E. Lidbrink: None. B. Linderholm: None. B. Lindh: None. N. Loman: None. M. Malmberg: None. S. Rotstein: None. M. Söderberg: Consultant/advisory role: BMS, Roche. M. Sundquist: None. T. M. Walz: None. M. Hellström: None. K. Hammarlund: None. H. Svensson: None. G. Åström: None. Y. Brandberg: None. J. Carstensen: None. M. Fernö: None. J. Bergh: Consultant/advisory role: Amgen, Astrazeneca, GlaxoSmithKline, Pfizer, Sanofi-aventis; Funding: Amgen, Merck, Sanofi-aventis.


  1. 1.
    Sledge GW, Neuberg D, Bernardo P, Ingle JN et al (2003) Phase III trial of doxorubicin, paclitaxel, and the combination of doxorubicin and paclitaxel as front-line chemotherapy for metastatic breast cancer: an Intergroup trial (E1193). J Clin Oncol 21:588–592PubMedCrossRefGoogle Scholar
  2. 2.
    Miwa M, Ura M, Nishida M, Sawada N et al (1998) Design of a novel oral fluoropyrimidine carbamate, capecitabine, which generates 5-fluorouracil selectively in tumors by enzymes concentrated in human liver and cancer tissue. Eur J Cancer 34:1274–1281PubMedCrossRefGoogle Scholar
  3. 3.
    Ishitsuka H (2000) Capecitabine: preclinical pharmacology studies. Invest New Drugs 18:343–354PubMedCrossRefGoogle Scholar
  4. 4.
    Sawada N, Ishikawa T, Fukase Y, Nishida M et al (1998) Induction of thymidine phosphorylase activity and enhancement of capecitabine efficacy by Taxol/Taxotere in human cancer xenografts. Clin Cancer Res 4:1013–1019PubMedGoogle Scholar
  5. 5.
    Puglisi F, Cardellino GG, Crivellari D, Di Loreto C et al (2008) Thymidine phosphorylase expression is associated with time to progression in patients receiving low-dose, docetaxel-modulated capecitabine for metastatic breast cancer. Ann Oncol 19:1541–1546PubMedCrossRefGoogle Scholar
  6. 6.
    Toi M, Bando H, Horiguchi S, Takada M et al (2004) Modulation of thymidine phosphorylase by neoadjuvant chemotherapy in primary breast cancer. Br J Cancer 90:2338–2343PubMedGoogle Scholar
  7. 7.
    Batista N, Perez-Manga G, Constenla M, Ruiz A et al (2004) Phase II study of capecitabine in combination with paclitaxel in patients with anthracycline-pretreated advanced/metastatic breast cancer. Br J Cancer 90:1740–1746PubMedGoogle Scholar
  8. 8.
    Venturini M, Durando A, Garrone O, Colozza MA et al (2003) Capecitabine in combination with docetaxel and epirubicin in patients with previously untreated, advanced breast carcinoma. Cancer 97:1174–1180PubMedCrossRefGoogle Scholar
  9. 9.
    Mansutti M, Cavazzini G, Lorusso V, Boni C et al (2008) Randomized, multicenter, phase III trial of docetaxel plus epirubicin (ET) with or without capecitabine (X) as first-line therapy for stage IV breast cancer (BC). J Clin Oncol 26:49s (May 20 suppl; abstr 1034)Google Scholar
  10. 10.
    Hryniuk W, Bush H (1984) The importance of dose intensity in chemotherapy of metastatic breast cancer. J Clin Oncol 2:1281–1288PubMedGoogle Scholar
  11. 11.
    Baker SD, Verweij J, Rowinsky EK, Donehower RC et al (2002) Role of body surface area in dosing of investigational anticancer agents in adults, 1991–2001. JNCI 94:1883–1888PubMedGoogle Scholar
  12. 12.
    Gurney HP, Ackland S, Gebski V, Farell G (1998) Factors affecting epirubicin pharmacokinetics and toxicity: evidence against using body-surface area for dose calculation. J Clin Oncol 16:2299–2304PubMedGoogle Scholar
  13. 13.
    Wiechec E, Hansen LL (2009) The effect of genetic variability on drug response in conventional breast cancer treatment. Eur J Pharmacol 625:122–130PubMedCrossRefGoogle Scholar
  14. 14.
    Einbeigi Z, Bergström D, Hatschek T, Malmberg M (2008) Paclitaxel, epirubicin and capecitabine (TEX) as first-line treatment for metastatic breast cancer: a pilot phase I/II feasibility study. Clin Med Oncol 2:533–538PubMedGoogle Scholar
  15. 15.
    Jassem J, Pienkowski T, Pluzanska A, Jelic S et al (2001) Doxorubicin and paclitaxel versus fluorouracil, doxorubicin, and cyclophosphamide as first-line therapy for women with metastatic breast cancer: final results of a randomized phase III multicenter trial. J Clin Oncol 19:1707–1715PubMedGoogle Scholar
  16. 16.
    Slamon DJ, Leyland-Jones B, Shak S et al (2001) Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med 344:783–792PubMedCrossRefGoogle Scholar
  17. 17.
    Marty M, Cognetti F, Maraninchi D et al (2005) Randomized phase II trial of the efficacy and safety of trastuzumab combined with docetaxel in patients with human epidermal growth factor receptor 2—positive metastatic breast cancer administered as first-line treatment: the M77001 Study Group. J Clin Oncol 23:4265–4274PubMedCrossRefGoogle Scholar
  18. 18.
    Therasse P, Arbuck SG, Eisenhauer EA, Wanders J 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 92:205–216PubMedCrossRefGoogle Scholar
  19. 19.
    WHO (1979) WHO Handbook for reporting results of cancer treatment. World Health Organization. WHO Offset Publication No. 48, GenevaGoogle Scholar
  20. 20.
    Collett D (1994) Modelling survival data in medical research. Chapman & Hall, London, p 255Google Scholar
  21. 21.
    Butters DJ, Ghersi D, Wilcken N, Kirk SJ et al (2010) Addition of drug/s to a chemotherapy regimen for metastatic breast cancer (Review). The Cochrane Collaboration. Wiley, ChichesterGoogle Scholar
  22. 22.
    Ghersi D, Wilcken N, Simes J, Donoghue E (2008) Taxane containing regimens for metastatic breast cancer (Review). The Cochrane Collaboration. Wiley, ChichesterGoogle Scholar
  23. 23.
    Biganzoli L, Cufer T, Bruning P (2002) Doxorubicin and paclitaxel versus doxorubicin and cyclophosphamide as first-line chemotherapy in metastatic breast cancer: the European Organization for Research and Treatment of Cancer 10961 multicenter phase III trial. J Clin Oncol 20:3114–3121PubMedCrossRefGoogle Scholar
  24. 24.
    Venturini M, Paridaens R, Rossner D, Vaslamatzis MM et al (2007) An open-label, multicenter study of outpatient capecitabine monotherapy in 631 patients with pretreated advanced breast cancer. Oncology 72:51–57PubMedCrossRefGoogle Scholar
  25. 25.
    Fossati R, Confalonierir C, Torri V, Ghislandi E et al (1998) Cytotoxic and hormonal treatment for metastatic breast cancer: a systematic review of published randomized trials involving 31, 510 women. J Clin Oncol 16:3439–3460PubMedGoogle Scholar
  26. 26.
    Jones SE, Erban J, Overmoyer B, Budd GT et al (2005) Randomized phase III study of docetaxel compared with paclitaxel in metastatic breast cancer. J Clin Oncol 23:5542–5551PubMedCrossRefGoogle Scholar
  27. 27.
    Wilking N, Lidbrink E, Wiklund T, Erikstein B et al (2007) Long-term follow-up of the SBG 9401 study comparing tailored FEC-based therapy versus marrow-supported high-dose therapy. Ann Oncol 18:694–700PubMedCrossRefGoogle Scholar
  28. 28.
    Gamelin E, Delva R, Jacob J, Merrouche Y et al (2008) Individual fluorouracil dose adjustment based on pharmacokinetic follow-up compared with conventional dosage: results of a multicenter randomized trial of patients with metastatic colorectal cancer. J Clin Oncol 26:2099–2105PubMedCrossRefGoogle Scholar
  29. 29.
    Fleming RA, Milano G, Thyss A, Etienne MC et al (1992) Correlation between dihydropyrimidine dehydrogenase activity in peripheral mononuclear cells and systemic clearance of fluorouracil in cancer patients. Cancer Res 52:2899–2902PubMedGoogle Scholar
  30. 30.
    Honda J, Sasa M, Moriya T, Bando Y et al (2008) Thymidine phosphorylase and dihydropyrimidine dehydrogenase are predictive factors of therapeutic efficacy of capecitabine monotherapy for breast cancer—preliminary results. J Med Invest 55:54–60PubMedCrossRefGoogle Scholar
  31. 31.
    Svensson H, Einbeigi Z, Johansson H, Hatschek T, Brandberg Y (2010) Quality of life in women with metastatic breast cancer during 9 months after randomization in the TEX trial (epirubicin and paclitaxel w/o capecitabine). Breast Cancer Res Treat 123:785–793PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC. 2011

Authors and Affiliations

  • T. Hatschek
    • 1
    Email author
  • L. Carlsson
    • 2
  • Z. Einbeigi
    • 3
  • E. Lidbrink
    • 1
  • B. Linderholm
    • 3
  • B. Lindh
    • 4
  • N. Loman
    • 5
  • M. Malmberg
    • 6
  • S. Rotstein
    • 1
  • M. Söderberg
    • 7
  • M. Sundquist
    • 8
  • T. M. Walz
    • 9
  • M. Hellström
    • 10
  • H. Svensson
    • 3
  • G. Åström
    • 1
    • 11
  • Y. Brandberg
    • 1
  • J. Carstensen
    • 12
  • M. Fernö
    • 13
  • J. Bergh
    • 1
  1. 1.Breast-Sarcoma Unit, Department of OncologyKarolinska University Hospital, Karolinska InstitutetStockholmSweden
  2. 2.Department of OncologySundsvall General HospitalSundsvallSweden
  3. 3.Department of OncologySahlgrenska University HospitalGothenburgSweden
  4. 4.Department of OncologyUmeå University HospitalUmeåSweden
  5. 5.Department of OncologySkåne University Hospital LundLundSweden
  6. 6.Department of OncologyHelsingborg General HospitalHelsingborgSweden
  7. 7.Department of OncologySkåne University HospitalMalmöSweden
  8. 8.Department of OncologyKalmar General HospitalKalmarSweden
  9. 9.Department of OncologyLinköping University HospitalLinköpingSweden
  10. 10.Clinical Trial Unit, Department of OncologyKarolinska University HospitalStockholmSweden
  11. 11.Department of RadiologyUppsala University HospitalUppsalaSweden
  12. 12.Department of Health and SocietyLinköping UniversityLinköpingSweden
  13. 13.Department of Oncology, Clinical SciencesLund UniversityLundSweden

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