Sequential administration of dose-dense epirubicin/cyclophosphamide followed by docetaxel/capecitabine for patients with HER2-negative and locally advanced or node-positive breast cancer

  • Yago Nieto
  • José Manuel Aramendía
  • Jaime Espinós
  • Susana De la Cruz
  • Oscar Fernández-Hidalgo
  • Marta Santisteban
  • Leyre Arbea
  • Javier Aristu
  • Rafael Martínez-Monge
  • Marta Moreno
  • Luis Pina
  • Josu Sola
  • Gerardo Zornoza
  • Fernando Martínez Regueira
Original Article



Capecitabine is effective against metastatic breast cancer (MBC). We hypothesized that sequential treatment with dose-dense epirubicin/cyclophosphamide (EC) and docetaxel/capecitabine would be active and tolerable in the adjuvant/neoadjuvant setting.


In this prospective phase II clinical trial patients with HER2-negative and node-positive or locally advanced tumors were eligible to receive four cycles of EC (100/600 mg/m2) every 2 weeks with G-CSF on days 3–10, followed by four cycles of docetaxel/capecitabine (75/1,000 mg/m2 b.i.d., days 1–14) every 3 weeks.


Fifty-five patients were enrolled with median age of 49, and 80% had hormone receptor-positive disease. The median tumor size was 2.5 cm, with a median of two axillary nodes involved. Seventy-five percent of the first 20 patients had grade 2/3 hand-foot syndrome (HFS). Dose reduction of capecitabine to 800 mg/m2 reduced the grade 2/3 HFS incidence to 31% in the remaining patients. No grade 4/5 toxicities were observed. All 20 patients treated preoperatively responded, with 5 (25%) pathologic complete responses and 3 additional pT0N1 tumors. At a median follow-up of 48 (range 28–60) months, the event-free and overall survival rates are 91 and 98%, respectively.


Sequential treatment with dose-dense EC followed by docetaxel/capecitabine, using a lower capecitabine dose than that approved for MBC, has an acceptable toxicity profile and encouraging activity when used as neoadjuvant or adjuvant treatment of breast cancer.


Phase II trial Capecitabine Docetaxel Adjuvant Neoadjuvant Breast cancer 


  1. 1.
    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 21:1431–1439CrossRefPubMedGoogle Scholar
  2. 2.
    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 21:976–983CrossRefPubMedGoogle Scholar
  3. 3.
    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 B-28. J Clin Oncol 23:3686–3696CrossRefPubMedGoogle Scholar
  4. 4.
    Gianni L, Baselga J, Eiermann W et al (2005) Feasibility and tolerability of sequential doxorubicin/paclitaxel followed by cyclophosphamide, methotrexate, and fluorouracil and its effects on tumor response as preoperative therapy. Clin Cancer Res 11:8715–8721CrossRefPubMedGoogle Scholar
  5. 5.
    Martín M, Pienkowski T, Mackey J et al (2005) Adjuvant docetaxel for node-positive breast cancer. N Engl J Med 352:2302–2313CrossRefPubMedGoogle Scholar
  6. 6.
    Roché H, Fumoleau P, Spielmann M et al (2004) Five years analysis of the PACS 01 trial: 6 cycles of FEC100 vs 3 cycles of FEC100 followed by 3 cycles of docetaxel (D) for the adjuvant treatment of node-positive breast cancer. Breast Cancer Res Treat 88(Suppl 1):S16Google Scholar
  7. 7.
    O’Shaughnessy J, Miles D, Vukelja S et al (2002) Superior survival with capecitabine plus docetaxel combination therapy in anthracycline-pretreated patients with advanced breast cancer: phase III results. J Clin Oncol 20:2812–2823CrossRefPubMedGoogle Scholar
  8. 8.
    Sawada N, Ishikawa T, Fukase Y 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
  9. 9.
    Kurosumi M, Tabei T, Suemasu K et al (2000) Enhancement of immunohistochemical reactivity for thymidine phosphorylase in breast carcinoma cells after administration of docetaxel as a neoadjuvant chemotherapy in advanced breast cancer patients. Oncol Rep 7:945–948PubMedGoogle Scholar
  10. 10.
    Takahashi H, Maeda Y, Watanabe K et al (2000) Correlation between elevated intratumoral thymidine phosphorylase and prognosis of node-positive breast carcinoma undergoing adjuvant doxifluridine treatment. Int J Oncol 17:1205–1211PubMedGoogle Scholar
  11. 11.
    Yang Q, Barbareschi M, Mori I et al (2002) Prognostic value of thymidine phosphorylase expression in breast carcinoma. Int J Cancer 97:512–517CrossRefPubMedGoogle Scholar
  12. 12.
    Tominaga T, Toi M, Ohashi Y et al (2002) Prognostic and predictive value of thymidine phosphorylase activity in early-stage breast cancer patients. Clin Breast Cancer 3:55–64CrossRefPubMedGoogle Scholar
  13. 13.
    Puglisi F, Cardellino GG, Crivellari D 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 19:1541–1546CrossRefPubMedGoogle Scholar
  14. 14.
    Toi M, Bando H, Horiguchi S et al (2004) Modulation of thymidine phosphorylase by neoadjuvant chemotherapy in primary breast cancer. Br J Cancer 90:2338–2343PubMedGoogle Scholar
  15. 15.
    Pegram M, Hsu S, Lewis G et al (1999) Inhibitory effects of combinations of HER-2/neu antibody and chemotherapeutic agents used for treatment of human breast cancers. Oncogene 18:2241–2251CrossRefPubMedGoogle Scholar
  16. 16.
    Pegram MD, Lopez A, Konecny G, Slamon DJ (2000) Trastuzumab and chemotherapeutics: drug interactions and synergies. Semin Oncol 27(6 Suppl 11):21–25PubMedGoogle Scholar
  17. 17.
    Therasse P, Arbuck SG, Eisenhauer EA et al (2000) New guidelines to evaluate the response to treatment in solid tumors. J Natl Cancer Inst 92:205–216CrossRefPubMedGoogle Scholar
  18. 18.
    Piccart M, Di Leo A, Beauduin M et al (2001) Phase III trial comparing two dose levels of epirubicin combined with cyclophosphamide with cyclophosphamide, methotrexate, and fluorouracil in node-positive breast cancer. J Clin Oncol 19:3103–3110PubMedGoogle Scholar
  19. 19.
  20. 20.
    Fleming TR (1982) One-sample multiple testing procedure for phase II clinical trials. Biometrics 38:143–151CrossRefPubMedGoogle Scholar
  21. 21.
    Francis P, Crown JP, Di Leo A et al (2008) Adjuvant chemotherapy with sequential of concurrent and anthracycline and docetaxel: Breast International Group 02–98 randomized trial. J Natl Cancer Inst 100:121–133CrossRefPubMedGoogle Scholar
  22. 22.
    Smith IC, Heys SD, Hutcheon AW et al (2002) Neoadjuvant chemotherapy in breast cancer: significantly enhanced response with docetaxel. J Clin Oncol 20:1456–1466CrossRefPubMedGoogle Scholar
  23. 23.
    Bear HD, Anderson S, Brown A et al (2003) The effect on tumor response of adding sequential preoperative docetaxel to preoperative doxorubicin and cyclophosphamide: preliminary results from National Surgical Adjuvant Breast and Bowel Project Protocol B-27. J Clin Oncol 21:4165–4174CrossRefPubMedGoogle Scholar
  24. 24.
    Bear HD, Anderson S, Smith RE et al (2006) Sequential preoperative or postoperative docetaxel added to preoperative doxorubicin plus cyclophosphamide for operable breast cancer: National Surgical Adjuvant Breast and Bowel Project Protocol B-27. J Clin Oncol 24:2019–2027CrossRefPubMedGoogle Scholar
  25. 25.
    Evans TR, Yellowlees A, Foster E et al (2005) Phase III randomized trial of doxorubicin and docetaxel versus doxorubicin and cyclophosphamide as primary medical therapy in women with breast cancer: an anglo-celtic cooperative oncology group study. J Clin Oncol 23:2988–2995CrossRefPubMedGoogle Scholar
  26. 26.
    Von Minckwitz G, Raab G, Caputo A et al (2005) Doxorubicin with cyclophosphamide followed by docetaxel every 21 days compared with doxorubicin and docetaxel every 14 days as preoperative treatment in operable breast cancer: the GEPARDUO study of the German Breast Group. J Clin Oncol 23:2676–2685CrossRefGoogle Scholar
  27. 27.
    Patterson AV, Zhang H, Moghaddam A et al (1995) Increased sensitivity to the prodrug 5′-deoxy-5-fluorouridine and modulation of 5-fluoro-2′-deoxyuridine sensitivity in MCF-7 cells transfected with thymidine phosphorylase. Br J Cancer 72:669–675PubMedGoogle Scholar
  28. 28.
    Evrard A, Cuq P, Ciccolini J et al (1999) Increased cytotoxicity and bystander effect of 5-fluorouracil and 5-deoxy-5-fluorouridine in human colorectal cancer cells transfected with thymidine phosphorylase. Br J Cancer 80:1726–1733CrossRefPubMedGoogle Scholar
  29. 29.
    Morita T, Matsuzaki A, Tokue A (2001) Enhancement of sensitivity to capecitabine in human renal carcinoma cells transfected with thymidine phosphorylase cDNA. Int J Cancer 92:451–456CrossRefPubMedGoogle Scholar
  30. 30.
    Ishikawa T, Sekiguchi F, Fukase Y et al (1998) Positive correlation between the efficacy of capecitabine and doxifluridine and the ratio of thymidine phosphorylase to dihydropyrimidine dehydrogenase activities in tumors in human cancer xenografts. Cancer Res 58:685–690PubMedGoogle Scholar
  31. 31.
    Fox SB, Engels K, Comley M et al (1997) Relationship of elevated tumour thymidine phosphorylase in node-positive breast carcinomas to the effects of adjuvant CMF. Ann Oncol 8:271–275CrossRefPubMedGoogle Scholar
  32. 32.
    Gasparini G, Toi M, Miceli R et al (1999) Clinical relevance of vascular endothelial growth factor and thymidine phosphorylase in patients with node-positive breast cancer treated with either adjuvant chemotherapy or hormone therapy. Cancer J Sci Am 5:101–111PubMedGoogle Scholar
  33. 33.
    Dang CT, D’Andrea GM, Moynahan ME et al (2004) Phase II study of feasibility of dose-dense FEC followed by alternating weekly taxanes in high-risk, four or more node-positive breast cancer. Clin Cancer Res 10:5754–5761CrossRefPubMedGoogle Scholar
  34. 34.
    Therasse P, Mauriac L, Welnicka-Jaskiewicz M et al (2003) Final results of a randomized phase III trial comparing cyclophosphamide, epirubicin, and fluorouracil with a dose-intensified epirubicin and cyclophosphamide + filgrastim as neoadjuvant treatment in locally advanced breast cancer: an EORTC-NCIC-SAKK multicenter study. J Clin Oncol 21:843–850CrossRefPubMedGoogle Scholar
  35. 35.
    Pronk LC, Vasey P, Sparreboom A et al (2000) A phase I and pharmacokinetic study of the combination of capecitabine and docetaxel in patients with advanced solid tumours. Br J Cancer 83:22–29CrossRefPubMedGoogle Scholar
  36. 36.
    Leonard R, O’Shaughnessy J, Vukelja S et al (2006) Detailed analysis of a randomized phase III trial: can the tolerability of capecitabine plus docetaxel be improved without compromising its survival advantage? Ann Oncol 17:1379–1385CrossRefPubMedGoogle Scholar
  37. 37.
    Miwa M, Ura M, Nishida M et al (1998) Design of a novel oral fluoropyrimidine carbamate, capecitabine, which generates 5-fluorouracil selectively in tumours by enzymes concentrated in human liver and cancer tissue. Eur J Cancer 34:1274–1281CrossRefPubMedGoogle Scholar
  38. 38.
    Schuller J, Cassidy J, Dumont E et al (2000) Preferential activation of capecitabine in tumor following oral administration to colorectal cancer patients. Cancer Chemother Pharmacol 45:291–297CrossRefPubMedGoogle Scholar
  39. 39.
    Joensuu H, Hemminki A, Huovinen M et al (2007) The FinXX trial: safety results in 600 patients (pts) randomized to either docetaxel (T) followed by cyclophosphamide (C)+ epirubicin (E)+ 5-FU (F) (CEF) or T+ capecitabine (X) followed by CEX as adjuvant therapy for early breast cancer (BC). J Clin Oncol 25:18S abstract 1103Google Scholar
  40. 40.
    André F, Mazouni C, Liedtke C et al (2008) HER2 expression and efficacy of preoperative paclitaxel/FAC chemotherapy in breast cancer. Breast Cancer Res Treat 108:183–190CrossRefPubMedGoogle Scholar
  41. 41.
    Colleoni M, Viale G, Zahrieh D et al (2004) Chemotherapy is more effective in patients with breast cancer not expressing steroid hormone receptors: a study of preoperative treatment. Clin Cancer Res 10:6622–6628CrossRefPubMedGoogle Scholar
  42. 42.
    Gianni L, Zambetti M, Clark K et al (2005) Gene expression profiles in paraffin-embedded core biopsy tissue predict response to chemotherapy in women with locally advanced breast cancer. J Clin Oncol 23:7265–7277CrossRefPubMedGoogle Scholar
  43. 43.
    Sparano JA, Wang M, Martino S et al (2008) Weekly paclitaxel in the adjuvant treatment of breast cancer. N Engl J Med 358:1663–1671CrossRefPubMedGoogle Scholar
  44. 44.
    Rivera E, Mejia JA, Arun BK et al (2008) Phase 3 study comparing the use of docetaxel on an every-3-week versus weekly schedule in the treatment of metastatic breast cancer. Cancer 112:1455–1461CrossRefPubMedGoogle Scholar
  45. 45.
    Lee KS, Ro J, Nam B-H et al (2008) A randomized phase-III trial of docetaxel/capecitabine versus doxorubicin/cyclophosphamide as primary chemotherapy for patients with stage II/III breast cancer. Breast Cancer Res Treat 109:481–489CrossRefPubMedGoogle Scholar
  46. 46.
    Layman RM, Thomas DG, Griffith KA et al (2007) Neoadjuvant docetaxel and capecitabine and the use of thymidine phosphorylase as a predictive biomarker in breast cancer. Clin Cancer Res 13:4092–4197CrossRefPubMedGoogle Scholar
  47. 47.
    Natoli C, Cianchetti E, Tinari N et al (2007) A phase II study of dose-dense epirubicin plus cyclophosphamide followed by docetaxel plus capecitabine and pegfilgrastim support as preoperative therapy for patients with stage II, IIIA breast cancer. Ann Oncol 18:1015–1020CrossRefPubMedGoogle Scholar
  48. 48.
    Untch M, Rezai M, Loibl S et al (2007) Evaluating the efficacy and safety of trastuzumab given concomitantly to epirubicin/cyclophosphamide → docetaxel ± capecitabine as neoadjuvant treatment of HER2 overexpressing primary breast cancer First analysis of the GBG/AGO intergroup study “GeparQuattro”. Breast Cancer Res Treat 106(Suppl 1):S224Google Scholar
  49. 49.
    von Minckwitz G, Rezai M, Loibl S et al (2008) Capecitabine given concomitantly or in sequence with EC → docetaxel as neoadjuvant treatment for early breast cancer: GeparQuattro–a GBG/ABO intergroup study. Eur J Cancer Suppl 6:108CrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2009

Authors and Affiliations

  • Yago Nieto
    • 1
    • 6
  • José Manuel Aramendía
    • 1
  • Jaime Espinós
    • 1
  • Susana De la Cruz
    • 1
  • Oscar Fernández-Hidalgo
    • 1
  • Marta Santisteban
    • 1
  • Leyre Arbea
    • 2
  • Javier Aristu
    • 2
  • Rafael Martínez-Monge
    • 2
  • Marta Moreno
    • 2
  • Luis Pina
    • 3
  • Josu Sola
    • 4
  • Gerardo Zornoza
    • 5
  • Fernando Martínez Regueira
    • 5
  1. 1.Department of Medical OncologyClínica Universitaria de NavarraPamplonaSpain
  2. 2.Department of Radiation OncologyClínica Universitaria de NavarraPamplonaSpain
  3. 3.Department of RadiologyClínica Universitaria de NavarraPamplonaSpain
  4. 4.Department of PathologyClínica Universitaria de NavarraPamplonaSpain
  5. 5.Department of Breast SurgeryClínica Universitaria de NavarraPamplonaSpain
  6. 6.UT MD Anderson Cancer CenterHoustonUSA

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