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Metronomic oral combination chemotherapy with capecitabine and cyclophosphamide: a phase II study in patients with HER2-negative metastatic breast cancer

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Abstract

Purpose

Metronomic combination chemotherapy with the oral fluoropyrimidine doxifluridine/5′-deoxy-5-fluorouridine (5 -DFUR) and oral cyclophosphamide (C) showed promising efficacy in a single-arm study. The oral fluoropyrimidine capecitabine was designed to deliver 5-fluorouracil preferentially to tumors, potentially improving efficacy over doxifluridine. We conducted a phase II multicenter study to evaluate an all-oral XC combination in patients with HER2-negative metastatic breast cancer (MBC).

Materials and methods

Patients received capecitabine 828 mg/m2 twice daily with cyclophosphamide 33 mg/m2 twice daily, days 1–14 every 3 weeks. The primary endpoint was overall response rate (ORR). Secondary endpoints included progression-free survival (PFS), overall survival (OS), and safety.

Results

Between May 2007 and April 2009, 51 patients were enrolled and 45 were included in the efficacy analysis. The median follow-up was 18.1 months. ORR was 44.4% and stable disease (≥24 weeks) was achieved in 13.4%, resulting in a 57.8% clinical benefit response rate. Median PFS was 12.3 months (95% confidence interval: 8.9–18.9 months). Median PFS was 10.7 months in triple-negative disease and 13.2 months in estrogen-receptor positive, HER2-negative disease. The 1- and 2-year OS rates were 86 and 71%, respectively. Median OS has not been reached. Grade 3 adverse events comprised leukopenia (26%), neutropenia (16%), and decreased hemoglobin (2%). There was no grade 3 hand-foot syndrome.

Conclusions

Oral XC is an effective first- or second-line therapy for MBC, demonstrating high activity in both luminal A and triple-negative disease with few severe side effects. This metronomic oral combination chemotherapy could be beneficial for the treatment of HER2-negative MBC.

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References

  1. Early Breast Cancer Trialist Collaborative Group (2005) Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials. Lancet 365:1687–1717

    Article  Google Scholar 

  2. Mauri D, Polyzos NP, Salanti G, Pavlidis N, Ioannidis JP (2008) Multiple-treatments meta-analysis of chemotherapy and targeted therapies in advanced breast cancer. J Natl Cancer Inst 100:1780–1791

    Article  PubMed  CAS  Google Scholar 

  3. Rahman ZU, Frye DK, Smith TL, Asmar L, Theriault RL, Buzdar AU, Hortobagyi GN (1999) Results and long term follow-up for 1581 patients with metastatic breast carcinoma treated with standard dose doxorubicin-containing chemotherapy: a reference. Cancer 85:104–111

    Article  PubMed  CAS  Google Scholar 

  4. Hortobagyi GN (2002) Can we cure limited metastatic breast cancer? J Clin Oncol 20:620–623

    PubMed  Google Scholar 

  5. Mancuso P, Colleoni M, Calleri A, Orlando L, Maisonneuve P, Pruneri G, Agliano A, Goldhirsch A, Shaked Y, Kerbel RS, Bertolini F (2006) Circulating endothelial-cell kinetics and viability predict survival in breast cancer patients receiving metronomic chemotherapy. Blood 108:452–459

    Article  PubMed  CAS  Google Scholar 

  6. Pasquier E, Kavallaris M, André N (2010) Metronomic chemotherapy: new rationale for new directions. Nat Rev Clin Oncol 7:455–465

    Article  PubMed  Google Scholar 

  7. Kamen BA, Rubin E, Aisner J, Glatstein E (2000) High-time chemotherapy or high time for low dose. J Clin Oncol 18:2935–2937

    PubMed  CAS  Google Scholar 

  8. Hanahan D, Bergers G, Bergsland E (2000) Less is more, regularly: metronomic dosing of cytotoxic drugs can target tumor angiogenesis in mice. J Clin Invest 105:1045–1047

    Article  PubMed  CAS  Google Scholar 

  9. Browder T, Butterfield CE, Kräling BM, Shi B, Marshall B, O’Reilly MS, Folkman J (2000) Antiangiogenic scheduling of chemotherapy improves efficacy against experimental drug-resistant cancer. Cancer Res 60:1878–1886

    PubMed  CAS  Google Scholar 

  10. Ishikawa F, Miyazono K, Hellman U, Drexler H, Wernstedt C, Hagiwara K, Usuki K, Takaku F, Risau W, Heldin CH (1989) Identification of angiogenic activity and the cloning and expression of platelet-derived endothelial cell growth factor. Nature 338:557–562

    Article  PubMed  CAS  Google Scholar 

  11. Sawada N, Ishikawa T, Fukase Y, Nishida M, Yoshikubo T, Ishitsuka H (1998) Induction of thymidine phosphorylase activity and enhancement of capecitabine efficacy by taxol/taxotere in human cancer xenografts. Clin Cancer Res 4:1013–1019

    PubMed  CAS  Google Scholar 

  12. Endo M, Shinbori N, Fukase Y, Sawada N, Ishikawa T, Ishitsuka H, Tanaka Y (1999) Induction of thymidine phosphorylase expression and enhancement of efficacy of capecitabine or 5′-deoxy-5-fluorouridine by cyclophosphamide in mammary tumor models. Int J Cancer 83:127–134

    Article  PubMed  CAS  Google Scholar 

  13. O’Shaughnessy J, Miles D, Vukelja S, Moiseyenko V, Ayoub JP, Cervantes G, Fumoleau P, Jones S, Lui WY, Mauriac L, Twelves C, Van Hazel G, Verma S, Leonard R (2002) Superior survival with capecitabine plus docetaxel combination therapy in anthracycline-pretreated patients with advanced breast cancer: phase III trial results. J Clin Oncol 20:2812–2823

    Article  PubMed  Google Scholar 

  14. Blum JL, Dees EC, Chacko A, Doane L, Ethirajan S, Hopkins J, McMahon R, Merten S, Negron A, Neubauer M, Ilegbodu D, Boehm KA, Asmar L, O’Shaughnessy JA (2006) Phase II trial of capecitabine and weekly paclitaxel as first-line therapy for metastatic breast cancer. J Clin Oncol 24:4384–4390

    Article  PubMed  CAS  Google Scholar 

  15. Endo M, Fujimoto-Ouchi K, Matsumoto T, Tanaka Y, Ishitsuka H (1997) Efficacy of combination chemotherapy of cyclophosphamide and 5′-deoxy-5-fluorouridine in a mammary tumor xenograft model, MX-1. Jpn J Cancer Chemother 24:1295–1301

    CAS  Google Scholar 

  16. Yoshimoto M, Tada K, Tokudome N, Kutomi G, Tanabe M, Goto T, Nishimura S, Makita M, Kasumi F (2003) The potential for oral combination chemotherapy of 5′-deoxy-5-fluorouridine, a 5-FU prodrug, and cyclophosphamide for metastatic breast cancer. Br J Cancer 89:1627–1632

    Article  PubMed  CAS  Google Scholar 

  17. Ebi H, Sigeoka Y, Saeki T, Kawada K, Igarashi T, Usubuchi N, Ueda R, Sasaki Y, Minami H (2005) Pharmacokinetic and pharmacodynamic comparison of fluoropyrimidine derivatives, capecitabine and 5′-deoxy-5-fluorouridine (5′-DFUR). Cancer Chemother Pharmacol 56:205–211

    Article  PubMed  CAS  Google Scholar 

  18. Ohno S, Mitsuyama S, Tamura K, Nishimura R, Tanaka M, Hamada Y, Kuroki S, Kyushu Breast Cancer Study Group (2007) Dosage of capecitabine and cyclophosphamide combination therapy in patients with metastatic breast cancer. Anticancer Res 27:1009–1013

    PubMed  CAS  Google Scholar 

  19. Common Terminology Criteria for Adverse Events (CTCAE v3.0) (2004) 2003 (Japanese translation JCOG/JCSP version, 2004) Int J Clin Oncol 9(Suppl III):1–82 (in Japanese)

    Google Scholar 

  20. Therasse P, Arbuck SG, Eisenhauer EA, Wanders J, Kaplan RS, Rubinstein L, Verweij J, Van Glabbeke M, van Oosterom AT, Christian MC, Gwyther SG (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 92:205–216

    Article  PubMed  CAS  Google Scholar 

  21. Kusama M, Nomizu T, Aogi K, Yoshimoto M, Horikoshi N, Tabei T, Noguchi S, Miura S, Yoshimura N, Kimura M, Toyama K, Shin E (2010) Phase II study of 4-weekly capecitabine monotherapy in advanced/metastatic breast cancer. Breast Cancer 17:233–240

    Article  PubMed  Google Scholar 

  22. Banna GL, Simonelli M, Santoro A (2007) High-dose chemotherapy followed by autologous hematopoietic stem-cell transplantation for the treatment of solid tumors in adults: a critical review. Curr Stem Cell Res Ther 2:65–82

    Article  PubMed  CAS  Google Scholar 

  23. Epstein RJ (1999) Drug-induced DNA damage and tumor chemosensitivity. J Clin Oncol 8:2062–2084

    Google Scholar 

  24. Goss PE, Chambers AF (2010) Does tumour dormancy offer a therapeutic target? Nat Rev Cancer 10:871–877

    Article  PubMed  CAS  Google Scholar 

  25. O’Shaughnessy J (2005) Extending survival with chemotherapy in metastatic breast cancer. Oncologist 10:20–29

    Article  PubMed  Google Scholar 

  26. Tanaka Y, Eda H, Fujimoto K, Tanaka T, Ishikawa T, Ishitsuka H (1990) Anticachectic activity of 5′-deoxy-5-fluorouridine in a murine tumor cachexia model, colon 26 adenocarcinoma. Cancer Res 50:4528–4532

    PubMed  CAS  Google Scholar 

  27. Huober J, von Minckwitz G, Denkert C, Tesch H, Weiss E, Zahm DM, Belau A, Khandan F, Hauschild M, Thomssen C, Högel B, Darb-Esfahani S, Mehta K, Loibl S (2010) Effect of neoadjuvant anthracycline-taxane-based chemotherapy in different biological breast cancer phenotypes: overall results from the GeparTrio study. Breast Cancer Res Treat 124:133–140

    Article  PubMed  CAS  Google Scholar 

  28. Hall C, Krishnamurthy S, Lodhi A, Mosalpuria K, Kuerer HM, Meric-Bernstam F, Bedrosian I, Hunt KK, Lucci A (2010) Disseminated tumor cells in biologic subtypes of stage I-III breast cancer patients. Ann Surg Oncol 17:3252–3259

    Article  PubMed  Google Scholar 

  29. Toi M, Nakamura S, Kuroi K, Iwata H, Ohno S, Masuda N, Kusama M, Yamazaki K, Hisamatsu K, Sato Y, Kashiwaba M, Kaise H, Kurosumi M, Tsuda H, Akiyama F, Ohashi Y, Takatsuka Y, Japan Breast Cancer Research Group (JBCRG) (2008) Phase II study of preoperative sequential FEC and docetaxel predicts of pathological response and disease free survival. Breast Cancer Res Treat 110:531–539

    Article  PubMed  CAS  Google Scholar 

  30. Albain KS, Paik S, van’t Veer L (2009) Prediction of adjuvant chemotherapy benefit in endocrine responsive, early breast cancer using multigene assays. Breast 18(Suppl 3):S141–S145

    Article  PubMed  Google Scholar 

  31. Piccart MJ (1999) Integration of new therapies into management of metastatic breast cancer: a focus on chemotherapy, treatment selection through use of molecular markers, and newly developed biologic therapies in late clinical development. ASCO Educ Book, pp 526–539

Download references

Acknowledgments

The authors wish to thank the participating patients and their families, and the clinical trial investigators. This clinical study was supported by the non-profit organization ECRIN (Epidemiological and Clinical Research Information Network, Kyoto, Japan).

Conflict of interest

There was no financial disclosure from any of the authors.

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Correspondence to Masataka Yoshimoto.

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Yoshimoto, M., Takao, S., Hirata, M. et al. Metronomic oral combination chemotherapy with capecitabine and cyclophosphamide: a phase II study in patients with HER2-negative metastatic breast cancer. Cancer Chemother Pharmacol 70, 331–338 (2012). https://doi.org/10.1007/s00280-012-1826-x

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  • DOI: https://doi.org/10.1007/s00280-012-1826-x

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