Skip to main content
SpringerLink
Log in

Pan-European Expert Meeting on the Use of Metronomic Chemotherapy in Advanced Breast Cancer Patients: The PENELOPE Project

  • Original Research
  • Published:
Advances in Therapy Aims and scope Submit manuscript

Abstract

Introduction

Metronomic chemotherapy (mCHT) is a treatment regimen in which drugs are administered frequently or continuously and that maintains low, prolonged, and pharmacologically active plasma concentrations of drugs to avoid toxicity associated with traditional chemotherapy regimens, while achieving tumor response. Despite the increasing use of mCHT in patients with metastatic breast cancer (MBC) and the endorsement of mCHT in guidelines, no consensus exists about which patients may substantially benefit from mCHT, which agents can be recommended, and in which treatment setting mCHT is most appropriate.

Methods

In October 2017, ten international experts in the management of breast cancer convened to develop a report describing the current status of the use of mCHT for the treatment of advanced breast cancer, based not only on current literature but also on their opinion. The Delphi method was used to reach consensus.

Results

A full consensus was reached concerning the acknowledgement that mCHT is not simply a different way of administering chemotherapy but a truly new treatment option. The best-known effect of mCHT is on angiogenesis inhibition, but exciting new data are on the way regarding potential activity on immune system activation. The experts strongly suggest that the ideal patients for mCHT are those with hormone receptor (HR)-positive tumors or those with triple-negative disease. Independently of HR status, mCHT could be an advantageous option for elderly patients, who are often under-treated simply because of their age.

Conclusion

Current data support the use of mCHT in selected patients with MBC.

Funding

Pierre Fabre.

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

Adapted with permission from Romiti et al. [21]

Similar content being viewed by others

References

  1. Bishop AJ, Ensor J, Moulder SL, et al. Prognosis for patients with metastatic breast cancer who achieve a no-evidence-of-disease status after systemic or local therapy. Cancer. 2015;121:4324–32.

    Article  Google Scholar 

  2. Cardoso F, Costa A, Senkus E, et al. 3rd ESO-ESMO international consensus guidelines for advanced breast cancer (ABC 3). Breast. 2017;31:244–59.

    Article  CAS  Google Scholar 

  3. Gennari A, Stockler M, Puntoni M, et al. Duration of chemotherapy for metastatic breast cancer: a systematic review and meta-analysis of randomized clinical trials. J Clin Oncol. 2011;29:2144–9.

    Article  Google Scholar 

  4. Bocci G, Kerbel RS. Pharmacokinetics of metronomic chemotherapy: a neglected but crucial aspect. Nat Rev Clin Oncol. 2016;13:659–73.

    Article  CAS  Google Scholar 

  5. Cazzaniga ME, Dionisio MR, Riva F. Metronomic chemotherapy for advanced breast cancer patients. Cancer Lett. 2017;400:252–8.

    Article  CAS  Google Scholar 

  6. Kareva I, Waxman DJ, Lakka Klement G. Metronomic chemotherapy: an attractive alternative to maximum tolerated dose therapy that can activate anti-tumor immunity and minimize therapeutic resistance. Cancer Lett. 2015;358:100–6.

    Article  CAS  Google Scholar 

  7. Liu Y, Gu F, Liang J, et al. The efficacy and toxicity profile of metronomic chemotherapy for metastatic breast cancer: a meta-analysis. PLoS One. 2017;12:e0173693.

    Article  Google Scholar 

  8. Folkins C, Man S, Xu P, Shaked Y, Hicklin DJ, Kerbel RS. Anticancer therapies combining antiangiogenic and tumor cell cytotoxic effects reduce the tumor stem-like cell fraction in glioma xenograft tumors. Cancer Res. 2007;67:3560–4.

    Article  CAS  Google Scholar 

  9. Hao YB, Yi SY, Ruan J, Zhao L, Nan KJ. New insights into metronomic chemotherapy-induced immunoregulation. Cancer Lett. 2014;354:220–6.

    Article  CAS  Google Scholar 

  10. Kerbel RS, Shaked Y. The potential clinical promise of ‘multimodality’ metronomic chemotherapy revealed by preclinical studies of metastatic disease. Cancer Lett. 2017;400:293–304.

    Article  CAS  Google Scholar 

  11. Emmenegger U, Shaked Y, Man S, et al. Pharmacodynamic and pharmacokinetic study of chronic low-dose metronomic cyclophosphamide therapy in mice. Mol Cancer Ther. 2007;6:2280–9.

    Article  CAS  Google Scholar 

  12. Chen A, Chen L, Al-Qaisi A, et al. Everolimus-induced hematologic changes in patients with metastatic breast cancer. Clin Breast Cancer. 2015;15:48–53.

    Article  CAS  Google Scholar 

  13. Cerrito MG, De Giorgi M, Pelizzoni D, et al. Metronomic combination of vinorelbine and 5fluorouracil is able to inhibit triple-negative breast cancer cells. Results from the proof-of-concept VICTOR-0 study. Oncotarget. 2018;9:27448–59.

    Article  Google Scholar 

  14. Man S, Bocci G, Francia G, et al. Antitumor effects in mice of low-dose (metronomic) cyclophosphamide administered continuously through the drinking water. Cancer Res. 2002;62:2731–5.

    CAS  PubMed  Google Scholar 

  15. Natale G, Bocci G. Does metronomic chemotherapy induce tumor angiogenic dormancy? A review of available preclinical and clinical data. Cancer Lett. 2018;432:28–37.

    Article  CAS  Google Scholar 

  16. Awwad M, North RJ. Cyclophosphamide-induced immunologically mediated regression of a cyclophosphamide-resistant murine tumor: a consequence of eliminating precursor L3T4+ suppressor T-cells. Cancer Res. 1989;49:1649–54.

    CAS  PubMed  Google Scholar 

  17. Berd D, Mastrangelo MJ. Effect of low dose cyclophosphamide on the immune system of cancer patients: reduction of T-suppressor function without depletion of the CD8+ subset. Cancer Res. 1987;47:3317–21.

    CAS  PubMed  Google Scholar 

  18. Ghiringhelli F, Menard C, Puig PE, et al. Metronomic cyclophosphamide regimen selectively depletes CD4+ CD25+ regulatory T cells and restores T and NK effector functions in end stage cancer patients. Cancer Immunol Immunother. 2007;56:641–8.

    Article  CAS  Google Scholar 

  19. Scurr M, Pembroke T, Bloom A, et al. Effect of modified vaccinia ankara-5T4 and low-dose cyclophosphamide on antitumor immunity in metastatic colorectal cancer: a randomized clinical trial. JAMA Oncol. 2017;3:e172579.

    Article  Google Scholar 

  20. Lien K, Georgsdottir S, Sivanathan L, Chan K, Emmenegger U. Low-dose metronomic chemotherapy: a systematic literature analysis. Eur J Cancer. 2013;49:3387–95.

    Article  CAS  Google Scholar 

  21. Romiti A, Falcone R, Roberto M, Marchetti P. Current achievements and future perspectives of metronomic chemotherapy. Invest New Drugs. 2017;35:359–74.

    Article  CAS  Google Scholar 

  22. Bottini A, Generali D, Brizzi MP, et al. Randomized phase II trial of letrozole and letrozole plus low-dose metronomic oral cyclophosphamide as primary systemic treatment in elderly breast cancer patients. J Clin Oncol. 2006;24:3623–8.

    Article  CAS  Google Scholar 

  23. Licchetta A, Correale P, Migali C, et al. Oral metronomic chemo-hormonal-therapy of metastatic breast cancer with cyclophosphamide and megestrol acetate. J Chemother. 2010;22:201–4.

    Article  CAS  Google Scholar 

  24. Schwartzberg LS, Wang G, Somer BG, et al. Phase II trial of fulvestrant with metronomic capecitabine for postmenopausal women with hormone receptor-positive, HER2-negative metastatic breast cancer. Clin Breast Cancer. 2014;14:13–9.

    Article  CAS  Google Scholar 

  25. Addeo R, Sgambato A, Cennamo G, et al. Low-dose metronomic oral administration of vinorelbine in the first-line treatment of elderly patients with metastatic breast cancer. Clin Breast Cancer. 2010;10:301–6.

    Article  CAS  Google Scholar 

  26. De Iuliis F, Salerno G, Taglieri L, Lanza R, Scarpa S. On and off metronomic oral vinorelbine in elderly women with advanced breast cancer. Tumori. 2015;101:30–5.

    Article  Google Scholar 

  27. Stockler MR, Harvey VJ, Francis PA, et al. Capecitabine versus classical cyclophosphamide, methotrexate, and fluorouracil as first-line chemotherapy for advanced breast cancer. J Clin Oncol. 2011;29:4498–504.

    Article  CAS  Google Scholar 

  28. Taguchi T, Nakayama T, Masuda N, et al. Study of low-dose capecitabine monotherapy for metastatic breast cancer. Chemotherapy. 2010;56:166–70.

    Article  CAS  Google Scholar 

  29. Fedele P, Marino A, Orlando L, et al. Efficacy and safety of low-dose metronomic chemotherapy with capecitabine in heavily pretreated patients with metastatic breast cancer. Eur J Cancer. 2012;48:24–9.

    Article  CAS  Google Scholar 

  30. Colleoni M, Rocca A, Sandri MT, et al. Low-dose oral methotrexate and cyclophosphamide in metastatic breast cancer: antitumor activity and correlation with vascular endothelial growth factor levels. Ann Oncol. 2002;13:73–80.

    Article  CAS  Google Scholar 

  31. Wang Z, Lu J, Leaw S, et al. An all-oral combination of metronomic cyclophosphamide plus capecitabine in patients with anthracycline- and taxane-pretreated metastatic breast cancer: a phase II study. Cancer Chemother Pharmacol. 2012;69:515–22.

    Article  CAS  Google Scholar 

  32. Cazzaniga ME, Cortesi L, Ferzi A, et al. Metronomic chemotherapy with oral vinorelbine (mVNR) and capecitabine (mCAPE) in advanced HER2-negative breast cancer patients: is it a way to optimize disease control? Final results of the VICTOR-2 study. Breast Cancer Res Treat. 2016;160:501–9.

    Article  CAS  Google Scholar 

  33. Cazzaniga ME, Torri V, Villa F, et al. Efficacy and safety of the all-oral schedule of metronomic vinorelbine and capecitabine in locally advanced or metastatic breast cancer patients: the phase I–II VICTOR-1 study. Int J Breast Cancer. 2014;2014:769790.

    Article  CAS  Google Scholar 

  34. Montagna E, Vingiani A, Maisonneuve P, et al. Unfavorable prognostic role of tumor-infiltrating lymphocytes in hormone-receptor positive, HER2 negative metastatic breast cancer treated with metronomic chemotherapy. Breast. 2017;34:83–8.

    Article  Google Scholar 

  35. Addeo R, Sperlongano P, Montella L, et al. Protracted low dose of oral vinorelbine and temozolomide with whole-brain radiotherapy in the treatment for breast cancer patients with brain metastases. Cancer Chemother Pharmacol. 2012;70:603–9.

    Article  CAS  Google Scholar 

  36. 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. 2012;70:331–8.

    Article  CAS  Google Scholar 

  37. Carrington C. Oral targeted therapy for cancer. Aust Prescr. 2015;38:171–6.

    Article  Google Scholar 

  38. Shaked Y, Pham E, Hariharan S, Magidey K, Beyar-Katz O, Xu P, et al. Evidence implicating immunological host effects in the efficacy of metronomic low-dose chemotherapy. Cancer Res. 2016;76:5983–93.

    Article  CAS  Google Scholar 

  39. Collova E, Sebastiani F, De Matteis E, Generali D, Aurilio G, Boccardo F, et al. Use of metronomic chemotherapy in oncology: results from a national Italian survey. Tumori. 2011;97:454–8.

    Article  CAS  Google Scholar 

  40. Montagna E, Palazzo A, Maisonneuve P, et al. Safety and efficacy study of metronomic vinorelbine, cyclophosphamide plus capecitabine in metastatic breast cancer: a phase II trial. Cancer Lett. 2017;400:276–81.

    Article  CAS  Google Scholar 

  41. Hammond ME, Hayes DF, Dowsett M, et al. American Society of Clinical Oncology/College of American Pathologists guideline recommendations for immunohistochemical testing of estrogen and progesterone receptors in breast cancer (unabridged version). Arch Pathol Lab Med. 2010;134:e48–72.

    CAS  PubMed  Google Scholar 

  42. Onitilo AA, Engel JM, Greenlee RT, Mukesh BN. Breast cancer subtypes based on ER/PR and Her2 expression: comparison of clinicopathologic features and survival. Clin Med Res. 2009;7:4–13.

    Article  CAS  Google Scholar 

  43. Munzone E, Colleoni M. Clinical overview of metronomic chemotherapy in breast cancer. Nat Rev Clin Oncol. 2015;12:631–44.

    Article  CAS  Google Scholar 

  44. Andre N, Banavali S, Snihur Y, Pasquier E. Has the time come for metronomics in low-income and middle-income countries? Lancet Oncol. 2013;14:e239–48.

    Article  Google Scholar 

  45. Kassam F, Enright K, Dent R, et al. Survival outcomes for patients with metastatic triple-negative breast cancer: implications for clinical practice and trial design. Clin Breast Cancer. 2009;9:29–33.

    Article  Google Scholar 

  46. Turner N, Zafarana E, Sanna G, Mottino G, Biganzoli L. The best treatment for older patients with breast cancer. EJC Suppl. 2013;11:299–300.

    Article  Google Scholar 

  47. Di Desidero T, Kerbel RS, Bocci G. Metronomic chemotherapy for triple negative breast cancer? Aging (Albany NY). 2016;8:573–4.

    Article  Google Scholar 

  48. Cazzaniga ME, Cortesi L, Ferzi A, et al. Metronomic chemotherapy in triple-negative metastatic breast cancer: the future is now? Int J Breast Cancer. 2017;2017:1683060.

    Article  CAS  Google Scholar 

  49. Cecconetto L, Casadei Gardini A, Tenti E, et al. Long-term complete response in a patient with liver metastases from breast cancer treated with metronomic chemotherapy. Tumori. 2014;100:e79–82.

    Article  Google Scholar 

  50. De Iuliis F, Salerno G, Taglieri L, Vicinanza R, Lanza R, Scarpa S. Elderly woman with triple-negative metastatic breast cancer successfully treated with metronomic capecitabine. Anticancer Res. 2014;34:4287–91.

    PubMed  Google Scholar 

  51. Kummar S, Wade JL, Oza AM, et al. Randomized phase II trial of cyclophosphamide and the oral poly (ADP-ribose) polymerase inhibitor veliparib in patients with recurrent, advanced triple-negative breast cancer. Invest New Drugs. 2016;34:355–63.

    Article  CAS  Google Scholar 

  52. Perry S, Kowalski TL, Chang CH. Quality of life assessment in women with breast cancer: benefits, acceptability and utilization. Health Qual Life Outcomes. 2007;5:24.

    Article  Google Scholar 

  53. Wildiers H. Mastering chemotherapy dose reduction in elderly cancer patients. Eur J Cancer. 2007;43:2235–41.

    Article  CAS  Google Scholar 

  54. Cazzaniga ME, Torri V, Riva F, et al. Efficacy and safety of vinorelbine-capecitabine oral metronomic combination in elderly metastatic breast cancer patients: vICTOR-1 study. Tumori. 2017;103:e4–8.

    Article  CAS  Google Scholar 

  55. Perroud HA, Alasino CM, Rico MJ, et al. Quality of life in patients with metastatic breast cancer treated with metronomic chemotherapy. Future Oncol. 2016;12:1233–42.

    Article  CAS  Google Scholar 

  56. Di Desidero T, Orlandi P, Fioravanti A, et al. Pharmacokinetic analysis of metronomic capecitabine in refractory metastatic colorectal cancer patients. Invest New Drugs. 2018;36:709–14.

    Article  Google Scholar 

  57. Carrick S, Parker S, Thornton CE, Ghersi D, Simes J, Wilcken N. Single agent versus combination chemotherapy for metastatic breast cancer. Cochrane Database Syst Rev. 2009:CD003372.

  58. Biziota E, Briasoulis E, Mavroeidis L, Marselos M, Harris AL, Pappas P. Cellular and molecular effects of metronomic vinorelbine and 4-O-deacetylvinorelbine on human umbilical vein endothelial cells. Anticancer Drugs. 2016;27:216–24.

    Article  CAS  Google Scholar 

  59. Langley RE, Carmichael J, Jones AL, et al. Phase III trial of epirubicin plus paclitaxel compared with epirubicin plus cyclophosphamide as first-line chemotherapy for metastatic breast cancer: United Kingdom National Cancer Research Institute trial AB01. J Clin Oncol. 2005;23:8322–30.

    Article  CAS  Google Scholar 

  60. Miller K, Wang M, Gralow J, et al. Paclitaxel plus bevacizumab versus paclitaxel alone for metastatic breast cancer. N Engl J Med. 2007;357:2666–76.

    Article  CAS  Google Scholar 

  61. O’Shaughnessy J, Miles D, Vukelja S, et al. Superior survival with capecitabine plus docetaxel combination therapy in anthracycline-pretreated patients with advanced breast cancer: phase III trial results. J Clin Oncol. 2002;20:2812–23.

    Article  Google Scholar 

  62. Nolè F, Crivellari D, Mattioli R, et al. Phase II study of an all-oral combination of vinorelbine with capecitabine in patients with metastatic breast cancer. Cancer Chemother Pharmacol. 2009;64:673–80.

    Article  Google Scholar 

  63. Hassan M, Osman MM. Combination of oral vinorelbine and capecitabine in the treatment of metastatic breast cancer patients previously exposed to anthracyclines: a pilot study. Hematol Oncol Stem Cell Ther. 2010;3:185–90.

    Article  CAS  Google Scholar 

  64. Tubiana-Mathieu N, Bougnoux P, Becquart D, et al. All-oral combination of oral vinorelbine and capecitabine as first-line chemotherapy in HER2-negative metastatic breast cancer: an international phase II trial. Br J Cancer. 2009;101:232–7.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

Funding

This study and associated article processing charges was funded by Pierre Fabre.

Editorial Assistance

We would like to thank Simone Tait of Springer Healthcare Communications who edited this manuscript for English before submission. This medical writing assistance was funded by Pierre Fabre.

Authorship

All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this article, take responsibility for the integrity of the work as a whole, and have given their approval for this version to be published.

Disclosures

Marina E Cazzaniga has received honoraria for participation in advisory boards for Pierre Fabre Pharma, Roche, Astra Zeneca, Novartis, and Celgene. Elisabetta Munzone has received honoraria for participation in advisory boards from Pierre Fabre Médicament. Guido Bocci has received honoraria for participation in advisory boards from Pierre Fabre Médicament. Noémia Afonso has received honoraria for participation in advisory boards from Pierre Fabre Médicament. Patricia Gomez has received honoraria for participation in advisory boards from Pierre Fabre Médicament. Edgar Petru has received honoraria for participation in advisory boards from Pierre Fabre Médicament. Xavier Pivot has received honoraria for participation in advisory boards from Pierre Fabre Médicament. Pedro Sánchez Rovira has received honoraria for participation in advisory boards from Pierre Fabre Médicament. Valter Torri has received honoraria for participation in advisory boards from Pierre Fabre Médicament. Sven Langkjer has received honoraria for participation in advisory boards of Pierre Fabre Médicament, research grants from the Danish Cancer Society, The Lundbeck Foundation and Pierre Fabre, and travel grants from Roche, Novartis, Bristol Myers Squibb and Pierre Fabre. Piotr J. Wysocki has received honoraria for advisory boards and speaker activities from Pierre Fabre Médicament, Roche, Astra Zeneca, Novartis, Pfizer, Eli Lilly.

Compliance with Ethics Guidelines

This article does not contain any studies with human participants or animals performed by any of the authors.

Data Availability

All data generated or analyzed during this study are included in this published article/as supplementary information files.

Author information

Authors and Affiliations

  1. ASST Monza, Monza, Italy

    Marina E. Cazzaniga

  2. IEO, European Institute of Oncology IRCCS, Milan, Italy

    Elisabetta Munzone

  3. Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy

    Guido Bocci

  4. Centro Hospitalar do Porto, Porto, Portugal

    Noémia Afonso

  5. Vall d’Hebron University Hospital, Vall d’Hebron Institute of Oncology, Barcelona, Spain

    Patricia Gomez

  6. Department of Oncology, Aarhus University Hospital, Aarhus, Denmark

    Sven Langkjer

  7. University of Graz, Graz, Austria

    Edgar Petru

  8. Centre Paul Strauss, Institut Régional du Cancer, Strasbourg, France

    Xavier Pivot

  9. Oncology Department, Complejo Hospitalario de Jaen, Jaen, Spain

    Pedro Sánchez Rovira

  10. Jagiellonian University, Medical College Hospital, Cracow, Poland

    Piotr Wysocki

  11. IRCCS Mario Negri Institute for Pharmacological Research, Milan, Italy

    Valter Torri

Authors
  1. Marina E. Cazzaniga
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Elisabetta Munzone
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Guido Bocci
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Noémia Afonso
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Patricia Gomez
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Sven Langkjer
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Edgar Petru
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Xavier Pivot
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Pedro Sánchez Rovira
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Piotr Wysocki
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Valter Torri
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Marina E. Cazzaniga.

Additional information

Enhanced Digital Features

To view enhanced digital features for this article go to https://doi.org/10.6084/m9.figshare.7334762.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (TIFF 58 kb)

Supplementary material 2 (DOCX 41 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Cazzaniga, M.E., Munzone, E., Bocci, G. et al. Pan-European Expert Meeting on the Use of Metronomic Chemotherapy in Advanced Breast Cancer Patients: The PENELOPE Project. Adv Ther 36, 381–406 (2019). https://doi.org/10.1007/s12325-018-0844-4

Download citation

  • Received:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12325-018-0844-4

Keywords

Search

Navigation