Geburtshilfe Frauenheilkd 2017; 77(02): 142-148
DOI: 10.1055/s-0043-100388
GebFra Science
Review
Georg Thieme Verlag KG Stuttgart · New York

Metronomic Chemotherapy for Primary Non-Metastatic Breast Cancer – a Systematic Review of the Literature

Metronomische Chemotherapie bei primärem nicht metastasierenden Brustkrebs – eine systematische Literaturübersicht
Malgorzata Banys-Paluchowski
1   Department of Gynecology and Obstetrics, Marienkrankenhaus Hamburg, Hamburg, Germany
,
Eugen Ruckhäberle
2   Department of Gynecology and Obstetrics, Heinrich-Heine University Düsseldorf, Düsseldorf, Germany
,
Florian Schütz
3   Department of Gynecology and Obstetrics, Heidelberg University Hospital, University of Heidelberg, Heidelberg, Germany
,
Natalia Krawczyk
2   Department of Gynecology and Obstetrics, Heinrich-Heine University Düsseldorf, Düsseldorf, Germany
,
Tanja Fehm
2   Department of Gynecology and Obstetrics, Heinrich-Heine University Düsseldorf, Düsseldorf, Germany
› Author Affiliations
Further Information

Publication History

received 17 October 2016
revised 06 January 2017

accepted 08 January 2017

Publication Date:
17 March 2017 (online)

   Permissions and Reprints

Abstract

Conventional chemotherapy is based on the “maximum tolerated dose” principle and aims at administering high doses of cytotoxic drugs followed by a rest period necessary for the body to recover. In the last decades alternative strategies have been developed to avoid serious side effects of conventional treatment, among them the metronomic chemotherapy. Much like a metronome keeps steady rhythm, metronomic therapy is administered continuously in low doses for a long time. In metastatic breast cancer, metronomic therapy is a valid option in pretreated or vulnerable patients and its use has recently been incorporated into various guidelines. In early breast cancer, the role of metronomic treatment remains to be clarified. A systematic review of PubMed/MEDLINE, ClinicalTrials.gov, the European Clinical Trials Database (EudraCT) and the Cochrane Database was conducted. In the present review, we discuss the current evidence on metronomic chemotherapy in non-metastatic breast cancer.

Zusammenfassung

Die konventionelle Chemotherapie basiert auf das Prinzip der „maximal tolerierbaren Dosis“. Es werden hohe Dosen zytotoxischer Medikamente verabreicht, gefolgt von Ruheperioden, die der Körper zur Erholung benötigt. In den letzten Jahrzehnten wurden auch alternative Strategien entwickelt, um die schwerwiegenden Nebenwirkungen konventioneller Behandlungen zu vermeiden, darunter die metronomische Chemotherapie. Ähnlich dem steten Rhythmus eines Metronoms werden bei der metronomischen Therapie Medikamente kontinuierlich in geringen Dosen und über einen längeren Zeitraum verabreicht. Die metronomische Therapie stellt eine wirksame Behandlungsoption für vorbehandelte oder geschwächte Patientinnen mit metastasierendem Brustkrebs dar, und der Einsatz der metronomischen Therapie wurde vor Kurzem in verschiedene Leitlinien aufgenommen. Die Rolle von metronomischer Therapie bei Brustkrebs im Frühstadium muss noch geklärt werden. Dazu wurde eine systematische Durchsicht von PubMed/MEDLINE, ClinicalTrials.gov, der Datenbank des European-Clinical-Trials-(EudraCT-)Registers und der Cochrane Datenbank durchgeführt. In dieser Übersichtsarbeit wird der aktuelle Forschungsstand zur metronomischen Chemotherapie bei nicht metastasierendem Brustkrebs diskutiert.

Key words

breast cancer - metronomic chemotherapy - survival - toxicity - maintenance therapy - systematic review

Schlüsselwörter

Brustkrebs - metronomische Chemotherapie - Überleben - Toxizität - Erhaltungstherapie - systematische Übersicht
 

  • References

  • 1 Banys-Paluchowski M, Schutz F, Ruckhaberle E. et al. Metronomic chemotherapy for metastatic breast cancer – a systematic review of the literature. Geburtsh Frauenheilk 2016; 76: 525-534
    Thieme ConnectPubMedSearch in Google Scholar
  • 2 Klement G, Baruchel S, Rak J. et al. Continuous low-dose therapy with vinblastine and VEGF receptor-2 antibody induces sustained tumor regression without overt toxicity. J Clin Invest 2000; 105: R15-R24
    CrossrefPubMedSearch in Google Scholar
  • 3 Browder T, Butterfield CE, Kraling BM. et al. Antiangiogenic scheduling of chemotherapy improves efficacy against experimental drug-resistant cancer. Cancer Res 2000; 60: 1878-1886
    PubMedSearch in Google Scholar
  • 4 Colleoni M, Orlando L, Sanna G. et al. Metronomic low-dose oral cyclophosphamide and methotrexate plus or minus thalidomide in metastatic breast cancer: antitumor activity and biological effects. Ann Oncol 2006; 17: 232-238
    CrossrefPubMedSearch in Google Scholar
  • 5 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: 641-648
    CrossrefPubMedSearch in Google Scholar
  • 6 Wu J, Waxman DJ. Metronomic cyclophosphamide eradicates large implanted GL261 gliomas by activating antitumor Cd8+ T-cell responses and immune memory. Oncoimmunology 2015; 4: e1005521
    CrossrefPubMedSearch in Google Scholar
  • 7 Shurin GV, Tourkova IL, Kaneno R. et al. Chemotherapeutic agents in noncytotoxic concentrations increase antigen presentation by dendritic cells via an IL-12-dependent mechanism. J Immunol 2009; 183: 137-144
    CrossrefPubMedSearch in Google Scholar
  • 8 Munzone E, Colleoni M. Clinical overview of metronomic chemotherapy in breast cancer. Nat Rev Clin Oncol 2015; 12: 631-644
    CrossrefPubMedSearch in Google Scholar
  • 9 Alagizy HA, Shehata MA, Hashem TA. et al. Metronomic capecitabine as extended adjuvant chemotherapy in women with triple negative breast cancer. Hematol Oncol Stem Cell Ther 2015; 8: 22-27
    PubMedSearch in Google Scholar
  • 10 Shawky H, Galal S. Preliminary results of capecitabine metronomic chemotherapy in operable triple-negative breast cancer after standard adjuvant therapy–a single-arm phase II study. J Egypt Natl Canc Inst 2014; 26: 195-202
    PubMedSearch in Google Scholar
  • 11 Colleoni M, Gray KP, Gelber S. et al. Low-dose oral cyclophosphamide and methotrexate maintenance for hormone receptor-negative early breast cancer: International Breast Cancer Study Group trial 22-00. J Clin Oncol 2016; 34: 3400-3408
    CrossrefPubMedSearch in Google Scholar
  • 12 Nasr KE, Osman MA, Elkady MS. et al. Metronomic methotrexate and cyclophosphamide after carboplatin included adjuvant chemotherapy in triple negative breast cancer: a phase III study. Ann Transl Med 2015; 3: 284
    PubMedSearch in Google Scholar
  • 13 Pruneri G, Gray KP, Vingiani A. et al. Tumor-infiltrating lymphocytes (TILs) are a powerful prognostic marker in patients with triple-negative breast cancer enrolled in the IBCSG phase III randomized clinical trial 22-00. Breast Cancer Res Treat 2016; 158: 323-331
    CrossrefPubMedSearch in Google Scholar
  • 14 Masuda N, Higaki K, Takano T. et al. A phase II study of metronomic paclitaxel/cyclophosphamide/capecitabine followed by 5-fluorouracil/epirubicin/cyclophosphamide as preoperative chemotherapy for triple-negative or low hormone receptor expressing/HER2-negative primary breast cancer. Cancer Chemother Pharmacol 2014; 74: 229-238
    CrossrefPubMedSearch in Google Scholar
  • 15 Dellapasqua S, Mazza M, Rosa D. et al. Pegylated liposomal doxorubicin in combination with low-dose metronomic cyclophosphamide as preoperative treatment for patients with locally advanced breast cancer. Breast 2011; 20: 319-323
    CrossrefPubMedSearch in Google Scholar
  • 16 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: 3623-3628
    CrossrefPubMedSearch in Google Scholar
  • 17 von Minckwitz G, Blohmer JU, Costa SD. et al. Response-guided neoadjuvant chemotherapy for breast cancer. J Clin Oncol 2013; 31: 3623-3630
    CrossrefPubMedSearch in Google Scholar
  • 18 Cancello G, Bagnardi V, Sangalli C. et al. Phase II study with epirubicin, cisplatin, and infusional fluorouracil followed by weekly paclitaxel with metronomic cyclophosphamide as a preoperative treatment of triple-negative breast cancer. Clin Breast Cancer 2015; 15: 259-265
    CrossrefPubMedSearch in Google Scholar
  • 19 Ellis GK, Barlow WE, Gralow JR. et al. Phase III comparison of standard doxorubicin and cyclophosphamide versus weekly doxorubicin and daily oral cyclophosphamide plus granulocyte colony-stimulating factor as neoadjuvant therapy for inflammatory and locally advanced breast cancer: SWOG 0012. J Clin Oncol 2011; 29: 1014-1021
    CrossrefPubMedSearch in Google Scholar
  • 20 Steger GG, Greil R, Lang A. et al. Epirubicin and docetaxel with or without capecitabine as neoadjuvant treatment for early breast cancer: final results of a randomized phase III study (ABCSG-24). Ann Oncol 2014; 25: 366-371
    CrossrefPubMedSearch in Google Scholar
  • 21 von Minckwitz G, Rezai M, Fasching PA. et al. Survival after adding capecitabine and trastuzumab to neoadjuvant anthracycline-taxane-based chemotherapy for primary breast cancer (GBG 40—GeparQuattro). Ann Oncol 2014; 25: 81-89
    CrossrefPubMedSearch in Google Scholar
  • 22 Petry V, Gagliato DM, Leal AI. et al. Metronomic chemotherapy in the neoadjuvant setting: results of two parallel feasibility trials (TraQme and TAME) in patients with HER2+ and HER2- locally advanced breast cancer. Braz J Med Biol Res 2015; 48: 479-485
    CrossrefPubMedSearch in Google Scholar
  • 23 Cho E, Schwemm AK, Rubinstein LM. et al. Adjuvant metronomic CMF in a contemporary breast cancer cohort: whatʼs old is new. Clin Breast Cancer 2015; 15: e277-e285
    CrossrefPubMedSearch in Google Scholar
  • 24 Crivellari D, Gray KP, Dellapasqua S. et al. Adjuvant pegylated liposomal doxorubicin for older women with endocrine nonresponsive breast cancer who are NOT suitable for a “standard chemotherapy regimen”: the CASA randomized trial. Breast 2013; 22: 130-137
    CrossrefPubMedSearch in Google Scholar
  • 25 Senkus E, Kyriakides S, Ohno S. et al. Primary breast cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2015; 26 (Suppl. 05) v8-v30
    CrossrefPubMedSearch in Google Scholar
  • 26 Colleoni M, Gray KP, Gelber SI. et al. Low-dose oral cyclophosphamide-methotrexate maintenance (CMM) for receptor-negative early breast cancer (BC). J Clin Oncol 2015; 33 (Suppl.) Abstr. 1002
    Search in Google Scholar
  • 27 Ohashi Y, Watanabe T, Sano M. et al. Efficacy of oral tegafur-uracil (UFT) as adjuvant therapy as compared with classical cyclophosphamide, methotrexate, and 5-fluorouracil (CMF) in early breast cancer: a pooled analysis of two randomized controlled trials (N.SAS-BC01 trial and CUBC trial). Breast Cancer Res Treat 2010; 119: 633-641
    CrossrefPubMedSearch in Google Scholar
  • 28 von Minckwitz G, Reimer T, Potenberg J. et al. The phase III ICE study: Adjuvant Ibandronate with or without capecitabine in elderly patients with moderate or high risk early breast cancer. San Antonio Breast Cancer Symposium. 2014; oral presentation (S3-04).