Metronomic chemotherapy for metastatic breast cancer – a systematic review of the literature

Abstract

Conventional chemotherapy is generally administered in high doses followed by a treatment-free period to give the body needful time to recover. This “maximum tolerated dose” approach results in high response rates. However, long periods between therapy cycles can lead to development of resistance mechanisms and consequently disease progression. One of the most interesting alternative strategies is metronomic chemotherapy. This concept relies on the continuous administration of chemotherapy at low doses and aims at targeting endothelial cells in the tumor bed as well. Recently, metronomic chemotherapy has been incorporated into the recommendations issued by the German AGO expert panel (www.ago-online.de). 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 metastatic breast cancer.

Zusammenfassung

Die herkömmliche Chemotherapie wird üblicherweise in hohen Dosen verabreicht, gefolgt von einer behandlungsfreien Periode, die dem Körper die nötige Erholungszeit gibt. Dieser Ansatz, bei welchem dem Patienten die „maximal verträgliche Dosis“ verabreicht wird, ist mit hohen Ansprechraten verbunden. Die langen Abstände zwischen den einzelnen Therapiezyklen können jedoch die Entwicklung von Resistenzmechanismen begünstigen und folglich zu einem Fortschreiten der Erkrankung führen. Die metronomische Chemotherapie stellt daher eine interessante Alternative dar. Das Konzept beruht auf der kontinuierlichen Verabreichung eines niedrig dosierten Chemotherapeutikums und zielt auch auf die Endothelzellen im Tumorbett ab. Vor Kurzem wurde die metronomische Chemotherapie in die vom Expertengremium der AGO herausgegebenen Empfehlungen aufgenommen (www.ago-online.de). Es wurde eine systematische Recherche in PubMed/Medline, ClinicalTrials.gov, European Clinical Trials Database (EudraCT) sowie Cochrane Database durchgeführt. In der hier vorgestellten Literaturübersicht werden die aktuellen Erkenntnisse über die metronomische Chemotherapie bei der Behandlung von metastasierendem Brustkrebs diskutiert.

Key words

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

Schlüsselwörter

Brustkrebs - metronomische Chemotherapie - Überleben - Toxizität - systematische Recherche

• References

• 1 Romiti A, Cox MC, Sarcina I. et al. Metronomic chemotherapy for cancer treatment: a decade of clinical studies. Cancer Chemother Pharmacol 2013; 72: 13-33
• 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
• 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
• 4 Sparano JA, Wang M, Martino S. et al. Weekly paclitaxel in the adjuvant treatment of breast cancer. N Engl J Med 2008; 358: 1663-1671
• 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
• 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
• 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
• 8 Blum JL, Barrios CH, Feldman N. et al. Pooled analysis of individual patient data from capecitabine monotherapy clinical trials in locally advanced or metastatic breast cancer. Breast Cancer Res Treat 2012; 136: 777-788
• 9 Partridge AH, Rumble RB, Carey LA. et al. Chemotherapy and targeted therapy for women with human epidermal growth factor receptor 2-negative (or unknown) advanced breast cancer: American Society of Clinical Oncology Clinical Practice Guideline. J Clin Oncol 2014; 32: 3307-3329
• 10 Yin W, Pei G, Liu G. et al. Efficacy and safety of capecitabine-based first-line chemotherapy in advanced or metastatic breast cancer: a meta-analysis of randomised controlled trials. Oncotarget 2015; 6: 39365-39372
• 11 Lam SW, de Groot SM, Honkoop AH. et al. Paclitaxel and bevacizumab with or without capecitabine as first-line treatment for HER2-negative locally recurrent or metastatic breast cancer: a multicentre, open-label, randomised phase 2 trial. Eur J Cancer 2014; 50: 3077-3088
• 12 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: 4498-4504
• 13 Wardley AM, Pivot X, Morales-Vasquez F. et al. Randomized phase II trial of first-line trastuzumab plus docetaxel and capecitabine compared with trastuzumab plus docetaxel in HER2-positive metastatic breast cancer. J Clin Oncol 2010; 28: 976-983
• 14 Mavroudis D, Papakotoulas P, Ardavanis A. et al. Randomized phase III trial comparing docetaxel plus epirubicin versus docetaxel plus capecitabine as first-line treatment in women with advanced breast cancer. Ann Oncol 2010; 21: 48-54
• 15 Rochlitz C, Moos R, Biger M. et al. SAKK 24/09: Safety and tolerability of bevacizumab plus paclitaxel versus bevacizumab plus metronomic cyclophosphamide and capecitabine as first-line therapy in patients with HER2-negative advanced stage breast cancer—A multicenter, randomized phase III trial. J Clin Oncol 2014; 32 (Suppl.) 5s (Abstr. 518)
• 16 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: 2144-2149
• 17 Gennari A, DʼAmico M, Corradengo D. Extending the duration of first-line chemotherapy in metastatic breast cancer: a perspective review. Ther Adv Med Oncol 2011; 3: 229-232
• 18 Coates A, Gebski V, Bishop JF. et al. Improving the quality of life during chemotherapy for advanced breast cancer. A comparison of intermittent and continuous treatment strategies. N Engl J Med 1987; 317: 1490-1495
• 19 Ozdemir N, Aksoy S, Sendur MA. et al. Capecitabine/cisplatin doublet in anthracycline and taxane pretreated and HER-2 negative metastatic breast carcinoma patients. J BUON 2013; 18: 831-837
• 20 Bello L, Carrabba G, Giussani C. et al. Low-dose chemotherapy combined with an antiangiogenic drug reduces human glioma growth in vivo. Cancer Res 2001; 61: 7501-7506
• 21 Garcia-Saenz JA, Martin M, Calles A. et al. Bevacizumab in combination with metronomic chemotherapy in patients with anthracycline- and taxane-refractory breast cancer. J Chemother 2008; 20: 632-639
• 22 Dellapasqua S, Bertolini F, Bagnardi V. et al. Metronomic cyclophosphamide and capecitabine combined with bevacizumab in advanced breast cancer. J Clin Oncol 2008; 26: 4899-4905
• 23 Goon PK, Lip GY, Boos CJ. et al. Circulating endothelial cells, endothelial progenitor cells, and endothelial microparticles in cancer. Neoplasia 2006; 8: 79-88
• 24 Montagna E, Cancello G, Bagnardi V. et al. Metronomic chemotherapy combined with bevacizumab and erlotinib in patients with metastatic HER2-negative breast cancer: clinical and biological activity. Clin Breast Cancer 2012; 12: 207-214
• 25 Saloustros E, Kalbakis K, Vardakis N. et al. Metronomic vinorelbine plus bevacizumab as salvage therapy for patients with metastatic breast cancer. J BUON 2011; 16: 215-218
• 26 DʼAmato RJ, Loughnan MS, Flynn E. et al. Thalidomide is an inhibitor of angiogenesis. Proc Natl Acad Sci U S A 1994; 91: 4082-4085
• 27 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
• 28 Mayer EL, Isakoff SJ, Klement G. et al. Combination antiangiogenic therapy in advanced breast cancer: a phase 1 trial of vandetanib, a VEGFR inhibitor, and metronomic chemotherapy, with correlative platelet proteomics. Breast Cancer Res Treat 2012; 136: 169-178
• 29 Swain SM, Baselga J, Kim SB. et al. Pertuzumab, trastuzumab, and docetaxel in HER2-positive metastatic breast cancer. N Engl J Med 2015; 372: 724-734
• 30 Verma S, Miles D, Gianni L. et al. Trastuzumab emtansine for HER2-positive advanced breast cancer. N Engl J Med 2012; 367: 1783-1791
• 31 Orlando L, Cardillo A, Ghisini R. et al. Trastuzumab in combination with metronomic cyclophosphamide and methotrexate in patients with HER-2 positive metastatic breast cancer. BMC Cancer 2006; 6: 225
• 32 Saura C, Garcia-Saenz JA, Xu B. et al. Safety and efficacy of neratinib in combination with capecitabine in patients with metastatic human epidermal growth factor receptor 2-positive breast cancer. J Clin Oncol 2014; 32: 3626-3633
• 33 Pritchard KI. Combining endocrine agents with chemotherapy: which patients and what sequence?. Cancer 2008; 112: 718-722
• 34 Pritchard KI, Paterson AH, Paul NA. et al. Increased thromboembolic complications with concurrent tamoxifen and chemotherapy in a randomized trial of adjuvant therapy for women with breast cancer. National Cancer Institute of Canada Clinical Trials Group Breast Cancer Site Group. J Clin Oncol 1996; 14: 2731-2737
• 35 Kataoka M, Yamaguchi Y, Moriya Y. et al. Antitumor activity of chemoendocrine therapy in premenopausal and postmenopausal models with human breast cancer xenografts. Oncol Rep 2012; 27: 303-310
• 36 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: 13-19
• 37 Aurilio G, Munzone E, Botteri E. et al. Oral metronomic cyclophosphamide and methotrexate plus fulvestrant in advanced breast cancer patients: a mono-institutional case-cohort report. Breast J 2012; 18: 470-474
• 38 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: 201-204
• 39 Cimino-Mathews A, Foote JB, Emens LA. Immune targeting in breast cancer. Oncology (Williston Park) 2015; 29: 375-385
• 40 Ge Y, Domschke C, Stoiber N. et al. Metronomic cyclophosphamide treatment in metastasized breast cancer patients: immunological effects and clinical outcome. Cancer Immunol Immunother 2012; 61: 353-362
• 41 Soriano JL, Batista N, Santiesteban E. et al. Metronomic cyclophosphamide and methotrexate chemotherapy combined with 1E10 anti-idiotype vaccine in metastatic breast cancer. Int J Breast Cancer 2011; 2011: 710292
• 42 Wang X, Ren J, Zhang J. et al. Prospective study of cyclophosphamide, thiotepa, carboplatin combined with adoptive DC-CIK followed by metronomic cyclophosphamide therapy as salvage treatment for triple negative metastatic breast cancers patients (aged < 45). Clin Transl Oncol 2015;
• 43 Young SD, Lafrenie RM, Clemons MJ. Phase ii trial of a metronomic schedule of docetaxel and capecitabine with concurrent celecoxib in patients with prior anthracycline exposure for metastatic breast cancer. Curr Oncol 2012; 19: e75-e83
• 44 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: 24-29
• 45 Taguchi T, Nakayama T, Masuda N. et al. Study of low-dose capecitabine monotherapy for metastatic breast cancer. Chemotherapy 2010; 56: 166-170
• 46 Taguchi T, Yamamoto D, Masuda N. et al. Low dose capecitabine plus weekly paclitaxel in patients with metastatic breast cancer: a multicenter phase II study KBCSG-0609. Cancer Chemother Pharmacol 2013; 71: 741-747
• 47 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
• 48 Miscoria M, Tonetto F, Deroma L. et al. Exploratory predictive and prognostic factors in advanced breast cancer treated with metronomic chemotherapy. Anticancer Drugs 2012; 23: 326-334
• 49 Gebbia V, Boussen H, Valerio MR. Oral metronomic cyclophosphamide with and without methotrexate as palliative treatment for patients with metastatic breast carcinoma. Anticancer Res 2012; 32: 529-536
• 50 Salem DA, Gado NM, Abdelaziz NN. et al. Phase II trial of metronomic chemotherapy as salvage therapy for patients with metastatic breast cancer. J Egypt Natl Canc Inst 2008; 20: 134-140
• 51 Wong NS, Buckman RA, Clemons M. et al. Phase I/II trial of metronomic chemotherapy with daily dalteparin and cyclophosphamide, twice-weekly methotrexate, and daily prednisone as therapy for metastatic breast cancer using vascular endothelial growth factor and soluble vascular endothelial growth factor receptor levels as markers of response. J Clin Oncol 2010; 28: 723-730
• 52 Perroud HA, Rico MJ, Alasino CM. et al. Safety and therapeutic effect of metronomic chemotherapy with cyclophosphamide and celecoxib in advanced breast cancer patients. Future Oncol 2013; 9: 451-462
• 53 Manso L, Valdiviezo N, Sepulveda J. et al. Safety and efficacy of metronomic non-pegylated liposomal encapsulated doxorubicin in heavily pretreated advanced breast cancer patients. Clin Transl Oncol 2013; 15: 467-471
• 54 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: 515-522
• 55 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: 331-338
• 56 Saridaki Z, Malamos N, Kourakos P. et al. A phase I trial of oral metronomic vinorelbine plus capecitabine in patients with metastatic breast cancer. Cancer Chemother Pharmacol 2012; 69: 35-42
• 57 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
• 58 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: 301-306
• 59 De Iuliis F, Salerno G, Taglieri L. et al. On and off metronomic oral vinorelbine in elderly women with advanced breast cancer. Tumori 2015; 101: 30-35
• 60 De la Haba J, Cazzaniga M, Freyer G. et al. Randomised phase II study evaluating, as first-line chemotherapy, single-agent oral vinorelbine administered with two different schedules in patients with hormone receptor positive, HER2-negative advanced breast cancer (TempoBreast-1 trial). In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium 2015. Cancer Res 2016; 76
• 61 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: 603-609
• 62 Otsuka H, Fujii T, Toh U. et al. Phase II clinical trial of metronomic chemotherapy with combined irinotecan and tegafur-gimeracil-oteracil potassium in metastatic and recurrent breast cancer. Breast Cancer 2015; 22: 335-342
• 63 Smith IE, Johnston SR, OʼBrien ME. et al. Low-dose oral fluorouracil with eniluracil as first-line chemotherapy against advanced breast cancer: a phase II study. J Clin Oncol 2000; 18: 2378-2384