Skip to main content

Advertisement

SpringerLink
Log in

Metastatic breast cancer patients treated with low-dose metronomic chemotherapy with cyclophosphamide and celecoxib: clinical outcomes and biomarkers of response

  • Original Article
  • Published:
Cancer Chemotherapy and Pharmacology Aims and scope Submit manuscript

Abstract

Background

Preclinical results showing therapeutic effect and low toxicity of metronomic chemotherapy with cyclophosphamide (Cy) + celecoxib (Cel) for mammary tumors encouraged its translation to the clinic for treating advanced breast cancer patients (ABCP).

Patients and methods

A single-arm, mono-institutional, non-randomized, phase II, two-step clinical trial (approved by Bioethics Committee and Argentine Regulatory Authority) was designed. Patients received Cy (50 mg po.d) + Cel (200 mg p.o.bid). Patient eligibility criteria included: ABCP who progressed to anthracyclines, taxanes and capecitabine, ≤4 chemotherapy schemes, with good performance status. Several pro- and anti-angiogenic molecules and cells were determined as biomarkers. Informed consent was signed by all patients. Primary endpoint was clinical benefit (CB).

Results

Twenty patients were enrolled. Main clinical outcomes were prolonged disease stabilization and partial remission in 10/20 and 1/20 patients, respectively. CB was 55 %, and time to progression (TTP) was 21.1 weeks. Median TTP in patients who achieved CB was 35.6 weeks, and mean overall survival was 44.20 weeks. There were no grade 3/4 toxicities associated with treatment. Circulating endothelial cells (CECs) increased at the time of progression in patients who showed CB (P = 0.014). Baseline CECs and circulating endothelial progenitor cells showed marginal associations with TTP. Serum VEGF decreased (P = 0.050), sVEGFR-2 increased (P = 0.005) and VEGF/sVEGFR-2 ratio decreased during treatment (P = 0.041); baseline VEGF and VEGF/sVEGFR-2 were associated with TTP (P = 0.035 and P = 0.030, respectively), while sVEGFR-2 did not.

Conclusions

Treatment was effective, showing low toxicity profile and excellent tolerability. The combination had anti-angiogenic effect. Increased levels of CEC could be useful for detecting progression. Baseline VEGF and VEGF/sVEGFR-2 values could be useful as early predictors of response.

Trial registration

ANMAT#4596/09.

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
Fig. 3

Similar content being viewed by others

References

  1. Palumbo R, Sottotetti F, Riccardi A, Teragni C, Pozzi E, Quaquarini E, Tagliaferri B, Bernardo A (2013) Which patients with metastatic breast cancer benefit from subsequent lines of treatment? An update for clinicians. Ther Adv Med Oncol 5(6):334–350. doi:10.1177/1758834013508197

    Article  PubMed Central  PubMed  Google Scholar 

  2. Nelson R (2013) Targeted therapies offer promise, but are they affordable? Medscape. http://www.medscape.com/viewarticle/810147#vp_2. Accessed March 13 2015

  3. 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(8):1045–1047. doi:10.1172/JCI9872

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  4. Colleoni M, Rocca A, Sandri MT, Zorzino L, Masci G, Nole F, Peruzzotti G, Robertson C, Orlando L, Cinieri S, de Braud F, Viale G, Goldhirsch A (2002) Low-dose oral methotrexate and cyclophosphamide in metastatic breast cancer: antitumor activity and correlation with vascular endothelial growth factor levels. Ann Oncol 13(1):73–80

    Article  CAS  PubMed  Google Scholar 

  5. Perroud HA, Rico MJ, Alasino CM, Queralt F, Mainetti LE, Pezzotto SM, Rozados VR, Scharovsky OG (2013) Safety and therapeutic effect of metronomic chemotherapy with cyclophosphamide and celecoxib in advanced breast cancer patients. Future Oncol 9(3):451–462. doi:10.2217/fon.12.196

    Article  CAS  PubMed  Google Scholar 

  6. Lansiaux A, Salingue S, Dewitte A, Clisant S, Penel N (2012) Circulating thrombospondin 1 level as a surrogate marker in patients receiving cyclophosphamide-based metronomic chemotherapy. Invest New Drugs 30(1):403–404. doi:10.1007/s10637-010-9443-1

    Article  CAS  PubMed  Google Scholar 

  7. Perroud HA, Rico MJ, Alasino CM, Pezzotto SM, Rozados VR, Scharovsky OG (2013) Association between baseline VEGF/sVEGFR-2 and VEGF/TSP-1 ratios and response to metronomic chemotherapy using cyclophosphamide and celecoxib in patients with advanced breast cancer. Indian J Cancer 50(2):115–121. doi:10.4103/0019-509X.117031

    Article  CAS  PubMed  Google Scholar 

  8. 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(2):452–459. doi:10.1182/blood-2005-11-4570

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  9. Rozados VR, Mainetti LE, Rico MJ, Zacarias Fluck MF, Matar P, Scharovsky OG (2010) The immune response and the therapeutic effect of metronomic chemotherapy with cyclophosphamide. Oncol Res 18(11–12):601–605

    PubMed  Google Scholar 

  10. Ghiringhelli F, Menard C, Puig PE, Ladoire S, Roux S, Martin F, Solary E, Le Cesne A, Zitvogel L, Chauffert B (2007) 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 56(5):641–648. doi:10.1007/s00262-006-0225-8

    Article  CAS  PubMed  Google Scholar 

  11. Martin-Padura I, Marighetti P, Agliano A, Colombo F, Larzabal L, Redrado M, Bleau AM, Prior C, Bertolini F, Calvo A (2012) Residual dormant cancer stem-cell foci are responsible for tumor relapse after antiangiogenic metronomic therapy in hepatocellular carcinoma xenografts. Lab Invest 92(7):952–966. doi:10.1038/labinvest.2012.65

    Article  CAS  PubMed  Google Scholar 

  12. Vives M, Ginesta MM, Gracova K, Graupera M, Casanovas O, Capella G, Serrano T, Laquente B, Vinals F (2013) Metronomic chemotherapy following the maximum tolerated dose is an effective anti-tumour therapy affecting angiogenesis, tumour dissemination and cancer stem cells. Int J Cancer 133(10):2464–2472. doi:10.1002/ijc.28259

    Article  CAS  PubMed  Google Scholar 

  13. Browder T, Butterfield CE, Kraling 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(7):1878–1886

    CAS  PubMed  Google Scholar 

  14. Dai ZJ, Ma XB, Kang HF, Gao J, Min WL, Guan HT, Diao Y, Lu WF, Wang XJ (2012) Antitumor activity of the selective cyclooxygenase-2 inhibitor, celecoxib, on breast cancer in vitro and in vivo. Cancer Cell Int 12(1):53. doi:10.1186/1475-2867-12-53

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  15. Young SD, Lafrenie RM, Clemons MJ (2012) 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 19(2):e75–e83. doi:10.3747/co.19.879

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  16. Simon R (1989) Optimal two-stage designs for phase II clinical trials. Control Clin Trials 10(1):1–10

    Article  CAS  PubMed  Google Scholar 

  17. Bouche G, Andre N, Banavali S, Berthold F, Berruti A, Bocci G, Brandi G, Cavallaro U, Cinieri S, Colleoni M, Curigliano G, Di Desidero T, Eniu A, Fazio N, Kerbel R, Hutchinson L, Ledzewicz U, Munzone E, Pasquier E, Graciela Scharovsky O, Shaked Y, Sterba J, Villalba M, Bertolini F (2014) Lessons from the fourth metronomic and anti-angiogenic therapy meeting, 24–25 June 2014, Milan. Ecancermedicalscience 8:463. doi:10.3332/ecancer.2014.463

    PubMed Central  PubMed  Google Scholar 

  18. Mainetti LE, Rozados VR, Rossa A, Bonfil RD, Scharovsky OG (2011) Antitumoral and antimetastatic effects of metronomic chemotherapy with cyclophosphamide combined with celecoxib on murine mammary adenocarcinomas. J Cancer Res Clin Oncol 137(1):151–163. doi:10.1007/s00432-010-0869-9

    Article  CAS  PubMed  Google Scholar 

  19. Mainetti LE, Rico MJ, Fernandez-Zenobi MV, Perroud HA, Roggero EA, Rozados VR, Scharovsky OG (2013) Therapeutic efficacy of metronomic chemotherapy with cyclophosphamide and doxorubicin on murine mammary adenocarcinomas. Ann Oncol 24(9):2310–2316. doi:10.1093/annonc/mdt164

    Article  CAS  PubMed  Google Scholar 

  20. Colleoni M, Orlando L, Sanna G, Rocca A, Maisonneuve P, Peruzzotti G, Ghisini R, Sandri MT, Zorzino L, Nole F, Viale G, Goldhirsch A (2006) Metronomic low-dose oral cyclophosphamide and methotrexate plus or minus thalidomide in metastatic breast cancer: antitumor activity and biological effects. Ann Oncol 17(2):232–238. doi:10.1093/annonc/mdj066

    Article  CAS  PubMed  Google Scholar 

  21. Dellapasqua S, Bertolini F, Bagnardi V, Campagnoli E, Scarano E, Torrisi R, Shaked Y, Mancuso P, Goldhirsch A, Rocca A, Pietri E, Colleoni M (2008) Metronomic cyclophosphamide and capecitabine combined with bevacizumab in advanced breast cancer. J Clin Oncol 26(30):4899–4905. doi:10.1200/JCO.2008.17.4789

    Article  CAS  PubMed  Google Scholar 

  22. Orlando L, Cardillo A, Ghisini R, Rocca A, Balduzzi A, Torrisi R, Peruzzotti G, Goldhirsch A, Pietri E, Colleoni M (2006) Trastuzumab in combination with metronomic cyclophosphamide and methotrexate in patients with HER-2 positive metastatic breast cancer. BMC Cancer 6:225. doi:10.1186/1471-2407-6-225

    Article  PubMed Central  PubMed  Google Scholar 

  23. Gampenrieder SP, Bartsch R, Matzneller P, Pluschnig U, Dubsky P, Gnant MX, Zielinski CC, Steger GG (2010) Capecitabine and vinorelbine as an all-oral chemotherapy in HER2-negative locally advanced and metastatic breast cancer. Breast Care (Basel) 5(3):158–162. doi:10.1159/000314214

    Article  Google Scholar 

  24. Rau KM, Li SH, Chen SM, Tang Y, Huang CH, Wu SC, Chen YY (2011) Weekly paclitaxel combining with gemcitabine is an effective and safe treatment for advanced breast cancer patients. Jpn J Clin Oncol 41(4):455–461. doi:10.1093/jjco/hyq232

    Article  PubMed  Google Scholar 

  25. Bottini A, Generali D, Brizzi MP, Fox SB, Bersiga A, Bonardi S, Allevi G, Aguggini S, Bodini G, Milani M, Dionisio R, Bernardi C, Montruccoli A, Bruzzi P, Harris AL, Dogliotti L, Berruti A (2006) 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 24(22):3623–3628. doi:10.1200/JCO.2005.04.5773

    Article  CAS  PubMed  Google Scholar 

  26. Montagna E, Cancello G, Bagnardi V, Pastrello D, Dellapasqua S, Perri G, Viale G, Veronesi P, Luini A, Intra M, Calleri A, Rampinelli C, Goldhirsch A, Bertolini F, Colleoni M (2012) Metronomic chemotherapy combined with bevacizumab and erlotinib in patients with metastatic HER2-negative breast cancer: clinical and biological activity. Clin Breast Cancer 12(3):207–214. doi:10.1016/j.clbc.2012.03.008

    Article  CAS  PubMed  Google Scholar 

  27. Gebbia V, Boussen H, Valerio MR (2012) Oral metronomic cyclophosphamide with and without methotrexate as palliative treatment for patients with metastatic breast carcinoma. Anticancer Res 32(2):529–536

    CAS  PubMed  Google Scholar 

  28. Taguchi T, Nakayama T, Masuda N, Yoshidome K, Akagi K, Nishida Y, Yoshikawa Y, Ogino N, Abe C, Sakamoto J, Noguchi S (2010) Study of low-dose capecitabine monotherapy for metastatic breast cancer. Chemotherapy 56(2):166–170. doi:10.1159/000313531

    Article  CAS  PubMed  Google Scholar 

  29. Fedele P, Marino A, Orlando L, Schiavone P, Nacci A, Sponziello F, Rizzo P, Calvani N, Mazzoni E, Cinefra M, Cinieri S (2012) Efficacy and safety of low-dose metronomic chemotherapy with capecitabine in heavily pretreated patients with metastatic breast cancer. Eur J Cancer 48(1):24–29. doi:10.1016/j.ejca.2011.06.040

    Article  CAS  PubMed  Google Scholar 

  30. Kraan J, Sleijfer S, Foekens JA, Gratama JW (2012) Clinical value of circulating endothelial cell detection in oncology. Drug Discov Today 17(13–14):710–717. doi:10.1016/j.drudis.2012.01.011

    Article  PubMed  Google Scholar 

  31. Cramarossa G, Lee EK, Sivanathan L, Georgsdottir S, Lien K, Santos KD, Chan K, Emmenegger U (2014) A systematic literature analysis of correlative studies in low-dose metronomic chemotherapy trials. Biomark Med 8(6):893–911. doi:10.2217/bmm.14.14

    Article  CAS  PubMed  Google Scholar 

  32. Ferrara N, Hillan KJ, Gerber HP, Novotny W (2004) Discovery and development of bevacizumab, an anti-VEGF antibody for treating cancer. Nat Rev Drug Discov 3(5):391–400. doi:10.1038/nrd1381

    Article  CAS  PubMed  Google Scholar 

  33. Kerbel RS, Kamen BA (2004) The anti-angiogenic basis of metronomic chemotherapy. Nat Rev Cancer 4(6):423–436. doi:10.1038/nrc1369

    Article  CAS  PubMed  Google Scholar 

  34. Guo S, Colbert LS, Fuller M, Zhang Y, Gonzalez-Perez RR (2010) Vascular endothelial growth factor receptor-2 in breast cancer. Biochim Biophys Acta 1806(1):108–121. doi:10.1016/j.bbcan.2010.04.004

    PubMed Central  CAS  PubMed  Google Scholar 

  35. Ebos JM, Lee CR, Bogdanovic E, Alami J, Van Slyke P, Francia G, Xu P, Mutsaers AJ, Dumont DJ, Kerbel RS (2008) Vascular endothelial growth factor-mediated decrease in plasma soluble vascular endothelial growth factor receptor-2 levels as a surrogate biomarker for tumor growth. Cancer Res 68(2):521–529. doi:10.1158/0008-5472.CAN-07-3217

    Article  CAS  PubMed  Google Scholar 

  36. El-Arab LR, Swellam M, El Mahdy MM (2012) Metronomic chemotherapy in metastatic breast cancer: impact on VEGF. J Egypt Natl Cancer Inst 24(1):15–22. doi:10.1016/j.jnci.2011.12.002

    Article  Google Scholar 

  37. Allegrini G, Di Desidero T, Barletta MT, Fioravanti A, Orlandi P, Canu B, Chericoni S, Loupakis F, Di Paolo A, Masi G, Fontana A, Lucchesi S, Arrighi G, Giusiani M, Ciarlo A, Brandi G, Danesi R, Kerbel RS, Falcone A, Bocci G (2012) Clinical, pharmacokinetic and pharmacodynamic evaluations of metronomic UFT and cyclophosphamide plus celecoxib in patients with advanced refractory gastrointestinal cancers. Angiogenesis 15(2):275–286. doi:10.1007/s10456-012-9260-6

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  38. Bhatt RS, Merchan J, Parker R, Wu HK, Zhang L, Seery V, Heymach JV, Atkins MB, McDermott D, Sukhatme VP (2010) A phase 2 pilot trial of low-dose, continuous infusion, or “metronomic” paclitaxel and oral celecoxib in patients with metastatic melanoma. Cancer 116(7):1751–1756. doi:10.1002/cncr.24902

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  39. Fontana A, Galli L, Fioravanti A, Orlandi P, Galli C, Landi L, Bursi S, Allegrini G, Fontana E, Di Marsico R, Antonuzzo A, D’Arcangelo M, Danesi R, Del Tacca M, Falcone A, Bocci G (2009) Clinical and pharmacodynamic evaluation of metronomic cyclophosphamide, celecoxib, and dexamethasone in advanced hormone-refractory prostate cancer. Clin Cancer Res 15(15):4954–4962. doi:10.1158/1078-0432.CCR-08-3317

    Article  CAS  PubMed  Google Scholar 

  40. Khan OA, Blann AD, Payne MJ, Middleton MR, Protheroe AS, Talbot DC, Taylor M, Kirichek O, Han C, Patil M, Harris AL (2011) Continuous low-dose cyclophosphamide and methotrexate combined with celecoxib for patients with advanced cancer. Br J Cancer 104(12):1822–1827. doi:10.1038/bjc.2011.154

    Article  PubMed Central  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

We would like to thank NCI “National Cancer Institute of Argentina” and the National Scientific and Technical Research Council (CONICET) for their support in this study, as well as Cibic S.A. and especially to Dr. Ricardo Giordano, for their help in flow cytometry studies.

Funding

This work was supported by Agencia Nacional de Promoción Científica y Tecnológica (ANPCyT) [Grant Number: PICT 2006/1908 to OGS, VRR, SMP and CMA]. The National Cancer Institute at the National Institutes of Health grants for doctoral fellows to HAP. HAP is a fellow of Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET).

Author information

Authors and Affiliations

  1. Institute of Experimental Genetics, School of Medical Sciences, National University of Rosario, Santa Fe 3100, S2000KTR, Rosario, Argentina

    Herman Andres Perroud, Maria Jose Rico, Leandro Ernesto Mainetti, Viviana Rosa Rozados & O. Graciela Scharovsky

  2. National Scientific and Technical Research Council (CONICET), Rosario, Argentina

    Herman Andres Perroud & Maria Jose Rico

  3. Institute of Oncology of Rosario, Rosario, Argentina

    Carlos Maria Alasino & Francisco Queralt

  4. Institute of Immunology, School of Medical Sciences, National University of Rosario, Rosario, Argentina

    Stella Maris Pezzotto

  5. Research Council of the National University of Rosario (CIUNR), Rosario, Argentina

    Stella Maris Pezzotto & O. Graciela Scharovsky

Authors
  1. Herman Andres Perroud
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Carlos Maria Alasino
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Maria Jose Rico
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Leandro Ernesto Mainetti
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Francisco Queralt
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Stella Maris Pezzotto
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Viviana Rosa Rozados
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. O. Graciela Scharovsky
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to O. Graciela Scharovsky.

Ethics declarations

Conflict of interest

The authors declare no potential conflict of interest.

Ethical standard

The authors declare that the protocol herein described complies with the current laws of Argentina. The protocol was authorized by the School of Medicine Bioethics Committee and by A.N.M.A.T. (Argentine Regulatory Agency).

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (DOC 37 kb)

Supplementary material 2 (DOC 169 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Perroud, H.A., Alasino, C.M., Rico, M.J. et al. Metastatic breast cancer patients treated with low-dose metronomic chemotherapy with cyclophosphamide and celecoxib: clinical outcomes and biomarkers of response. Cancer Chemother Pharmacol 77, 365–374 (2016). https://doi.org/10.1007/s00280-015-2947-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00280-015-2947-9

Keywords

Search

Navigation