Development and Evolution of the Concept of Metronomic Chemotherapy: A Personal Perspective

Chapter

Abstract

The concept of metronomic dosing and scheduling of conventional chemotherapy drugs was first published in 2000, based on preclinical findings. Tentative validation for the treatment concept has now been obtained based on randomized phase III clinical trial testing. Most promising applications of metronomic chemotherapy may be in the maintenance treatment setting after induction therapy, using oral chemotherapeutic drugs, especially when combined with certain types of targeted agents such as VEGF pathway inhibiting antiangiogenic agents. A personal account of the historical development of the metronomic chemotherapy concept is summarized along with suggestions for improving its impact as a promising means of achieving better and less toxic cancer control, not only in patients in low and middle income countries, but also patients in highly developed high income countries as well.

Keywords

Toxicity Income Cyclophosphamide Bevacizumab Trastuzumab 

Notes

Acknowledgment

I have been very fortunate since the beginning studies of metronomic chemotherapy to have had a number of wonderful trainees and technicians contributing to the progress of the work. Most have been mentioned in this review but their names are worth repeating or mentioning. They include Janusz Rak, Giannoula Klement, Guido Bocci, Yuval Shaked, Terence Tang, Urban Emmenegger, Kae Hashimoto, Christina Hackl, Giulio Francia, William Cruz, Shan Man, Ping Xu, and Christina Lee. In addition, I have also been fortunate to have had substantial financial support from both academic grant funding agencies and industry-sponsored research agreements. Support from academic agencies includes the National Institutes of Health, USA (grant #CA41233), the Canadian Institutes of Health Research (MOP-119499), the Canadian Cancer Society Research Institute, the Ontario Institute for Cancer Research, and the Canadian Breast Cancer Foundation. With respect to industry, financial support was received, especially in the early years of my studies, from ImClone Systems, Inc., New York, and Taiho Pharmaceuticals, Japan. I have also been very fortunate to have collaborated with a number of senior investigators, including Francesco Bertolini in Milan, Emil Voest in the Netherlands, Robert Benezra in New York, the late Dr. Barton Ramen, New Jersey, Anil Sood, and with local medical oncologists who evaluated metronomic chemotherapy in some small clinical trials, e.g., Dr. Rena Buckstein, Dr. Kathy Pritchard, and the late Dr. Rob Buckman. Finally, I would like to apologize to the many investigators whose work on metronomic chemotherapy I have not discussed in any detail – or at all – in this review. Some notable examples of significant contributions include Dr. David Waxman, Dr. G. Scharovsky, and Dr. Eddy Pasquier.

References

  1. 1.
    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 105:1045–1047PubMedCentralPubMedCrossRefGoogle Scholar
  2. 2.
    Browder T, Butterfield CE, Kraling BM, Marshall B, O’Reilly MS, Folkman J (2000) Antiangiogenic scheduling of chemotherapy improves efficacy against experimental drug-resistant cancer. Cancer Res 60:1878–1886PubMedGoogle Scholar
  3. 3.
    Klement G, Baruchel S, Rak J, Man S, Clark K, Hicklin D, Bohlen P, Kerbel RS (2000) Continuous low-dose therapy with vinblastine and VEGF receptor-2 antibody induces sustained tumor regression without overt toxicity. J Clin Invest 105:R15–R24PubMedCentralPubMedCrossRefGoogle Scholar
  4. 4.
    Koopman M, Simkens LHJ, Ten Tije AJ, Creemers G-J, Loosveld OJL, de Jongh FE, Erdkamp F, Erjavee Z, van der Torren AME, van der Hoeven JJM, Nieboer P, Braun JJ, Jansen RL, Haasjes JG, Cats A, Wals JJ, Mol L, Dalesio O, van Tinteren H, Punt CJA (2013) Maintenance treatment with capecitabine and bevacizumab versus observation after induction treatment with chemotherapy and bevacizumab in metastatic colorectal cancer (mCRC): the phase III CAIRO3 study of the Dutch Colorectal Cancer Group (DCCG). J Clin Oncol 31:Abstr 3502Google Scholar
  5. 5.
    Kerbel RS (1991) Inhibition of tumor angiogenesis as a strategy to circumvent acquired resistance to anti-cancer therapeutic agents. Bioessays 13:31–36PubMedCrossRefGoogle Scholar
  6. 6.
    Rini BI, Atkins MB (2009) Resistance to targeted therapy in renal-cell carcinoma. Lancet Oncol 10:992–1000PubMedCrossRefGoogle Scholar
  7. 7.
    Bergers G, Hanahan D (2008) Modes of resistance to anti-angiogenic therapy. Nat Rev Cancer 8:592–603PubMedCentralPubMedCrossRefGoogle Scholar
  8. 8.
    Yu JL, Rak JW, Coomber BL, Hicklin DJ, Kerbel RS (2002) Effect of p53 status on tumor response to antiangiogenic therapy. Science 295:1526–1528PubMedCrossRefGoogle Scholar
  9. 9.
    Kerbel RS, Yu J, Tran J, Man S, Viloria-Petit A, Klement G, Coomber BL, Rak J (2001) Possible mechanisms of acquired resistance to anti-angiogenic drugs: implications for the use of combination therapy approaches. Cancer Metastasis Rev 20:79–86PubMedCrossRefGoogle Scholar
  10. 10.
    Kerbel RS, Viloria-Petit A, Klement G, Rak J (2000) ‘Accidental’ anti-angiogenic drugs. anti-oncogene directed signal transduction inhibitors and conventional chemotherapeutic agents as examples. Eur J Cancer 36:1248–1257PubMedCrossRefGoogle Scholar
  11. 11.
    Klement G, Huang P, Mayer B, Green SK, Man S, Bohlen P, Hicklin D, Kerbel RS (2002) Differences in therapeutic indexes of combination metronomic chemotherapy and an anti-VEGFR-2 antibody in multidrug resistant human breast cancer xenograft. Clin Cancer Res 8:221–232PubMedGoogle Scholar
  12. 12.
    Hahnfeldt P, Hlatky L, Klement GL (2013) Center of cancer systems biology second annual workshop–tumor metronomics: timing and dose level dynamics. Cancer Res 73:2949–2954PubMedCentralPubMedCrossRefGoogle Scholar
  13. 13.
    Mayer EL, Isakoff SJ, Klement G, Downing SR, Chen WY, Hannagan K, Gelman R, Winer EP, Burstein HJ (2012) 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 136:169–178PubMedCrossRefGoogle Scholar
  14. 14.
    Kumar S, Bayat Mokhtari R, Sheikh R, Wu B, Zhang L, Xu P, Man S, Dias Oliveira I, Yeger H, Kerbel RS, Baruchel S (2011) Metronomic oral topotecan with pazopanib is an active antiangiogenic regimen in mouse models of aggressive pediatric solid tumor. Clin Cancer Res 17:5656–5667PubMedCentralPubMedCrossRefGoogle Scholar
  15. 15.
    Kelley RK, Hwang J, Magbanua MJ, Watt L, Beumer JH, Christner SM, Baruchel S, Wu B, Fong L, Yeh BM, Moore AP, Ko AH, Korn WM, Rajpal S, Park JW, Tempero MA, Venook AP, Bergsland EK (2013) A phase 1 trial of imatinib, bevacizumab, and metronomic cyclophosphamide in advanced colorectal cancer. Br J Cancer 109:1725–1734PubMedCentralPubMedCrossRefGoogle Scholar
  16. 16.
    Kumar S, Mokhtari RB, Oliveira ID, Islam S, Toledo SR, Yeger H, Baruchel S (2013) Tumor dynamics in response to antiangiogenic therapy with oral metronomic topotecan and pazopanib in neuroblastoma xenografts. Transl Oncol 6:493–503PubMedCentralPubMedCrossRefGoogle Scholar
  17. 17.
    Pasquier E, Kieran MW, Sterba J, Shaked Y, Baruchel S, Oberlin O, Kivivuori MS, Peyrl A, Diawarra M, Casanova M, Zacharoulis S, Vassal G, Berthold F, Verschuur A, Andre N (2011) Moving forward with metronomic chemotherapy: meeting report of the 2nd International Workshop on Metronomic and Anti-Angiogenic Chemotherapy in Paediatric Oncology. Transl Oncol 4:203–211PubMedCentralPubMedCrossRefGoogle Scholar
  18. 18.
    Mitchell MS (1989) Relapse in the central nervous system in melanoma patients successfully treated with biomodulators. J Clin Oncol 7:1701–1709PubMedGoogle Scholar
  19. 19.
    Mokyr MB, Dray S (1983) Some advantages of curing mice bearing a large subcutaneous MOPC-315 tumor with a low dose rather than a high dose of cyclophosphamide. Cancer Res 43:3112–3119PubMedGoogle Scholar
  20. 20.
    Berd D, Maguire HC Jr, Mastrangelo MJ (1984) Potentiation of human cell-mediated and humoral immunity by low-dose cyclophosphamide. Cancer Res 44:5439–5443PubMedGoogle Scholar
  21. 21.
    Berd D, Mastrangelo MJ (1987) 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 47:3317–3321PubMedGoogle Scholar
  22. 22.
    Wersall P, Mellstedt H (1995) Increased LAK and T cell activation in responding renal cell carcinoma patients after low dose cyclophosphamide, IL-2 and alpha-IFN. Med Oncol 12:69–77PubMedCrossRefGoogle Scholar
  23. 23.
    Pasquier E, Kavallaris M, Andre N (2010) Metronomic chemotherapy: new rationale for new directions. Nat Rev Clin Oncol 7:455–465PubMedCrossRefGoogle Scholar
  24. 24.
    Kerbel RS, Kamen BA (2004) Antiangiogenic basis of low-dose metronomic chemotherapy. Nat Rev Cancer 4:423–436PubMedCrossRefGoogle Scholar
  25. 25.
    Bertolini F, Paul S, Mancuso P, Monestiroli S, Gobbi A, Shaked Y, Kerbel RS (2003) Maximum tolerable dose and low-dose metronomic chemotherapy have opposite effects on the mobilization and viability of circulating endothelial progenitor cells. Cancer Res 63:4342–4346PubMedGoogle Scholar
  26. 26.
    Shaked Y, Ciarrocchi A, Franco M, Lee CR, Man S, Cheung AM, Hicklin DJ, Chaplin D, Foster FS, Benezra R, Kerbel RS (2006) Therapy-induced acute recruitment of circulating endothelial progenitor cells to tumors. Science 313:1785–1787PubMedCrossRefGoogle Scholar
  27. 27.
    Shaked Y, Henke E, Roodhart J, Mancuso P, Langenberg M, Colleoni M, Daenen L, Man S, Xu P, Emmenegger U, Tang T, Zhu Z, Witte L, Bertolini F, Voest E, Benezra R, Kerbel RS (2008) Rapid chemotherapy-induced surge in endothelial progenitor cells: implications for antiangiogenic drugs as chemosensitizing agents. Cancer Cell 14:263–273PubMedCentralPubMedCrossRefGoogle Scholar
  28. 28.
    Shaked Y, Kerbel RS (2007) Antiangiogenic strategies on defense: blocking rebound by the tumor vasculature after chemotherapy. Cancer Res 67:7055–7058PubMedCrossRefGoogle Scholar
  29. 29.
    Man S, Bocci G, Francia G, Green S, Jothy S, Bergers G, Hanahan D, Bohlen P, Hicklin DJ, Kerbel RS (2002) Antitumor and anti-angiogenic effects in mice of low-dose (metronomic) cyclophosphamide administered continuously through the drinking water. Cancer Res 62:2731–2735PubMedGoogle Scholar
  30. 30.
    Shaked Y, Cervi D, Neuman M, Pak B, Kerbel RS, Ben-David Y (2005) Splenic microenvironment is a source of angiogenesis/inflammatory mediators accelerating the extramedullary expansion of murine erythroleukemic cells. Blood 105:4500–4507PubMedCentralPubMedCrossRefGoogle Scholar
  31. 31.
    Bocci G, Francia G, Man S, Lawler J, Kerbel RS (2003) Thrombospondin-1, a mediator of the antiangiogenic effects of low-dose metronomic chemotherapy. Proc Natl Acad Sci U S A 100:12917–12922PubMedCentralPubMedCrossRefGoogle Scholar
  32. 32.
    Hamano Y, Sugimoto H, Soubasakos MA, Kieran M, Olsen BR, Lawler J, Sudhakar A, Kalluri R (2004) Thrombospondin-1 associated with tumor microenvironment contributes to low-dose cyclophosphamide-mediated endothelial cell apoptosis and tumor growth suppression. Cancer Res 64:1570–1574PubMedCrossRefGoogle Scholar
  33. 33.
    Melillo G (2007) Targeting hypoxia cell signaling for cancer therapy. Cancer Metastasis Rev 26:341–352PubMedCrossRefGoogle Scholar
  34. 34.
    Melillo G (2006) Inhibiting hypoxia-inducible factor 1 for cancer therapy. Mol Cancer Res 4:601–605PubMedCrossRefGoogle Scholar
  35. 35.
    Onnis B, Rapisarda A, Melillo G (2009) Development of HIF-1 inhibitors for cancer therapy. J Cell Mol Med 13:2780–2786PubMedCentralPubMedCrossRefGoogle Scholar
  36. 36.
    Rapisarda A, Zalek J, Hollingshead M, Braunschweig T, Uranchimeg B, Bonomi CA, Borgel SD, Carter JP, Hewitt SM, Shoemaker RH, Melillo G (2004) Schedule-dependent inhibition of hypoxia-inducible factor-1 alpha protein accumulation, angiogenesis, and tumor growth by topotecan in U251-HRE glioblastoma xenografts. Cancer Res 64:6845–6848PubMedCrossRefGoogle Scholar
  37. 37.
    Rapisarda A, Uranchimeg B, Sordet O, Pommier Y, Shoemaker RH, Melillo G (2004) Topoisomerase I-mediated inhibition of hypoxia-inducible factor 1: mechanism and therapeutic implications. Cancer Res 64:1475–1482PubMedCrossRefGoogle Scholar
  38. 38.
    Rapisarda A, Hollingshead M, Uranchimeg B, Bonomi CA, Borgel SD, Carter JP, Gehrs B, Raffeld M, Kinders RJ, Parchment R, Anver MR, Shoemaker RH, Melillo G (2009) Increased antitumor activity of bevacizumab in combination with hypoxia inducible factor-1 inhibition. Mol Cancer Ther 8:1867–1877PubMedCentralPubMedCrossRefGoogle Scholar
  39. 39.
    Rapisarda A, Melillo G (2009) Role of the hypoxic tumor microenvironment in the resistance to anti-angiogenic therapies. Drug Resist Updat 12:74–80PubMedCentralPubMedCrossRefGoogle Scholar
  40. 40.
    Rapisarda A, Melillo G (2012) Overcoming disappointing results with antiangiogenic therapy by targeting hypoxia. Nat Rev Clin Oncol 9:378–390PubMedCrossRefGoogle Scholar
  41. 41.
    Lee K, Qian DZ, Rey S, Wei H, Liu JO, Semenza GL (2009) Anthracycline chemotherapy inhibits HIF-1 transcriptional activity and tumor-induced mobilization of circulating angiogenic cells. Proc Natl Acad Sci U S A 106:2353–2358PubMedCentralPubMedCrossRefGoogle Scholar
  42. 42.
    Semenza GL (2003) Targeting HIF-1 for cancer therapy. Nat Rev Cancer 3:721–732PubMedCrossRefGoogle Scholar
  43. 43.
    Ghiringhelli F, Larmonier N, Schmitt E, Parcellier A, Cathelin D, Garrido C, Chauffert B, Solary E, Bonnotte B, Martin F (2004) CD4+CD25+ regulatory T cells suppress tumor immunity but are sensitive to cyclophosphamide which allows immunotherapy of established tumors to be curative. Eur J Immunol 34:336–344PubMedCrossRefGoogle Scholar
  44. 44.
    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 56:641–648PubMedCrossRefGoogle Scholar
  45. 45.
    Couzin-Frankel J (2013) Breakthrough of the year 2013. Cancer immunotherapy. Science 342:1432–1433PubMedCrossRefGoogle Scholar
  46. 46.
    Lipson EJ (2013) Re-orienting the immune system: durable tumor regression and successful re-induction therapy using anti-PD1 antibodies. Oncoimmunology 2:e23661PubMedCentralPubMedCrossRefGoogle Scholar
  47. 47.
    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 18:601–605PubMedCrossRefGoogle Scholar
  48. 48.
    Doloff JC, Waxman DJ (2012) VEGF receptor inhibitors block the ability of metronomically dosed cyclophosphamide to activate innate immunity-induced tumor regression. Cancer Res 72:1103–1115PubMedCentralPubMedCrossRefGoogle Scholar
  49. 49.
    Ma J, Waxman DJ (2008) Modulation of the antitumor activity of metronomic cyclophosphamide by the angiogenesis inhibitor axitinib. Mol Cancer Ther 7:79–89PubMedCentralPubMedCrossRefGoogle Scholar
  50. 50.
    Cruz-Munoz W, Di DT, Man S, Xu P, Jaramillo ML, Hashimoto K, Collins C, Banville M, O’Connor-McCourt MD, Kerbel RS (2014) Analysis of acquired resistance to metronomic oral topotecan chemotherapy plus pazopanib after prolonged preclinical potent responsiveness in advanced ovarian cancer. Angiogenesis 17:661–673Google Scholar
  51. 51.
    Emmenegger U, Man S, Shaked Y, Francia G, Wong JW, Hicklin DJ, Kerbel RS (2004) A comparative analysis of low dose metronomic cyclophosphamide reveals absent or low grade toxicity on tissues highly sensitive to the toxic effects of maximum tolerated dose regimens. Cancer Res 64:3994–4000PubMedCrossRefGoogle Scholar
  52. 52.
    Emmenegger U, Morton GC, Francia G, Shaked Y, Franco M, Weinerman A, Man S, Kerbel RS (2006) Low-dose metronomic cyclophosphamide and weekly tirapazamine: a well tolerated combination regimen with enhanced efficacy that exploits tumor hypoxia. Cancer Res 66:1664–1674PubMedCrossRefGoogle Scholar
  53. 53.
    Emmenegger U, Kerbel RS (2005) A dynamic de-escalating dosing strategy to determine the optimal biological dose for antiangiogenic drugs. Clin Cancer Res 11:7589–7592PubMedCrossRefGoogle Scholar
  54. 54.
    Emmenegger U, Shaked Y, Man S, Bocci G, Spasojevic I, Francia G, Kouri A, Coke R, Cruz-Munoz W, Ludeman SM, Colvin OM, Kerbel RS (2007) Pharmacodynamic and pharmacokinetic study of chronic low-dose metronomic cyclophosphamide therapy in mice. Mol Cancer Ther 6:2280–2289PubMedCrossRefGoogle Scholar
  55. 55.
    Emmenegger U, Kerbel RS (2007) Five years of clinical experience with metronomic chemotherapy: achievements and perspectives. Onkologie 30:606–608PubMedCrossRefGoogle Scholar
  56. 56.
    Emmenegger U, Francia G, Chow A, Shaked Y, Kouri A, Man S, Kerbel RS (2011) Tumors that acquire resistance to metronomic cyclophosphamide retain sensitivity to maximum tolerated dose cyclophosphamide. Neoplasia 13:40–48PubMedCentralPubMedGoogle Scholar
  57. 57.
    Hashimoto K, Man S, Xu P, Cruz-Munoz W, Tang T, Kumar R, Kerbel RS (2010) Potent preclinical impact of metronomic low-dose oral topotecan combined with the antiangiogenic drug pazopanib for the treatment of ovarian cancer. Mol Cancer Ther 9:996–1006PubMedCentralPubMedCrossRefGoogle Scholar
  58. 58.
    Munoz R, Man S, Shaked Y, Lee C, Wong J, Francia G, Kerbel RS (2006) Highly efficacious non-toxic treatment for advanced metastatic breast cancer using combination UFT-cyclophosphamide metronomic chemotherapy. Cancer Res 66:3386–3391PubMedCrossRefGoogle Scholar
  59. 59.
    Francia G, Cruz-Munoz W, Man S, Xu P, Kerbel RS (2011) Mouse models of advanced spontaneous metastasis for experimental therapeutics. Nat Rev Cancer 11:135–141PubMedCrossRefGoogle Scholar
  60. 60.
    Cruz-Munoz W, Man S, Xu P, Kerbel RS (2008) Development of a preclinical model of spontaneous human melanoma central nervous system metastasis. Cancer Res 68:4500–4505Google Scholar
  61. 61.
    Hackl C, Man S, Francia G, Xu P, Kerbel RS (2013) Metronomic oral topotecan prolongs survival and reduces liver metastasis in improved preclinical orthotopic and adjuvant therapy colon cancer models. Gut 62:259–271PubMedCentralPubMedCrossRefGoogle Scholar
  62. 62.
    Hurwitz H, Fehrenbacher L, Novotny W, Cartwright T, Hainsworth H, Helm W, Berlin J, Baron A, Griffing S, Holmgren E, Ferrara N, Fyfe G, Rogers B, Ross R, Kabbinavar F (2004) Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med 350:2335–2342PubMedCrossRefGoogle Scholar
  63. 63.
    Guerin E, Man S, Xu P, Kerbel RS (2013) A model of postsurgical advanced metastatic breast cancer more accurately replicates the clinical efficacy of antiangiogenic drugs. Cancer Res 73:2743–2748PubMedCrossRefGoogle Scholar
  64. 64.
    Al Hajj M, Wicha MS, Benito-Hernandez A, Morrison SJ, Clarke MF (2003) Prospective identification of tumorigenic breast cancer cells. Proc Natl Acad Sci U S A 100:3983–3988PubMedCentralPubMedCrossRefGoogle Scholar
  65. 65.
    Folkins C, Man S, Shaked Y, Xu P, Hicklin DJ, Kerbel RS (2007) Anti-cancer therapies combining antiangiogenic and tumor cell cytotoxic effects reduce the tumor stem-like cell fraction in glioma xenograft tumors. Cancer Res 67:3560–3564PubMedCrossRefGoogle Scholar
  66. 66.
    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 92:952–966PubMedCrossRefGoogle Scholar
  67. 67.
    Vives M, Ginesta MM, Gracova K, Graupera M, Casanovas O, Capella G, Serrano T, Laquente B, Viñals F (2013) Metronomic chemotherapy following the maximum tolerated dose is an effective anti-tumor therapy affecting angiogenesis, tumor differentiation and cancer stem cells. Int J Cancer 133:2464–2472Google Scholar
  68. 68.
    Rich JN, Bao S (2007) Chemotherapy and cancer stem cells. Cell Stem Cell 1:353–355PubMedCrossRefGoogle Scholar
  69. 69.
    Pietras K, Hanahan D (2005) A multitargeted, metronomic, and maximum-tolerated dose “chemo-switch” regimen is antiangiogenic, producing objective responses and survival benefit in a mouse model of cancer. J Clin Oncol 23:939–952PubMedCrossRefGoogle Scholar
  70. 70.
    Fidler IJ, Ellis LM (2000) Chemotherapeutic drugs–more really is not better. Nat Med 6:500–502PubMedCrossRefGoogle Scholar
  71. 71.
    Dellapasqua S, Bertolini F, Bagnardi V, Campagnoli E, Scarano E, Torrisi R, Kerbel RS, Shaked Y, Mancuso P, Goldhirsch A, Rocca A, Pietri E, Colleoni M (2008) Metronomic cyclophosphamide and capecitabine combined with bevacizumab in advanced breast cancer: clinical and biological activity. J Clin Oncol 26:4899–4905PubMedCrossRefGoogle Scholar
  72. 72.
    Bellmunt J, Trigo JM, Calvo E, Carles J, Perez-Gracia JL, Rubio J, Virizuela JA, Lopez R, Lazaro M, Albanell J (2010) Activity of a multitargeted chemo-switch regimen (sorafenib, gemcitabine, and metronomic capecitabine) in metastatic renal-cell carcinoma: a phase 2 study (SOGUG-02-06). Lancet Oncol 11:350–357PubMedCrossRefGoogle Scholar
  73. 73.
    Koeberie D, Betticher DC, von Moos R, Dietrich D, Brauchli P, Baertschi D et al (2014) Bevacizumab continuation versus no continuation after first-line chemo-bevacizumab therapy in patients with metastatic colorectal cancer: a randomized phase III noninferiority trial (SAKK 41/06). J Clin Oncol Suppl: abstract 3503Google Scholar
  74. 74.
    Garcia AA, Hirte H, Fleming G, Yang D, Tsao-Wei DD, Roman L, Groshen S, Swenson S, Markland F, Gandara D, Scudder S, Morgan R, Chen H, Lenz HJ, Oza AM (2008) Phase II clinical trial of bevacizumab and low-dose metronomic oral cyclophosphamide in recurrent ovarian cancer: a trial of the California, Chicago, and Princess Margaret Hospital phase II consortia. J Clin Oncol 26:76–82PubMedCrossRefGoogle Scholar
  75. 75.
    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 24:3623–3628PubMedCrossRefGoogle Scholar
  76. 76.
    du Manoir JM, Francia G, Man S, Mossoba M, Medin JA, Viloria-Petit A, Hicklin DJ, Emmenegger U, Kerbel RS (2006) Strategies for delaying or treating in vivo acquired resistance to trastuzumab (Herceptin®) in human breast cancer xenografts. Clin Cancer Res 12:904–916PubMedCrossRefGoogle Scholar
  77. 77.
    Rico MJ, Perroud HA, Mainetti LE, Rozados VR, Scharovsky OG (2014) Comparative effectiveness of two metronomic chemotherapy schedules-our experience in the preclinical field. Cancer Invest 32:92–98PubMedCrossRefGoogle Scholar
  78. 78.
    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 24:2310–2316PubMedCrossRefGoogle Scholar
  79. 79.
    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 9:451–462PubMedCrossRefGoogle Scholar
  80. 80.
    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 137:151–163PubMedCrossRefGoogle Scholar
  81. 81.
    Bocci G, Tuccori M, Emmenegger U, Liguori V, Kerbel RS, Del Tacca M (2004) Cyclophosphamide-methotrexate “metronomic” chemotherapy for the palliative treatment of metastatic breast cancer. A comparative pharmacoeconomic evaluation. Ann Oncol 16:1243–1252CrossRefGoogle Scholar
  82. 82.
    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 6:225PubMedCentralPubMedCrossRefGoogle Scholar
  83. 83.
    Kato H, Ichinose Y, Ohta M, Hata E, Tsubota N, Tada H, Watanabe Y, Wada H, Tsuboi M, Hamajima N, Ohta M (2004) A randomized trial of adjuvant chemotherapy with uracil-tegafur for adenocarcinoma of the lung. N Engl J Med 350:1713–1721PubMedCrossRefGoogle Scholar
  84. 84.
    Watanabe T, Sano M, Takashima S, Kitaya T, Tokuda Y, Yoshimoto M, Kohno N, Nakagami K, Iwata H, Shimozuma K, Sonoo H, Tsuda H, Sakamoto G, Ohashi Y (2009) Oral uracil and tegafur compared with classic cyclophosphamide, methotrexate, fluorouracil as postoperative chemotherapy in patients with node-negative, high-risk breast cancer: National Surgical Adjuvant Study for Breast Cancer 01 Trial. J Clin Oncol 27:1368–1374PubMedCrossRefGoogle Scholar
  85. 85.
    Kerbel RS (2012) Strategies for improving the clinical benefit of antiangiogenic drug based therapies for breast cancer. J Mammary Gland Biol Neoplasia 17(34):229–239PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  1. 1.Biological Sciences Platform, S-217Sunnybrook Research Institute, University of TorontoTorontoCanada

Personalised recommendations