Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Pharmacokinetics of metronomic chemotherapy: a neglected but crucial aspect

Nature Reviews Clinical Oncology volume 13, pages 659–673 (2016)Cite this article

Subjects

Key Points

  • Metronomic chemotherapy is the frequent, regular administration of drug doses designed to maintain low, but active, concentrations of chemotherapeutic drugs over prolonged periods of time, without causing serious toxicities

  • Despite the important information they provide, preclinical and clinical pharmacokinetic studies have had a secondary role during the conceptual development of metronomic chemotherapy

  • Different metronomic drug concentrations and schedules might affect different prevalent mechanisms of antitumour action, which suggests that therapy protocols could be selected on the basis of different prevalent effects

  • To develop better computational models for future metronomic chemotherapy studies, pharmacokinetic parameters of metronomic chemotherapy should be investigated more extensively in relation to pharmacodynamics (with a PK/PD approach) in future clinical trials

  • Therapeutic drug monitoring of metronomic chemotherapy is essential to maintain drug concentrations in the 'activity range', while maintaining a low toxicity profile

  • Randomized, prospective, clinical studies on metronomic chemotherapy should include pharmacokinetic/pharmacodynamic substudies with the aim of achieving personalized metronomic chemotherapy protocols in the future

Abstract

Metronomic chemotherapy describes the close, regular administration of chemotherapy drugs at less-toxic doses over prolonged periods of time. In 2015, the results of randomized phase III clinical trials demonstrated encouraging, albeit limited, efficacy benefits of metronomic chemotherapy regimens administered as adjuvant maintenance therapy for the treatment of breast cancer, or as maintenance therapy in combination with an antiangiogenic agent for metastatic colorectal cancer. Owing to the investigational nature of this approach, metronomic chemotherapy regimens are highly empirical in terms of the optimal dose and schedule for the drugs administered; therefore, greater knowledge of the pharmacokinetics of metronomic chemotherapy is critical to the future success of this treatment strategy. Unfortunately, such preclinical and clinical pharmacokinetic studies are rare. Herein, we present situations in which active drug concentrations have been achieved with metronomic schedules, and discuss their associated pharmacokinetic parameters. We summarize examples from the limited number of clinical studies in order to illustrate the importance of assessing such pharmacokinetic parameters, and discuss the influence this information can have on improving efficacy and reducing toxicity.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Similar content being viewed by others

References

  1. Kerbel, R. S. & Kamen, B. A. The anti-angiogenic basis of metronomic chemotherapy. Nat. Rev. Cancer 4, 423–436 (2004).

    Google Scholar 

  2. Andre, N., Carre, M. & Pasquier, E. Metronomics: towards personalized chemotherapy? Nat. Rev. Clin. Oncol. 11, 413–431 (2014).

    Google Scholar 

  3. Munzone, E. & Colleoni, M. Clinical overview of metronomic chemotherapy in breast cancer. Nat. Rev. Clin. Oncol. 12, 631–644 (2015).

    Google Scholar 

  4. Browder, T. et al. Antiangiogenic scheduling of chemotherapy improves efficacy against experimental drug-resistant cancer. Cancer Res. 60, 1878–1886 (2000).

    Google Scholar 

  5. Klement, G. et al. Continuous low-dose therapy with vinblastine and VEGF receptor-2 antibody induces sustained tumor regression without overt toxicity. J. Clin. Invest. 105, R15–R24 (2000).

    Google Scholar 

  6. Bocci, G., Nicolaou, K. C. & Kerbel, R. S. Protracted low-dose effects on human endothelial cell proliferation and survival in vitro reveal a selective antiangiogenic window for various chemotherapeutic drugs. Cancer Res. 62, 6938–6943 (2002).

    Google Scholar 

  7. Hao, Y. B., Yi, S. Y., Ruan, J., Zhao, L. & Nan, K. J. New insights into metronomic chemotherapy-induced immunoregulation. Cancer Lett. 354, 220–226 (2014).

    Google Scholar 

  8. Folkins, C. et al. Anticancer therapies combining antiangiogenic and tumor cell cytotoxic effects reduce the tumor stem-like cell fraction in glioma xenograft tumors. Cancer Res. 67, 3560–3564 (2007).

    Google Scholar 

  9. Derosa, L. et al. Docetaxel plus oral metronomic cyclophosphamide: a phase II study with pharmacodynamic and pharmacogenetic analyses in castration-resistant prostate cancer patients. Cancer 120, 3923–3931 (2014).

    Google Scholar 

  10. Shaked, Y. et al. Low-dose metronomic combined with intermittent bolus-dose cyclophosphamide is an effective long-term chemotherapy treatment strategy. Cancer Res. 65, 7045–7051 (2005).

    Google Scholar 

  11. Jedeszko, C. et al. Postsurgical adjuvant or metastatic renal cell carcinoma therapy models reveal potent antitumor activity of metronomic oral topotecan with pazopanib. Sci. Transl. Med. 7, 282ra50 (2015).

    Google Scholar 

  12. Cruz-Munoz, W. et al. Analysis of acquired resistance to metronomic oral topotecan chemotherapy plus pazopanib after prolonged preclinical potent responsiveness in advanced ovarian cancer. Angiogenesis 17, 661–673 (2014).

    Google Scholar 

  13. Srivastava, K. et al. Postsurgical adjuvant tumor therapy by combining anti-angiopoietin-2 and metronomic chemotherapy limits metastatic growth. Cancer Cell 26, 880–895 (2014).

    Google Scholar 

  14. Dellapasqua, S. et al. Increased mean corpuscular volume of red blood cells predicts response to metronomic capecitabine and cyclophosphamide in combination with bevacizumab. Breast 21, 309–313 (2012).

    Google Scholar 

  15. Bocci, G. et al. Increased plasma vascular endothelial growth factor (VEGF) as a surrogate marker for optimal therapeutic dosing of VEGF receptor-2 monoclonal antibodies. Cancer Res. 64, 6616–6625 (2004).

    Google Scholar 

  16. Orlando, L. et al. Trastuzumab in combination with metronomic cyclophosphamide and methotrexate in patients with HER-2 positive metastatic breast cancer. BMC Cancer 6, 225 (2006).

    Google Scholar 

  17. Denies, S., Cicchelero, L., Van Audenhove, I. & Sanders, N. N. Combination of interleukin-12 gene therapy, metronomic cyclophosphamide and DNA cancer vaccination directs all arms of the immune system towards tumor eradication. J. Control. Release 187, 175–182 (2014).

    Google Scholar 

  18. Weir, G. M. et al. Metronomic cyclophosphamide enhances HPV16E7 peptide vaccine induced antigen-specific and cytotoxic T-cell mediated antitumor immune response. Oncoimmunology 3, e953407 (2014).

    Google Scholar 

  19. Bottini, A. 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. 24, 3623–3628 (2006).

    Google Scholar 

  20. Emmenegger, U. et al. Pharmacodynamic and pharmacokinetic study of chronic low-dose metronomic cyclophosphamide therapy in mice. Mol. Cancer Ther. 6, 2280–2289 (2007).

    Google Scholar 

  21. Wang, Z., Butner, J. D., Cristini, V. & Deisboeck, T. S. Integrated PK-PD and agent-based modeling in oncology. J. Pharmacokinet. Pharmacodyn. 42, 179–189 (2015).

    Google Scholar 

  22. Penel, N. et al. Megestrol acetate versus metronomic cyclophosphamide in patients having exhausted all effective therapies under standard care. Br. J. Cancer 102, 1207–1212 (2010).

    Google Scholar 

  23. Patil, V. M. et al. A prospective randomized phase II study comparing metronomic chemotherapy with chemotherapy (single agent cisplatin), in patients with metastatic, relapsed or inoperable squamous cell carcinoma of head and neck. Oral Oncol. 51, 279–286 (2015).

    Google Scholar 

  24. Chen, Y. M. et al. A phase II randomized trial of gefitinib alone or with tegafur/uracil treatment in patients with pulmonary adenocarcinoma who had failed previous chemotherapy. J. Thorac. Oncol. 6, 1110–1116 (2011).

    Google Scholar 

  25. Simkens, L. H. et al. Maintenance treatment with capecitabine and bevacizumab in metastatic colorectal cancer (CAIRO3): a phase 3 randomised controlled trial of the Dutch Colorectal Cancer Group. Lancet 385, 1843–1852 (2015).

    Google Scholar 

  26. Rowland, M. & Tozer, T. N. in Clinical Pharmacokinetics: Concepts and Applications 53–105 (Lippincot Williams & Wilkins, 1995).

    Google Scholar 

  27. Gillis, N. K., Patel, J. N. & Innocenti, F. Clinical implementation of germ line cancer pharmacogenetic variants during the next-generation sequencing era. Clin. Pharmacol. Ther. 95, 269–280 (2014).

    Google Scholar 

  28. Roy, P. & Waxman, D. J. Activation of oxazaphosphorines by cytochrome P450: application to gene-directed enzyme prodrug therapy for cancer. Toxicol. In Vitro 20, 176–186 (2006).

    Google Scholar 

  29. Bocci, G. et al. A pharmacokinetic-based test to prevent severe 5-fluorouracil toxicity. Clin. Pharmacol. Ther. 80, 384–395 (2006).

    Google Scholar 

  30. Kerbel, R. S. & Grothey, A. Gastrointestinal cancer: rationale for metronomic chemotherapy in phase III trials. Nat. Rev. Clin. Oncol. 12, 313–314 (2015).

    Google Scholar 

  31. Fan, J. & de Lannoy, I. A. Pharmacokinetics. Biochem. Pharmacol. 87, 93–120 (2014).

    Google Scholar 

  32. Barbolosi, D. et al. Metronomics chemotherapy: time for computational decision support. Cancer Chemother. Pharmacol. 74, 647–652 (2014).

    Google Scholar 

  33. McCune, J. S., Jacobson, P., Wiseman, A. & Militano, O. Optimizing drug therapy in pediatric SCT: focus on pharmacokinetics. Bone Marrow Transplant. 50, 165–172 (2015).

    Google Scholar 

  34. Widmer, N. et al. Review of therapeutic drug monitoring of anticancer drugs part two — targeted therapies. Eur. J. Cancer 50, 2020–2036 (2014).

    Google Scholar 

  35. Zhou, Q., Guo, P., Wang, X., Nuthalapati, S. & Gallo, J. M. Preclinical pharmacokinetic and pharmacodynamic evaluation of metronomic and conventional temozolomide dosing regimens. J. Pharmacol. Exp. Ther. 321, 265–275 (2007).

    Google Scholar 

  36. Banissi, C., Ghiringhelli, F., Chen, L. & Carpentier, A. F. Treg depletion with a low-dose metronomic temozolomide regimen in a rat glioma model. Cancer Immunol. Immunother. 58, 1627–1634 (2009).

    Google Scholar 

  37. Penel, N., Adenis, A. & Bocci, G. Cyclophosphamide-based metronomic chemotherapy: after 10 years of experience, where do we stand and where are we going? Crit. Rev. Oncol. Hematol. 82, 40–50 (2012).

    Google Scholar 

  38. Bocci, G., Francia, G., Man, S., Lawler, J. & Kerbel, R. S. Thrombospondin 1, a mediator of the antiangiogenic effects of low-dose metronomic chemotherapy. Proc. Natl Acad. Sci. USA 100, 12917–12922 (2003).

    Google Scholar 

  39. Man, S. et al. Antitumor effects in mice of low-dose (metronomic) cyclophosphamide administered continuously through the drinking water. Cancer Res. 62, 2731–2735 (2002).

    Google Scholar 

  40. Klink, T. et al. Metronomic trofosfamide inhibits progression of human lung cancer xenografts by exerting anti-angiogenic effects. J. Cancer Res. Clin. Oncol. 132, 643–652 (2006).

    Google Scholar 

  41. Chen, C. S., Doloff, J. C. & Waxman, D. J. Intermittent metronomic drug schedule is essential for activating antitumor innate immunity and tumor xenograft regression. Neoplasia 16, 84–96 (2014).

    Google Scholar 

  42. Bocci, G., Di Paolo, A. & Danesi, R. The pharmacological bases of the antiangiogenic activity of paclitaxel. Angiogenesis 16, 481–492 (2013).

    Google Scholar 

  43. Di Paolo, A., Bocci, G. & Danesi, R. The preclinical bases of the rational combination of paclitaxel and antiangiogenic drugs. Clin. Cancer Drugs 1, 100–115 (2014).

    Google Scholar 

  44. Pasquier, E., Andre, N. & Braguer, D. Targeting microtubules to inhibit angiogenesis and disrupt tumour vasculature: implications for cancer treatment. Curr. Cancer Drug Targets 7, 566–581 (2007).

    Google Scholar 

  45. Schwartz, E. L. Antivascular actions of microtubule-binding drugs. Clin. Cancer Res. 15, 2594–2601 (2009).

    Google Scholar 

  46. Huang, Y. et al. Antiangiogenic activity of sterically stabilized liposomes containing paclitaxel (SSL-PTX): in vitro and in vivo. AAPS PharmSciTech 11, 752–759 (2010).

    Google Scholar 

  47. Koziara, J. M., Whisman, T. R., Tseng, M. T. & Mumper, R. J. In-vivo efficacy of novel paclitaxel nanoparticles in paclitaxel-resistant human colorectal tumors. J. Control. Release 112, 312–319 (2006).

    Google Scholar 

  48. Hammady, T., Rabanel, J. M., Dhanikula, R. S., Leclair, G. & Hildgen, P. Functionalized nanospheres loaded with anti-angiogenic drugs: cellular uptake and angiosuppressive efficacy. Eur. J. Pharm. Biopharm. 72, 418–427 (2009).

    Google Scholar 

  49. Ng, S. S. et al. Influence of formulation vehicle on metronomic taxane chemotherapy: albumin-bound versus cremophor EL-based paclitaxel. Clin. Cancer Res. 12, 4331–4338 (2006).

    Google Scholar 

  50. Miele, E., Spinelli, G. P., Tomao, F. & Tomao, S. Albumin-bound formulation of paclitaxel (Abraxane® ABI-007) in the treatment of breast cancer. Int. J. Nanomedicine 4, 99–105 (2009).

    Google Scholar 

  51. Lee, S. J. et al. Metronomic activity of CD44-targeted hyaluronic acid-paclitaxel in ovarian carcinoma. Clin. Cancer Res. 18, 4114–4121 (2012).

    Google Scholar 

  52. Luo, L. M. et al. Anti-tumor and anti-angiogenic effect of metronomic cyclic NGR-modified liposomes containing paclitaxel. Biomaterials 34, 1102–1114 (2013).

    Google Scholar 

  53. Bradshaw-Pierce, E. L., Eckhardt, S. G. & Gustafson, D. L. A physiologically based pharmacokinetic model of docetaxel disposition: from mouse to man. Clin. Cancer Res. 13, 2768–2776 (2007).

    Google Scholar 

  54. Bradshaw-Pierce, E. L., Steinhauer, C. A., Raben, D. & Gustafson, D. L. Pharmacokinetic-directed dosing of vandetanib and docetaxel in a mouse model of human squamous cell carcinoma. Mol. Cancer Ther. 7, 3006–3017 (2008).

    Google Scholar 

  55. Kumar, S. et al. Metronomic oral topotecan with pazopanib is an active antiangiogenic regimen in mouse models of aggressive pediatric solid tumor. Clin. Cancer Res. 17, 5656–5667 (2011).

    Google Scholar 

  56. van Geel, R. M., Beijnen, J. H. & Schellens, J. H. Concise drug review: pazopanib and axitinib. Oncologist 17, 1081–1089 (2012).

    Google Scholar 

  57. Hartmann, J. T. & Lipp, H. P. Camptothecin and podophyllotoxin derivatives: inhibitors of topoisomerase I and II — mechanisms of action, pharmacokinetics and toxicity profile. Drug Saf. 29, 209–230 (2006).

    Google Scholar 

  58. Andre, N., Padovani, L. & Verschuur, A. Metronomic chemotherapy: back to the future! Drug News Perspect. 23, 143–151 (2010).

    Google Scholar 

  59. Allegrini, G. et al. A pharmacokinetic and pharmacodynamic study on metronomic irinotecan in metastatic colorectal cancer patients. Br. J. Cancer 98, 1312–1319 (2008).

    Google Scholar 

  60. Tillmanns, T. D. et al. Daily oral topotecan: utilization of a metronomic dosing schedule to treat recurrent or persistent solid tumors. J. Clin. Oncol. 26, 2571 (2008).

    Google Scholar 

  61. Turner, D. C., Tillmanns, T. D., Harstead, K. E., Throm, S. L. & Stewart, C. F. Combination metronomic oral topotecan and pazopanib: a pharmacokinetic study in patients with gynecological cancer. Anticancer Res. 33, 3823–3829 (2013).

    Google Scholar 

  62. Briasoulis, E. et al. Dose-ranging study of metronomic oral vinorelbine in patients with advanced refractory cancer. Clin. Cancer Res. 15, 6454–6461 (2009).

    Google Scholar 

  63. Briasoulis, E. et al. Dose selection trial of metronomic oral vinorelbine monotherapy in patients with metastatic cancer: a hellenic cooperative oncology group clinical translational study. BMC Cancer 13, 263 (2013).

    Google Scholar 

  64. Allegrini, G. et al. Clinical, pharmacokinetic and pharmacodynamic evaluations of metronomic UFT and cyclophosphamide plus celecoxib in patients with advanced refractory gastrointestinal cancers. Angiogenesis 15, 275–286 (2012).

    Google Scholar 

  65. Moes, J. et al. Development of an oral solid dispersion formulation for use in low-dose metronomic chemotherapy of paclitaxel. Eur. J. Pharm. Biopharm. 83, 87–94 (2013).

    Google Scholar 

  66. Bazzola, L. et al. Combination of letrozole, metronomic cyclophosphamide and sorafenib is well-tolerated and shows activity in patients with primary breast cancer. Br. J. Cancer 112, 52–60 (2015).

    Google Scholar 

  67. Stempak, D. et al. A pilot pharmacokinetic and antiangiogenic biomarker study of celecoxib and low-dose metronomic vinblastine or cyclophosphamide in pediatric recurrent solid tumors. J. Pediatr. Hematol. Oncol. 28, 720–728 (2006).

    Google Scholar 

  68. Baruchel, S. et al. Safety and pharmacokinetics of temozolomide using a dose-escalation, metronomic schedule in recurrent paediatric brain tumours. Eur. J. Cancer 42, 2335–2342 (2006).

    Google Scholar 

  69. Haefeli, W. E. & Carls, A. Drug interactions with phytotherapeutics in oncology. Expert Opin. Drug Metab. Toxicol. 10, 359–377 (2014).

    Google Scholar 

  70. Roby, C. A., Anderson, G. D., Kantor, E., Dryer, D. A. & Burstein, A. H. St John's Wort: effect on CYP3A4 activity. Clin. Pharmacol. Ther. 67, 451–457 (2000).

    Google Scholar 

  71. Leveque, D. et al. Mechanisms of pharmacokinetic interactions involving oral anticancer agents. Bull. Cancer 102, 65–72 (2015).

    Google Scholar 

  72. Lasalvia-Prisco, E. et al. Insulin-induced enhancement of antitumoral response to methotrexate in breast cancer patients. Cancer Chemother. Pharmacol. 53, 220–224 (2004).

    Google Scholar 

  73. Damyanov, C., Gerasimova, D., Maslev, I. & Gavrilov, V. Low-dose chemotherapy with insulin (insulin potentiation therapy) in combination with hormone therapy for treatment of castration-resistant prostate cancer. ISRN Urol. 2012, 140182 (2012).

    Google Scholar 

  74. Chen, C., Xu, T., Lu, Y., Chen, J. & Wu, S. The efficacy of temozolomide for recurrent glioblastoma multiforme. Eur. J. Neurol. 20, 223–230 (2013).

    Google Scholar 

  75. Adenis, A. et al. A dose-escalating phase I of imatinib mesylate with fixed dose of metronomic cyclophosphamide in targeted solid tumours. Br. J. Cancer 109, 2574–2578 (2013).

    Google Scholar 

  76. Villano, J. L., Seery, T. E. & Bressler, L. R. Temozolomide in malignant gliomas: current use and future targets. Cancer Chemother. Pharmacol. 64, 647–655 (2009).

    Google Scholar 

  77. US National Library of Science. ClinicalTrials.gov, https://clinicaltrials.gov/ct2/show/NCT01285817?term=NCT01285817&rank=1 (2015).

  78. US National Library of Science. ClinicalTrials.gov, https://clinicaltrials.gov/ct2/show/NCT00200161?term=NCT00200161&rank=1 (2015).

  79. Di Paolo, A., Bocci, G., Danesi, R. & Del Tacca, M. Clinical pharmacokinetics of irinotecan-based chemotherapy in colorectal cancer patients. Curr. Clin. Pharmacol. 1, 311–323 (2006).

    Google Scholar 

  80. Falcone, A. et al. Sequence effect of irinotecan and fluorouracil treatment on pharmacokinetics and toxicity in chemotherapy-naive metastatic colorectal cancer patients. J. Clin. Oncol. 19, 3456–3462 (2001).

    Google Scholar 

  81. Herben, V. M. et al. Phase I and pharmacokinetic study of irinotecan administered as a low-dose, continuous intravenous infusion over 14 days in patients with malignant solid tumors. J. Clin. Oncol. 17, 1897–1905 (1999).

    Google Scholar 

  82. Bocci, G. et al. Antiangiogenic and anticolorectal cancer effects of metronomic irinotecan chemotherapy alone and in combination with semaxinib. Br. J. Cancer 98, 1619–1629 (2008).

    Google Scholar 

  83. Hashimoto, K. et al. 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, 996–1006 (2010).

    Google Scholar 

  84. Merritt, W. M. et al. Anti-angiogenic properties of metronomic topotecan in ovarian carcinoma. Cancer Biol. Ther. 8, 1596–1603 (2009).

    Google Scholar 

  85. Minturn, J. E. et al. A phase II study of metronomic oral topotecan for recurrent childhood brain tumors. Pediatr. Blood Cancer 56, 39–44 (2011).

    Google Scholar 

  86. Herben, V. M. et al. Oral topotecan: bioavailablity and effect of food co-administration. Br. J. Cancer 80, 1380–1386 (1999).

    Google Scholar 

  87. Schellens, J. H. et al. Bioavailability and pharmacokinetics of oral topotecan: a new topoisomerase I inhibitor. Br. J. Cancer 73, 1268–1271 (1996).

    Google Scholar 

  88. Kerklaan, B. M. et al. Phase I study of safety, tolerability, and pharmacokinetics of pazopanib in combination with oral topotecan in patients with advanced solid tumors. J. Clin. Oncol. 31, 2536 (2013).

    Google Scholar 

  89. Kerklaan, B. M. et al. Phase I and pharmacological study of pazopanib in combination with oral topotecan in patients with advanced solid tumours. Br. J. Cancer 113, 706–715 (2015).

    Google Scholar 

  90. US National Library of Science. ClinicalTrials.gov, https://clinicaltrials.gov/ct2/show/NCT01931098?term=NCT01931098&rank=1 (2016).

  91. Cazzaniga, M. E. et al. Metronomic oral vinorelbine in advanced breast cancer and non-small-cell lung cancer: current status and future development. Future Oncol. 12, 373–387 (2016).

    Google Scholar 

  92. Kontopodis, E. et al. A phase II study of metronomic oral vinorelbine administered in the second line and beyond in non-small cell lung cancer (NSCLC): a phase II study of the Hellenic Oncology Research Group. J. Chemother. 25, 49–55 (2013).

    Google Scholar 

  93. Addeo, R. et al. Low-dose metronomic oral administration of vinorelbine in the first-line treatment of elderly patients with metastatic breast cancer. Clin. Breast Cancer 10, 301–306 (2010).

    Google Scholar 

  94. Addeo, R. 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. 70, 603–609 (2012).

    Google Scholar 

  95. Pappas, P., Biziota, I., Marselos, M. & Briasoulis, E. Evaluation of antiproliferative and molecular effects of vinorelbine and its active metabolite 4-Odeacetyl-vinorelbine on human endothelial cells in an in vitro simulation model of metronomic chemotherapy. Eur. J. Cancer 6, 138–139 (2008).

    Google Scholar 

  96. Mavroeidis, L. et al. Metronomic vinorelbine: anti-angiogenic activity in vitro in normoxic and severe hypoxic conditions, and severe hypoxia-induced resistance to its anti-proliferative effect with reversal by Akt inhibition. Int. J. Oncol. 47, 455–464 (2015).

    Google Scholar 

  97. Vacca, A. et al. Antiangiogenesis is produced by nontoxic doses of vinblastine. J. Clin. Oncol. 94, 4143–4155 (1999).

    Google Scholar 

  98. Rock, B. M., Hengel, S. M., Rock, D. A., Wienkers, L. C. & Kunze, K. L. Characterization of ritonavir-mediated inactivation of cytochrome P450 3A4. Mol. Pharmacol. 86, 665–674 (2014).

    Google Scholar 

  99. Wang, J., Lou, P., Lesniewski, R. & Henkin, J. Paclitaxel at ultra low concentrations inhibits angiogenesis without affecting cellular microtubule assembly. Anticancer Drugs 14, 13–19 (2003).

    Google Scholar 

  100. Gianni, L. et al. Nonlinear pharmacokinetics and metabolism of paclitaxel and its pharmacokinetic/pharmacodynamic relationships in humans. J. Clin. Oncol. 13, 180–190 (1995).

    Google Scholar 

  101. Chatelut, E., Delord, J. P. & Canal, P. Toxicity patterns of cytotoxic drugs. Invest. New Drugs 21, 141–148 (2003).

    Google Scholar 

  102. US National Library of Science. ClinicalTrials.gov, https://clinicaltrials.gov/ct2/show/NCT02555007?term=02555007&rank=1 (2015).

  103. Bennouna, J., Saunders, M. & Douillard, J. Y. The role of UFT in metastatic colorectal cancer. Oncology 76, 301–310 (2009).

    Google Scholar 

  104. Tanaka, F., Wada, H. & Fukushima, M. UFT and S-1 for treatment of primary lung cancer. Gen. Thorac. Cardiovasc. Surg. 58, 3–13 (2010).

    Google Scholar 

  105. Kato, H. et al. A randomized trial of adjuvant chemotherapy with uracil-tegafur for adenocarcinoma of the lung. N. Engl. J. Med. 350, 1713–1721 (2004).

    Google Scholar 

  106. Bocci, G. & Francia, G. in Metronomic Chemotherapy. Pharmacology and Clinical Applications (eds Bocci, G. & Francia, G.) 229–246 (Springer-Verlag, 2014).

    Google Scholar 

  107. Paci, A. et al. Review of therapeutic drug monitoring of anticancer drugs part 1 — cytotoxics. Eur. J. Cancer 50, 2010–2019 (2014).

    Google Scholar 

  108. Pesenti, C., Gusella, M., Sirchia, S. M. & Miozzo, M. Germline oncopharmacogenetics, a promising field in cancer therapy. Cell. Oncol. (Dordr.) 38, 65–89 (2015).

    Google Scholar 

  109. Hubbard, J. M. & Grothey, A. When less is more: maintenance therapy in colorectal cancer. Lancet 385, 1808–1810 (2015).

    Google Scholar 

  110. Colleoni, F. et al. Low-dose oral cyclophosphamide-methotrexate maintenance (CMM) for receptor-negative early breast cancer (BC) [abstract]. J. Clin. Oncol. 33 (Suppl.), 1002 (2015).

    Google Scholar 

  111. Malik, P. S., Raina, V. & Andre, N. Metronomics as maintenance treatment in oncology: time for chemo-switch. Front. Oncol. 4, 76 (2014).

    Google Scholar 

  112. Dellapasqua, S. et al. Metronomic cyclophosphamide and capecitabine combined with bevacizumab in advanced breast cancer. J. Clin. Oncol. 26, 4899–4905 (2008).

    Google Scholar 

  113. Farkouh, A. et al. Clinical pharmacokinetics of capecitabine and its metabolites in combination with the monoclonal antibody bevacizumab. Anticancer Res. 34, 3669–3673 (2014).

    Google Scholar 

  114. US National Library of Science. ClinicalTrials.gov, https://clinicaltrials.gov/ct2/show/NCT02271464?term=NCT02271464&rank=1 (2015).

  115. Lutsiak, M. E. et al. Inhibition of CD4+25+ T regulatory cell function implicated in enhanced immune response by low-dose cyclophosphamide. Blood 105, 2862–2868 (2005).

    Google Scholar 

  116. Wu, J. & Waxman, D. J. Metronomic cyclophosphamide eradicates large implanted GL261 gliomas by activating antitumor Cd8 T-cell responses and immune memory. Oncoimmunology 4, e1005521 (2015).

    Google Scholar 

  117. Doloff, J. C. & Waxman, D. J. Transcriptional profiling provides insights into metronomic cyclophosphamide-activated, innate immune-dependent regression of brain tumor xenografts. BMC Cancer 15, 375 (2015).

    Google Scholar 

  118. Wu, J. & Waxman, D. J. Metronomic cyclophosphamide schedule-dependence of innate immune cell recruitment and tumor regression in an implanted glioma model. Cancer Lett. 353, 272–280 (2014).

    Google Scholar 

  119. Doloff, J. C., Chen, C. S. & Waxman, D. J. Anti-tumor innate immunity activated by intermittent metronomic cyclophosphamide treatment of 9L brain tumor xenografts is preserved by anti-angiogenic drugs that spare VEGF receptor 2. Mol. Cancer 13, 158 (2014).

    Google Scholar 

  120. Doloff, J. C. & Waxman, D. J. VEGF receptor inhibitors block the ability of metronomically dosed cyclophosphamide to activate innate immunity-induced tumor regression. Cancer Res. 72, 1103–1115 (2012).

    Google Scholar 

  121. Jia, L. & Waxman, D. J. Thrombospondin-1 and pigment epithelium-derived factor enhance responsiveness of KM12 colon tumor to metronomic cyclophosphamide but have disparate effects on tumor metastasis. Cancer Lett. 330, 241–249 (2013).

    Google Scholar 

  122. Shaked, Y. et al. Optimal biologic dose of metronomic chemotherapy regimens is associated with maximum antiangiogenic activity. Blood 106, 3058–3061 (2005).

    Google Scholar 

  123. Mancuso, P. et al. Circulating endothelial-cell kinetics and viability predict survival in breast cancer patients receiving metronomic chemotherapy. Blood 108, 452–459 (2006).

    Google Scholar 

  124. Calleri, A. et al. Predictive potential of angiogenic growth factors and circulating endothelial cells in breast cancer patients receiving metronomic chemotherapy plus bevacizumab. Clin. Cancer Res. 15, 7652–7657 (2009).

    Google Scholar 

  125. Ge, Y. et al. Metronomic cyclophosphamide treatment in metastasized breast cancer patients: immunological effects and clinical outcome. Cancer Immunol. Immunother. 61, 353–362 (2012).

    Google Scholar 

  126. Ghiringhelli, F. 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. 56, 641–648 (2007).

    Google Scholar 

  127. Koumarianou, A. et al. The effect of metronomic versus standard chemotherapy on the regulatory to effector T-cell equilibrium in cancer patients. Exp. Hematol. Oncol. 3, 3 (2014).

    Google Scholar 

  128. Nars, M. S. & Kaneno, R. Immunomodulatory effects of low dose chemotherapy and perspectives of its combination with immunotherapy. Int. J. Cancer 132, 2471–2478 (2013).

    Google Scholar 

  129. Tagliamonte, M. et al. Novel metronomic chemotherapy and cancer vaccine combinatorial strategy for hepatocellular carcinoma in a mouse model. Cancer Immunol. Immunother. 64, 1305–1314 (2015).

    Google Scholar 

  130. Chen, C. A. et al. Metronomic chemotherapy enhances antitumor effects of cancer vaccine by depleting regulatory T lymphocytes and inhibiting tumor angiogenesis. Mol. Ther. 18, 1233–1243 (2010).

    Google Scholar 

  131. Hermans, I. F., Chong, T. W., Palmowski, M. J., Harris, A. L. & Cerundolo, V. Synergistic effect of metronomic dosing of cyclophosphamide combined with specific antitumor immunotherapy in a murine melanoma model. Cancer Res. 63, 8408–8413 (2003).

    Google Scholar 

  132. Bouche, G. et al. Lessons from the Fourth Metronomic and Anti-angiogenic Therapy Meeting, 24–25 June 2014, Milan. ecancer 8, 463 (2014).

    Google Scholar 

  133. Barbolosi, D., Ciccolini, J., Lacarelle, B., Barlesi, F. & Andre, N. Computational oncology — mathematical modelling of drug regimens for precision medicine. Nat. Rev. Clin. Oncol. 13, 242–254 (2015).

    Google Scholar 

  134. Benzekry, S. et al. Metronomic reloaded: theoretical models bringing chemotherapy into the era of precision medicine. Semin. Cancer Biol. 35, 53–61 (2015).

    Google Scholar 

  135. Faivre, C., Barbolosi, D., Pasquier, E. & Andre, N. A mathematical model for the administration of temozolomide: comparative analysis of conventional and metronomic chemotherapy regimens. Cancer Chemother. Pharmacol. 71, 1013–1019 (2013).

    Google Scholar 

  136. Panetta, J. C. et al. Population pharmacokinetics of temozolomide and metabolites in infants and children with primary central nervous system tumors. Cancer Chemother. Pharmacol. 52, 435–441 (2003).

    Google Scholar 

  137. Fioravanti, A. et al. Metronomic 5-fluorouracil, oxaliplatin and irinotecan in colorectal cancer. Eur. J. Pharmacol. 619, 8–14 (2009).

    Google Scholar 

  138. Chow, A. et al. Preclinical analysis of resistance and cross-resistance to low-dose metronomic chemotherapy. Invest. New Drugs 32, 47–59 (2014).

    Google Scholar 

  139. Bocci, G. et al. Cyclophosphamide-methotrexate 'metronomic' chemotherapy for the palliative treatment of metastatic breast cancer. A comparative pharmacoeconomic evaluation. Ann. Oncol. 16, 1243–1252 (2005).

    Google Scholar 

  140. Andre, N., Banavali, S., Snihur, Y. & Pasquier, E. Has the time come for metronomics in low-income and middle-income countries? Lancet Oncol. 14, e239–e248 (2013).

    Google Scholar 

  141. Craven, O., Hughes, C. A., Burton, A., Saunders, M. P. & Molassiotis, A. Is a nurse-led telephone intervention a viable alternative to nurse-led home care and standard care for patients receiving oral capecitabine? Results from a large prospective audit in patients with colorectal cancer. Eur. J. Cancer Care (Engl.) 22, 413–419 (2013).

    Google Scholar 

  142. Cowan, D. A. Drug testing. Essays Biochem. 44, 139–148 (2008).

    Google Scholar 

  143. Adaway, J. E. & Keevil, B. G. Therapeutic drug monitoring and LC-MS/MS. J. Chromatogr. B Analyt. Technol. Biomed. Life Sci. 883–884, 33–49 (2012).

    Google Scholar 

  144. Millership, J. S. Microassay of drugs and modern measurement techniques. Paediatr. Anaesth. 21, 197–205 (2011).

    Google Scholar 

  145. Anderson, L. W., Ludeman, S. M., Colvin, O. M., Grochow, L. B. & Strong, J. M. Quantitation of 4-hydroxycyclophosphamide/aldophosphamide in whole blood. J. Chromatogr. B Biomed. Appl. 667, 247–257 (1995).

    Google Scholar 

  146. Gurney, H. Dose calculation of anticancer drugs: a review of the current practice and introduction of an alternative. J. Clin. Oncol. 14, 2590–2611 (1996).

    Google Scholar 

  147. Gao, B., Klumpen, H. J. & Gurney, H. Dose calculation of anticancer drugs. Expert Opin. Drug Metab. Toxicol. 4, 1307–1319 (2008).

    Google Scholar 

  148. Gurney, H. Developing a new framework for dose calculation. J. Clin. Oncol. 24, 1489–1490 (2006).

    Google Scholar 

  149. Gurney, H. I don't underdose my patients...do I? Lancet Oncol. 6, 637–638 (2005).

    Google Scholar 

  150. Gurney, H. How to calculate the dose of chemotherapy. Br. J. Cancer 86, 1297–1302 (2002).

    Google Scholar 

  151. Bergh, J. et al. Tailored fluorouracil, epirubicin, and cyclophosphamide compared with marrow-supported high-dose chemotherapy as adjuvant treatment for high-risk breast cancer: a randomised trial. Scandinavian Breast Group 9401 study. Lancet 356, 1384–1391 (2000).

    Google Scholar 

  152. Zhang, A. Y. et al. Effect of toxicity-adjusted dose (TAD) of sunitinib on intra-patient variation of trough levels: a longitudinal study in metastatic renal cell cancer (mRCC) [abstract]. J. Clin. Oncol. 32 (Suppl.), 2597 (2014).

    Google Scholar 

  153. Morabito, A. et al. A multicenter, randomised, phase II trial comparing fixed dose versus toxicity-adjusted dose of cisplatin + etoposide in advanced SCLC patients. The STAD-1 trial [abstract]. J. Clin. Oncol. 33 (Suppl.), 7505 (2015).

    Google Scholar 

  154. Minasian, L. et al. Optimizing dosing of oncology drugs. Clin. Pharmacol. Ther. 96, 572–579 (2014).

    Google Scholar 

Download references

Acknowledgements

G.B. and R.S.K. would like to thank C. Cheng for excellent secretarial assistance, and the whole editorial team of Nature Reviews Clinical Oncology for the important editing process. G.B.'s research is currently supported by grants from the Italian Association of Cancer Research (AIRC, IG 17672) and the Istituto Toscano Tumori (ITT). R.S.K's research on metronomic chemotherapy is currently supported by grants from the Canadian Institute of Health Research, the Israel Cancer Research Fund, and the Canadian Breast Cancer Foundation.

Author information

Authors and Affiliations

  1. Divisione di Farmacologia, Dipartimento di Medicina Clinica e Sperimentale, Università di Pisa, Via Roma, 55, Pisa, I-56126, Italy

    Guido Bocci

  2. Sunnybrook Research Institute/Odette Cancer Centre, Biologic Sciences Platform, S-217, 2075 Bayview Avenue, Toronto, M4N 3M5, Ontario, Canada

    Robert S. Kerbel

  3. Department of Medical Biophysics, University of Toronto, S-217, 2075 Bayview Avenue, Toronto, M4N 3M5, Ontario, Canada

    Robert S. Kerbel

Authors
  1. Guido Bocci
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Robert S. Kerbel
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

G.B. and R.S.K. researched data for article, contributed to discussion of the content, wrote the manuscript, and reviewed/edited the article before submission.

Corresponding author

Correspondence to Guido Bocci.

Ethics declarations

Competing interests

R.S.K. is a Scientific Advisory Board member of Angiocrine Biosciences, Eli Lilly, and MolMed; is a consultant to Cerulean Pharma, Merrimack Pharmaceuticals, and Triphase Accelerator; and holds stock from Angiocrine Biosciences. Over the past 2 years, R.S.K. has received honoraria from Boehringer-Ingelheim, Eli Lilly, Oncology Education, NED Biosciences and Regeneron. G.B. declares no competing interests.

PowerPoint slides

Glossary

Clearance

(Cl). Is the volume of blood cleared of the drug over the time unit. In other words, the loss of drug across an organ of elimination (for example, the liver or kidney). The systemic clearance is the sum of the clearances by each of the eliminating organs26.

Volume of distribution

(Vd). Is the theoretical volume in which the drug is distributed to achieve a mean concentration equal to that measured in plasma26.

Steady state concentrations

(CSS). Also referred to as concentrations of the drug achieved at the steady state. Is the equilibrium reached such that the amount of drug eliminated during each dosing interval is equivalent to the amount of drug administered during that same interval. The time to achieve the steady state, regardless of the drug or dose, corresponds to five drug elimination half-lives26.

Area under the curve

(AUC). Refers to the area under the plasma drug-concentration time curve and represents the total drug exposure within the body over time26.

Mean residence time

(MRT). Is the average time the number of molecules introduced (injected or taken orally) reside in the body26.

Bioavailability

(F). Is the percentage of a drug dose that reaches the systemic circulation, whatever the route of administration. In other words, a term commonly applied to both the rate and extent of drug input into the systemic circulation26.

Elimination half-life

(elimination t1/2). Is the time taken for the plasma concentration, as well as the total amount of the drug in the body, to decline by one-half26.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Bocci, G., Kerbel, R. Pharmacokinetics of metronomic chemotherapy: a neglected but crucial aspect. Nat Rev Clin Oncol 13, 659–673 (2016). https://doi.org/10.1038/nrclinonc.2016.64

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrclinonc.2016.64

This article is cited by

Search

Advanced search

Quick links

Nature Briefing: Cancer

Sign up for the Nature Briefing: Cancer newsletter — what matters in cancer research, free to your inbox weekly.

Get what matters in cancer research, free to your inbox weekly. Sign up for Nature Briefing: Cancer