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Metronomic chemotherapy: new rationale for new directions

Abstract

Tumor angiogenesis is recognized as a major therapeutic target in the fight against cancer. The key involvement of angiogenesis in tumor growth and metastasis has started to redefine chemotherapy and new protocols have emerged. Metronomic chemotherapy, which is intended to prevent tumor angiogenesis, is based on more frequent and low-dose drug administrations compared with conventional chemotherapy. The potential of metronomic chemotherapy was revealed in animal models a decade ago and the efficacy of this approach has been confirmed in the clinic. In the past 5 years, multiple clinical trials have investigated the safety and efficacy of metronomic chemotherapy in a variety of human cancers. While the results have been variable, clinical studies have shown that these new treatment protocols represent an interesting alternative for either primary systemic therapy or maintenance therapy. We review the latest clinical trials of metronomic chemotherapy in adult and pediatric cancer patients. Accumulating evidence suggests that the efficacy of such treatment may not only rely on anti-angiogenic activity. Potential new mechanisms of action, such as restoration of anticancer immune response and induction of tumor dormancy are discussed. Finally, we highlight the research efforts that need to be made to facilitate the optimal development of metronomic chemotherapy.

Key Points

  • Metronomic chemotherapy is based on the chronic administration of chemotherapeutic agents at relatively low, minimally toxic doses, and with no prolonged drug-free breaks

  • Metronomic chemotherapy was originally developed to overcome drug resistance by shifting the therapeutic target from tumor cells to the tumor vasculature

  • In the past decade, several pilot and phase II clinical studies have established the potential efficacy and low toxicity of metronomic chemotherapy in adult and childhood cancer patients

  • Metronomic chemotherapy combined with conventional chemotherapy, radiotherapy and/or targeted therapy is an emerging anti-cancer strategy

  • Recent findings suggest that metronomic chemotherapy may be a multi-targeted cancer therapy rather than a simple anti-angiogenic therapy

  • In addition to inhibiting tumor angiogenesis, metronomic chemotherapy might also restore anticancer immune response and induce tumor dormancy

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Figure 1: Schematic model of a tumor and its microenvironment.
Figure 2: Metronomic chemotherapy as a multi-targeted therapy.

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Acknowledgements

E. Pasquier and M. Kavallaris are supported by the Children's Cancer Institute Australia for Medical Research, which is affiliated with the University of New South Wales and Sydney Children's Hospital. E. Pasquier is supported by an “Early Career Development” Fellowship from the Cancer Institute New South Wales and a grant from the “Young Researchers Fund” from the Balnaves Foundation. M. Kavallaris is supported by an Australian Government, National Health and Medical Research Council (NHMRC) Senior Research Fellowship, NHMRC Project Grants and Cancer Council New South Wales Program Grant.

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Pasquier, E., Kavallaris, M. & André, N. Metronomic chemotherapy: new rationale for new directions. Nat Rev Clin Oncol 7, 455–465 (2010). https://doi.org/10.1038/nrclinonc.2010.82

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