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Metronomic dosing of chemotherapy - defined as frequent administration at lower doses - has been shown to be more efficacious than maximum tolerated dose treatment in preclinical studies, and is currently being tested in the clinic. Although multiple mechanisms of benefit from metronomic chemotherapy have been proposed, how these mechanisms are related to one another and which one is dominant for a given tumor-drug combination is not known. To this end, we have developed a mathematical model that incorporates various proposed mechanisms, and report here that improved function of tumor vessels is a key determinant of benefit from metronomic chemotherapy. In our analysis, we used multiple dosage schedules and incorporated interactions among cancer cells, stem-like cancer cells, immune cells, and the tumor vasculature. We found that metronomic chemotherapy induces functional normalization of tumor blood vessels, resulting in improved tumor perfusion. Improved perfusion alleviates hypoxia, which reprograms the immunosuppressive tumor microenvironment toward immunostimulation and improves drug delivery and therapeutic outcomes. Indeed, in our model, improved vessel function enhanced the delivery of oxygen and drugs, increased the number of effector immune cells, and decreased the number of regulatory T cells, which in turn killed a larger number of cancer cells, including cancer stem-like cells. Vessel function was further improved owing to decompression of intratumoral vessels as a result of increased killing of cancer cells, setting up a positive feedback loop. Our model enables evaluation of the relative importance of these mechanisms, and suggests guidelines for the optimal use of metronomic therapy. © 2017, National Academy of Sciences. All rights reserved. 114 1994 1999 1994-1999

Metastatic breast cancer (MBC) is quite sensitive to chemotherapy, with patients often benefiting from multiple lines of treatment. Continuation of chemotherapy until disease progression, if tolerable, prolongs disease control and improves patient outcomes. Compared to combination regimens, sequential single-agent chemotherapy provides similar efficacy and improved tolerability and may represent the preferred option for most patients. Numerous agents are available, but there are few data to advise optimal sequencing. Oral chemotherapeutic agents, including capecitabine and vinorelbine, have demonstrated significant efficacy in patients with MBC. These drugs prolong disease control with good tolerability, especially when used as single agents. In addition, oral chemotherapy reduces the time and cost associated with treatment and usually is preferred by patients if compared with intravenous delivery. Metronomic administration of oral chemotherapy also represents a promising therapeutic approach for select patients with MBC, inhibiting tumor progression through multiple mechanisms of action. Ongoing clinical trials are exploring metronomic regimens as a strategy to prolong disease control with favorable tolerability. Key data on the role for oral chemotherapy in the therapeutic landscape for MBC will be reviewed and accompanied by expert perspectives on important considerations for the integration of oral chemotherapeutic agents into the treatment of patients with MBC.