Metronomic chemotherapy from rationale to clinical studies: a dream or reality?

Metronomic chemotherapy (MC) refers to the close administration of a chemotherapeutic drug for a long time with no extended drug-free breaks. It was developed to overcome drug resistance, partly by shifting the therapeutic target from tumor cells to the tumor vasculature, with less toxicity. Because of this peculiar way of administration, MC can be viewed as a form of long-term 'maintenance' treatment, and can be integrated with standard and conventional chemotherapy in a "chemo-switching" strategy. Additional mechanisms are involved in its antitumor activity, such as activation of immunity, induction of tumor dormancy, chemotherapy-driven dependency of cancer cells, and the '4D effect'. In this paper we report the most important studies that have analyzed these processes. In fact, a number of preclinical and clinical studies in solid tumors as well as in multiple myeloma, have been reported regarding several chemotherapy drugs which have been proposed with a metronomic schedule: vinorelbine, cyclophosphamide, capecitabine, methotrexate, bevacizumab, etoposide, gemcitabine, sorafenib, everolimus and temozolomide. The results of these studies have been sometimes conflicting, highlighting the need to develop reliable tools for patient selection and stratification. However, a more precise evaluation of MC strategies with the ongoing randomized phase II/III clinical is fundamental, because of the strict correlation of this approach with translational research and target therapy. Moreover, because of the low toxicity of MC, these studies will also help to better evaluate the clinical benefit of this treatment, with a special focus on elderly and low performance status patients.