Low-dose metronomic chemotherapy: from past experience to new paradigms in the treatment of cancer

► Preclinical and clinical studies utilizing LDM chemotherapy regimens are reviewed. ► Several mechanisms for antitumor activity of LDM chemotherapy are proposed. ► The weaknesses and strengthens of LDM Phase II clinical studies are raised. ► The current Phase III clinical studies of LDM chemotherapy are listed. Low-dose metronomic (LDM) chemotherapy represents an emerging concept in the treatment of cancer. Directed against tumor cells and other types of cells, such as endothelial and immune cells, this treatment regimen alters the tumor microenvironment and suppresses innate features which support tumor growth. Ongoing Phase III clinical studies explore various applications of LDM chemotherapy, mostly combined with other anticancer agents, to act as complementary treatments to conventional maximum tolerated dose (MTD) chemotherapy. In this article we summarize preclinical and clinical experience with LDM chemotherapy, emphasizing the potential contribution of this new treatment modality to future paradigms in the systemic treatment of patients with cancer.