Metronomic antiangiogenic chemotherapy: Questions and answers

Metronomic(antiangiogenic) chemo-therapy refers to the close, regular administration of low doses (non-toxic) of conventional chemotherapy drugs, in the absence of any prolonged drug-free break periods, over long periods of time, even several years. Unlike dose-dense and intensive chemotherapy it is minimally toxic and thus does not usually require supportive care drugs. The preclinical antitumor effects of certain metronomic chemotherapy regimens can be surprisingly good, especially when used in combination with concurrent administration of a targeted biologic antiangiogenic agent. It is thought that the antitumor basis of metronomic chemotherapy is mainly via antiangiogenic mechanisms as a result of the local targeting of dividing endothelial cells in the growing tumor neovasculature, and also the systemic targeting of bone marrow-derived circulating endothelial progenitor cells (CEPs). Maximum tolerated dose (MTD) chemotherapy may, in some circumstances, also target CEPs but a hemopoiesis-like proangiogenic acute CEP rebound can occur immediately afterwards which is hypothesized to nullify this potential antiangiogenic effect. Shortening or eliminating the drug-free break periods compromises this robust repair process. This CEP rebound phenomenon may also help explain the ability of certain antiangiogenic drugs such as bevacizumab (Avastin®) to enhance the efficacy of some conventional chemotherapy regimens, i.e., by preventing the systemic CEP rebound. Several phase II metronomic chemotherapy clinical trials, some randomized, have been completed, most using daily low-dose (e.g. 50 mg) oral cyclophosphamide, in conjunction with a targeted biologic agent such as bevacizumab or letrozole for treatment of either advanced or early stage breast cancer, or celecoxib for advanced non-Hodgkin' s lymphoma, with encouraging results, despite the obvious drawback of the empiricism associated with metronomic dosing. However, advances are being made, both preclinically and clinically, in the discovery of surrogate markers to monitor biologic activity of metronomic chemotherapy and help determine the optimal biologic dose. These markers include circulating apoptotic endothelial cells and CEPs.