Cyclophosphamide-based metronomic chemotherapy: after 10 years of experience, where do we stand and where are we going?

Metronomic (low-dose, long-term and frequently administered) chemotherapy has attracted renewed interest for the past few years, in particular because of possible positive association with molecular targeted agents. Cyclophosphamide is the most widely-explored agent in such an approach. The main possible mechanisms of actions identified in preclinical models, whatever the histology of tumor, are the stimulation of the immune system and anti-angiogenic action. Retrospective studies and numerous phase II clinical trials have been published in diverse clinical settings, mainly in patients with highly pretreated advanced tumors. The tolerance seems to be acceptable; some objective responses have been reported. Nevertheless, the regimens were very heterogeneous, and most of these studies are not randomized. This makes it difficult to objectively evaluate the additional value of the metronomic administration of cyclophosphamide. Further clinical trials integrating translational research are necessary to better evaluate the clinical benefit of this promising approach.