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Sir, An emerging strategy for refractory adult solid malignancies is to manage cancer as a chronic but stable disease state, where the total tumour burden is kept at the lowest possible level. One of the most likely strategies to achieve this would seem to be the targeting of neoangiogenesis. Recently, a new paradigm has emerged based on the targeting of tumour vasculature rather than tumour parenchyma with low-dose but long-term, continuous, chemotherapy using classical cytotoxic agents. The term ‘metronomic dosing’ was first used by Hanahan et al (2000). For further details on metronomic chemotherapy (MC), see the recent, extensive, review by Kerbel and Kamen (2004). While intuitively there should be no disagreement with what constitutes a metronomic schedule, our major concern relates to the dosing levels. The starting point for conventional dosing is empirical, for example, th of the LD50 of a preclinical, animal-based, toxicity study. From then on, the dose for human use is based on the Phase I study. The starting dose for MC is equally empirical with the major proponents commencing clinical or preclinical trials at 10–33% of conventional doses; no further effort to define this dose is made! The historical variability of clinical response to chemotherapy and the concern about intertrial reproducibility of results will be compounded by the lack of dose uniformity. It is hard enough correlating responses among different conventional dosing schemes, for example, taxanes in ovarian cancer; it will be even more difficult if the dosing scheme has little rhyme or reason justifying its selection. Given the large number of drugs with potential antiangiogenic properties when given metronomically, the further development of combination treatments will become even more contentious. We think that a strategy to deal with this problem is necessary given that extreme empiricism could breed scepticism which in turn would significantly delay progress in this field. Fortunately, we would suggest that there are already enough data to allow for a principled approach to metronomic dosing. Reflecting conventional design, the metronomic Phase I trial methodology that we propose is based on the following principles:  In conclusion, scheduling of MC is arguably unequivocal; dosing, however, is poorly defined. We argue that even in the subclinical dose range, there is a dose–response effect on the endothelium, and that using an arbitrary 10–33% of the conventional dose is not always appropriate. Given that bone marrow suppression is a proangiogenic stimulus, we propose that the MetD should be the maximum dose that can be delivered in a metronomic schedule without detectable bone marrow perturbation. Such a rational strategy would allow MC dosing to be derived via a principled approach.

Can a rational design for metronomic chemotherapy dosing be devised?