  While chemoresistance in primary tumors is well-studied, much less is known
about the influence of systemic chemotherapy on the development of drug
resistance at metastatic sites. In this work, we use a hybrid spatial model of
tumor response to a DNA damaging drug to study how the development of
chemoresistance in micrometastases depends on the drug dosing schedule. We
separately consider cell populations that harbor pre-existing resistance to the
drug, and those that acquire resistance during the course of treatment. For
each of these independent scenarios, we consider one hypothetical cell line
that is responsive to metronomic chemotherapy, and another that with high
probability cannot be eradicated by a metronomic protocol. Motivated by
experimental work on ovarian cancer xenografts, we consider all possible
combinations of a one week treatment protocol, repeated for three weeks, and
constrained by the total weekly drug dose. Simulations reveal a small number of
fractionated-dose protocols that are at least as effective as metronomic
therapy in eradicating micrometastases with acquired resistance (weak or
strong), while also being at least as effective on those that harbor weakly
pre-existing resistant cells. Given the responsiveness of very different
theoretical cell lines to these few fractionated-dose protocols, these may
represent more effective ways to schedule chemotherapy with the goal of
limiting metastatic tumor progression.
