A mathematical model for the administration of temozolomide: comparative analysis of conventional and metronomic chemotherapy regimens

We propose a mathematical model that takes into account a classical maximum tolerated dose (MTD) chemotherapy regimen (whose primary targets are the tumor cells) as well as a metronomic chemotherapy regimen (whose primary targets are the tumor endothelial cells) for the administration of temozolomide (Temodal^®) in order to compare the effectiveness of these two types of protocols. The model is built from 4 natural hypotheses: (H1) without treatment the tumor growth follows a Gompertz model, (H2) endothelial cells are more sensitive to temozolomide than cancer cells, (H3) the anti-angiogenic effect blocks tumor growth, and (H4) endothelial cells are more genetically stable than cancer cells and thus less likely to develop resistance to temozolomide. Then, we compared a conventional MTD regimen of 200 mg/m² temozolomide J1–J5 every 28 days with a daily metronomic regimen of 85 mg/m²/day for cycles of 42 days. Our mathematical model shows that the metronomic regimen induces tumor regression through anti-angiogenic effects while the MTD regimen fails to do so, due to the emergence of temozolomide resistance in cancer cells. Overall, our model is consistent with clinical observations and provides an interesting tool toward the personalization of anticancer treatments, through optimization of dose and schedule of chemotherapy based on individual patient characteristics.