Administration of temozolomide : Comparison of conventional and metronomic chemotherapy regimens

Purpose. We compare the Maximum Tolerated Dose (MTD) and Metronomic Chemotherapy (MC) protocols for temozolomide administration. We develop an innovative methodology for characterizing optimal chemotherapy regimens. Methods. We use a PK/PD model based on Faivre et al. (2013) for the pharmacokinetics of temozolomide, as well as the pharmacodynamics of its efficacy. For toxicity, which is measured by the nadir of the normalized absolute neutrophil count, we formalize the myelosuppression effect of temozolomide with the physiological model of Panetta et al. (2003b). We introduce a multi-criteria tool for comparing protocols along their efficacy and toxicity dimensions. Results. We show that the toxicity of the MC regimen proposed by Faivre et al. (2013) can greatly be reduced without affecting its efficacy, while the standard MTD protocol efficacy cannot be improved without impairing its toxicity. We also show that for any acceptable toxicity level, the optimal protocol remains closely related to standard MTD. Conclusions. Overall, our new method enables a rich comparison between protocols along multiple dimensions. We can rank protocols for temozolomide administration. It is a first step toward building optimal individual protocols.