Abstract

In cancer chemotherapy, it is important to design treatment strategies that ensure a desired rate of tumor cell kill without unacceptable toxicity. To optimize treatment, we used a mathematical model describing the pharmacokinetics of anticancer drugs, antitumor efficacy, and drug toxicity. This model was associated with constraints on the allowed plasma concentrations, drug exposure, and leukopenia. Given a schedule of drug administrations, the mathematical model optimized the drug doses that could minimize the tumor burden while limiting toxicity on the white blood cells. Simulation suggests that the optimal drug administration is an initial high dose chemotherapy up to saturation of constraints associated with normal cell toxicity followed by a maintenance continuous infusion at a moderate rate. Data related to etoposide investigations were next used in a feasibility study. Simulations made with the usual clinical protocols and optimized protocols revealed that model-based optimal drug doses lead to greater cytoreduction. Also, examples showed how to use this new approach for the dose ranging problem and they evaluated the sensitivity of the optimized protocols with respect to the clinical constraints.