Optimizing drug regimens in cancer chemotherapy by an efficacy-toxicity mathematical model.

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 can minimize the tumor burden while limiting toxicity at the level of the white blood cells. The main result is that the optimal drug administration is an initial high-dose chemotherapy up to saturation of constraints associated with normal cell toxicity and a maintenance continuous infusion at a moderate rate. Data related to etoposide investigations were used in a feasibility study. Simulations with the optimized protocol showed better performances than usual clinical protocols. Model-based optimal drug doses provide for greater cytoreduction, while limiting the risk of unacceptable toxicity. Copyright 2000 Academic Press.