Combined chemo-radiation treatments are often used to enhance tumor cell kill, with respect to their separate treatments. Currently, chemo-radiation therapy treatments are prescribed as a separately optimized radiotherapy treatment with the addition of a generic chemotherapy regimen. The dosing of the combined therapies is mostly based on clinical experience. Hence there is a clear need for the optimization of dosing for combined chemo-radiation therapy treatments. The goal of this thesis is to propose novel approaches to optimize cancer treatment efficiency when combining chemotherapy and radiotherapy by using control-theoretical methods as well as radiation therapy models. A positive switched system is a dynamic system consisting of a set of Metzler state-space matrices and a specific switching law, which determines when and how to switch between the subsystems. Positive switched systems seem particularly appropriate to model cancer evolution under different treatments, and therefore to determine optimal treatment scheduling. They are used to model the effect of combined chemo-radiation treatments, thus enabling the systematic design of optimal therapy planning. The proposed model is especially appropriate for heterogeneous tumors, since it describes the impact of therapies on different tumor cell lines, and includes the possibility of mutations. Metastases are also included since the model considers separate tumor compartments, and the possibility of migrations between compartments are modeled as well. Undesired consequences due to toxicities are incorporated, and an upper bound can be set to limit the possible damage. A clinical dataset was obtained from the Erasmus MC, which was used to validate chemotherapy-alone model outcomes. Combined chemo-radiation treatments were also developed for a set of initial tumors. The model shows promising applications for cancer treatment design. The use of positive switched systems for combined chemo-radiation treatments is a new approach to obtain optimal drug usage and radiation fractionation schemes for each body compartment. The achieved findings could have a significant impact on effective treatment planning by choosing optimal drug durations or by using radiotherapy in combination with chemotherapy, for instance, to target certain chemotherapy-resistant areas, to achieve tumor control with minimal side effects.