Multi-input Optimal Control Problems for Combined Tumor Anti-angiogenic and Radiotherapy Treatments

A cell-population-based model for tumor growth under anti-angiogenic treatment, with the tumor volume and its variable carrying capacity as variables, is combined with the linear-quadratic model for damage done by radiation ionization. The resulting multi-input system is analyzed as an optimal control problem with the objective of minimizing the tumor volume subject to isoperimetric constraints that limit the overall amounts of anti-angiogenic agents, respectively, the damage done to healthy tissue by radiotherapy. For various model formulations, explicit expressions for singular controls are derived for both the dosage of the anti-angiogenic therapeutic agent and the radiation dose schedule. Their role in the structure of optimal protocols is discussed.