Optimization of antitumor radiotherapy fractionation via mathematical modeling with account of 4 R's of radiobiology

A spatially-distributed continuous mathematical model of solid tumor growth and treatment by fractionated radiotherapy is presented. The model explicitly accounts for the factors, widely referred to as 4 R's of radiobiology, which influence the efficacy of radiotherapy fractionation protocols: tumor cell repopulation, their redistribution in cell cycle, reoxygenation and repair of sublethal damage of both tumor and normal tissues. With the use of special algorithm the fractionation protocols that provide increased tumor control probability, compared to standard clinical protocol, are found for various physiologically-based values of model parameters under the constraints of fixed overall normal tissue damage and maximum admissible fractional dose. In particular, it is shown that significant gain in treatment efficacy can be achieved for tumors of low malignancy by the use of protracted hyperfractionated protocols. The optimized non-uniform protocols are characterized by gradual escalation of fractional doses in their last parts, which start after the levels of oxygen and nutrients significantly elevate throughout the tumor and accelerated tumor proliferation manifests itself, which is a well-known experimental phenomenon. © 2022 Elsevier Ltd