UCLA

Purpose Beam orientation and biological dose optimization are interdependent features of Intensity-Modulated Proton Therapy (IMPT). Current automated beam orientation optimization (BOO) methods are robust and able to provide beam convergence but have not accounted for accurate biological modeling that narrows the therapeutic window. Biological models such as relative biological effectiveness (RBE) and oxygen enhancement ratio (OER) and machine parameters such as dose-averaged dose rate (DADR) are highly complex and lead to computationally challenging frameworks that may be solved by novel optimization methods. Methods The robust BOO framework for IMPT was formulated with physical dose fidelity to provide accurate dose to the tumor and limit dose to organs at risk (OARs), a heterogeneity-weighted L2,1/2-norm group sparsity term to reduce the number of active beams to 2-4, and a sensitivity regularization term. The dose fidelity term was updated to consider variable RBE values, lower oxygenation status in tumor regions, and the normal tissue sparing effects caused by high dose rate. These biologically-informed BOO frameworks were solved with RBE and dose rate linearization along with splitting schemes. The plans were generally tested on challenging head-and-neck (H&N) cases and compared against previous plans in terms of dosimetry and robustness. Results Compared to IMPT BOO plans solved with constant RBE=1.1, McNamara RBE-based dose was able to improve OAR [Dmean, Dmax, worst Dmean, worst Dmax] by an average of [36.1%, 26.4%, 25.0%, 19.2%] with modest CTV coverage and robustness improvement. Additionally, hypoxia-based RBE dose fidelity was able to increase tumor [HI, Dmax, worst HI, worst Dmax] by [31.3%, 48.6%, 12.5%, 7.3%] with only [8.0%, 13.1%] increase in OAR [Dmean, Dmax], increasing the therapeutic index. Next, compared to spread-out Bragg peak IMPT BOO plans, dose rate-optimized plans with Bragg peak and shoot-through beams combined were able to increase volume of ROIs receiving >40 Gy/s by approximately 41.1%, while improving CTV homogeneity by 5.6% and improving OAR dose in several structures. Conclusions Novel optimization methods were developed for biologically-guided IMPT. The objective function integrates RBE-weighted dose, hypoxia-informed dose, and dose rate optimization into a unified framework with BOO as the baseline objective. Compared with the physical dose BOO or manual selection, our method generates plans with superior tumor and normal tissue dosimetry and robustness.