Microvascular morphology affects radiotherapy outcomes: a computational study

Radiotherapy (RT) is the most common cancer treatment, and hypoxia is one of the main causes of resistance to RT. We investigate how microvascular morphology affects radiation therapy results, exploring the role of the microvasculature. Several computational models have been developed to analyze microvascular oxygen delivery. However, few of these models have been applied to study RT and the microenvironment. We generated 27 different networks, covering 9 scenarios defined by the vascular density and the network regularity. Leveraging these networks, we solved a computational mixed-dimensional model for fluid flow, red blood cell distribution, and oxygen delivery in the microenvironment. Then, we simulated a fractionated RT treatment (30 × 2 Gy RBE ) using the Linear Quadratic model, accounting for oxygen-related (OER) modifications by two different models from the literature. First, the analysis of the hypoxic volume fraction and its distribution reveals a correlation between hypoxia and treatment outcome. The study also shows how vascular density and regularity are essential in determining the success of treatment. Indeed, in our computational dataset, an insufficient vascular density or regularity is sufficient to decrease the success probability for photon-based RT. We also applied our quantitative analysis to hadron therapy and different oxygenation states to assess the consistency of the microvasculature’s role in various treatments and conditions. While proton RT provides a Tumor Control Probability similar to photons, carbon ions mark a clear difference, especially with bad vascular scenarios, i.e., where strong hypoxia is present. These data also suggest a scenario where carbon-based hadron therapy can help overcome hypoxia-mediated resistance to RT. As a final remark, we discuss the importance of these data with reference to clinical data and the possible identification of subvoxel hypoxia, given the size similarity between the computational domain and the imaging voxel. Author summary The study focuses on investigating the role of microvascular density and morphology in radiation therapy, with particular reference to its role in shaping hypoxia-mediated resistance to treatment. While several computational models have been developed to analyze microvascular oxygen delivery, few have been applied to study RT and the microenvironment. We generated 27 different vascular networks to fill this gap, considering three oxygenation states and three radiation sources (photons, protons, and carbon ions). These cases were analyzed using a complex computational model to describe the state of oxygenation and radiation treatment. The results highlight the importance of vascular density and regularity in determining the success of treatment by shaping hypoxia in the microenvironment. Data suggest that carbon-based hadron therapy can help overcome hypoxia-mediated radiation resistance. As a final remark, these data are also helpful in interpreting possible subvoxel hypoxia with reference to clinical data from different imaging techniques. ### Competing Interest Statement The authors have declared no competing interest.