Analysis of the response of prostate cancer to ultra-hypofractionated high-dose-rate brachytherapy: the role of hypoxia and reoxygenation

Clinical studies of prostate cancer treated with radically hypofractionated highdose-rate brachytherapy (HDR-BT) have reported a significant loss of tumor control that contradicts the standard linear-quadratic (LQ) and low /{beta} ratio paradigm for prostate cancer. In a previous study by our group, we showed that the linear-quadraticlinear (LQL) model could describe this response, but the underlying biological drivers remained unclear. In this follow-up study, we further investigate whether the interplay between hypoxia and reoxygenation kinetics can explain the poor response to extreme hypofractionation. We analyzed a large dataset of 3,239 patients (44 schedules) using a three-compartment reoxygenation model (the MSK model) that simulates the dynamics of oxic, intermediate, and hypoxic cell populations. Results show that the MSK model achieves an excellent fit to the clinical data (p > 0.99) while maintaining a biologically plausible low /{beta} ratio ([≤] 8 Gy). The reoxygenation model provided a performance comparable to the LQL model for low-risk prostate cancer, being slightly inferior to the LQL model to describe the response of intermediate-risk. This suggests that the observed reduction in tumor control is not necessarily a failure of the LQ formalism, but rather a consequence of oxygen dynamics associated with ultra-fractionated schedules, and provides a mechanistic basis for designing clinical trials exploring the response of prostate cancer to ultra-hypofractionation and the role of reoxygenation.