Radiobiological Meta-Analysis of the Response of Prostate Cancer to High-Dose-Rate Brachytherapy: Investigation of the Reduction in Control for Extreme Hypofractionation

Abstract

Background/Objectives: Clinical studies have shown a marked reduction in tumor control in prostate cancer treated with radically hypofractionated high-dose-rate brachytherapy (HDR-BT). The purpose of this study was to analyze the dose–response of prostate cancer treated with HDR-BT, specifically aiming at investigating the potential failure of the linear–quadratic (LQ) model to describe the response at large doses-per-fraction. Methods: We collated a dataset of dose–response to HDR-BT (3239 patients). The analysis was conducted separately for low and intermediate risk, resulting in 21 schedules (1633 patients) and 23 schedules (1606 patients), respectively. Data were fitted to tumor control probability models based on the LQ model, the linear–quadratic–linear (LQL), and a modification of the LQ model to include the effect of reoxygenation during treatment. Results: The LQ cannot fit the data unless the (Formula presented.) is allowed to be high (∼[20, >100] Gy, 95% confidence interval). If the (Formula presented.) is constrained to be low (≤8 Gy), the LQ model cannot reproduce the clinical results, and the LQL model, which includes a moderation of radiation damage with increasing dose, significantly improves the fitting. On the other hand, the reoxygenation model does not match the results obtained with the LQL. The clinically observed reduction in tumor control in prostate cancer treated with radical HDR-BT is better described by the LQL model. Using the best-fitting parameters, the BED for a 20 Gy × 1 treatment (128 (Formula presented.)) is far less than that of a conventional 2 Gy × 37 fractionation (196 (Formula presented.)). Conclusions: Our analysis showed that the substantial loss of tumor control observed in extremely hypofractionated HDR-BT trials can only be explained by the LQ model if the (Formula presented.) is very large (≥100 Gy), in clear disagreement with the limits set in the analysis of external radiotherapy data. It seems more reasonable that there is a moderation of the LQ-predicted effect with increasing dose per fraction. These results may assist in the design of radical HDR-BT treatments.