Unveiling the impact of modified cell death models on hypofractionated radiation therapy efficacy.

Objective: Nowadays the linear-quadratic model (LQ) is the most used model to estimate the biological effective dose (BED) and the equivalent dose in 2 Gy fractions (EQD2) for different fractionation regimens. Nevertheless, it is debated of applicability to use LQ model for hypofractionation. The objective of this study is to evaluate the LQ model in comparison with other radiobiological models concerning the adequacy of biological equivalent dose in 2 Gy fractions assessment across various hypofractionation regimens. Methods: The study was conducted for two cases: the prostate gland in the pelvic region and squamous cell carcinoma (SCC) in the head and neck region. Five radiobiological models including the LQ model, modified linear-quadratic (MLQ), linear-quadratic-linear (LQL), universal survival curve (USC), and Pade linear-quadratic (PLQ) models were compared for tumor control probability (TCP) and EQD₂ predictions. Published clinical outcomes (including local control, disease-free survival, and overall survival rates) were analyzed to identify clinically equivalent fractionation regimens. The radiobiological models were then evaluated by comparing calculated EQD2 and TCP values with clinical data for these equivalent regimens. Results: Modified radiobiological models showed that the LQ model overestimates the dose in hypofractionation. The dose limit at which the LQ model is applicable depends on the localization and type of tumor: for the prostate gland the value was 4.3 Gy, for the head and neck region 8.5 Gy. Conclusions: The applicability of the LQ model in hypofractionation depends on the tumor \alpha/\beta value: the LQ model more sensitive to locations with low \alpha/\beta values and, conversely, less sensitive to locations with high \alpha/\beta values. Among the alternatives, the MLQ model is recognized as the most practical alternative, combining a small number of parameters with resistance to variations. While modified models show efficacy, further clinical validation is needed to balance tumor control with normal tissue toxicity risks.