The photon isoeffective dose model for proton therapy

Objective. Proton therapy (PT) doses are commonly prescribed assuming a constant relative biological effectiveness (RBE) of 1.1, despite extensive evidence that RBE varies with radiation quality, dose, and tissue type. Here, we introduce the photon isoeffective dose (PHID) model, a cell line-specific formalism for computing photon isoeffective (IsoE) doses in PT. The model is based on the linear-quadratic framework and accounts for mixed charged-particle fields, linear energy transfer (LET)-dependent radiobiological parameters, sublethal damage repair, and synergistic effects among field components. Approach. PHID was developed for head-and-neck squamous cell carcinoma (HNSCC), human skin fibroblasts, and Chinese hamster fibroblasts (V79 cell lines, using ion-specific, LET-dependent alpha and beta parameters derived from the BIANCA biophysical model. PHID was evaluated for monoenergetic and modulated proton beams by analyzing the impact of secondary particles, cell line, reference radiation, and LET on dose calculations. Results were compared with those obtained using fixed-RBE approach and with several phenomenological RBE models. A tumor control probability (TCP) model explored clinical implications in a proof-of-concept scenario. Main results. PHID predicts depth- and dose-dependent IsoE doses that can substantially deviate from RBE-weighted doses, particularly in high-LET regions near the distal edge of the Bragg peak. The model reproduces the increase of RBE with increasing LET and decreasing dose per fraction, and reveals a strong dependence on cell line and reference radiation. Alpha particles were the dominant high-LET contributors beyond protons. Compared with phenomenological RBE models, PHID yields intermediate RBE ranges consistent with its cell-specific construction and provides a mechanistic interpretation of observed trends. TCP calculations showed measurable differences relative to the fixed-RBE approach. Significance. PHID provides a biophysically grounded alternative to fixed-RBE prescriptions in PT. This framework can be extended to other particle-based radiotherapy modalities, including carbon-ion and alpha-particle therapy, where high-LET components play a central role.