A mechanism-guided approach for quantifying the biological effects of tumor hypoxia in particle therapy.

PURPOSE: To quantify how acute tumor hypoxia modifies the biological effectiveness of proton, helium, and carbon ions and to derive mechanistic hypoxia-compensation factors for representative spread-out Bragg peaks (SOBPs). METHODS: The Monte Carlo Damage Simulation (MCDS) was used to generate DNA double-strand break (DSB) yields as functions of radiation quality q = (Zeff/β)2 and oxygen level pO2 (0.0001-100%). MCDS-derived DSB yields were integrated into Geant4 Monte Carlo simulations, and Repair-Misrepair-Fixation (RMF) model calculations were used to derive linear-quadratic radiosensitivity parameters. We distinguish hypoxic RBE (RBEH), which compares the biological effects of particles at reduced pO2 with photons under normoxic conditions (137Cs γ-rays at pO2 = 100%), from isoeffective RBE (RBEiso), which compares particles and photons at the same pO2. SOBP (10-15 cm depth) optimizations used either a uniform 2 Gy absorbed dose or a uniform RBEH-weighted dose (DRBE = 3.8 Gy) corresponding to 10% clonogenic survival in H460 cells; hypoxia reduction factors (HRFs) quantified the absorbed-dose compensation required to preserve this modeled endpoint. RESULTS: At pO2 = 21%, at DRBE = 3.8 Gy, RBEH was 1.04-1.16 for protons, 1.23-1.67 for helium ions, and 1.84-3.55 for carbon ions. At pO2 = 0.001%, RBEH decreased to 0.39-0.41, 0.50-0.70, and 0.87-2.28, respectively. Because RBEH uses the fixed photon reference at pO2 = 100%, values below unity quantify the combined oxygen and radiation-quality penalty and do not indicate that particles are less effective than photons irradiating the same hypoxic tissue. At pO2 = 0.001%, RBEiso remained >1 (protons 1.13-1.19; helium 1.46-2.03; carbon 2.54-6.63). The corresponding HRFs were 2.73-2.89, 2.42-2.53, and 1.57-2.07. CONCLUSION: Within the H460 single-fraction clonogenic-survival framework examined here, high-LET carbon ions are less sensitive to severe hypoxia than helium ions or protons and require smaller model-derived hypoxia-compensation factors.