A Mechanism-Guided Approach for Quantifying the Biological Effects of Tumor Hypoxia in Particle Therapy

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.

The Monte Carlo Damage Simulation was used to generate DNA double-strand break yields as functions of radiation quality q = (Z_eff/β)² and oxygen level pO₂ (0.0001%-100%). Monte Carlo Damage Simulation-derived double-strand break yields were integrated into Geant4 Monte Carlo simulations, and Repair-Misrepair-Fixation model calculations were used to derive linear-quadratic radiosensitivity parameters. We distinguish hypoxic RBE (RBE_H), which compares the biological effects of particles at reduced pO₂ with photons under normoxic conditions (¹³⁷Cs γ-rays at pO₂ = 100%), from isoeffective RBE (RBE_iso), which compares particles and photons at the same pO₂. Spread-out Bragg peak (10-15 cm depth) optimizations used either a uniform 2 Gy absorbed dose or a uniform RBE_H-weighted dose (D_RBE = 3.8 Gy) corresponding to 10% clonogenic survival in H460 cells; hypoxia reduction factors quantified the absorbed-dose compensation required to preserve this modeled endpoint.

At pO₂ = 21%, at D_RBE = 3.8 Gy, RBE_H 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%, RBE_H decreased to 0.39-0.41, 0.50-0.70, and 0.87-2.28, respectively. Because RBE_H 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%, RBE_iso remained >1 (protons 1.13-1.19; helium 1.46-2.03; carbon 2.54-6.63). The corresponding hypoxia reduction factors were 2.73-2.89, 2.42-2.53, and 1.57-2.07.

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.