Ultra-High Dose-Rate, Pulsed (FLASH) Radiotherapy with Carbon Ions: Generation of Early, Transient, Highly Oxygenated Conditions in the Tumor Environment

Abstract

It is well known that molecular oxygen is a product of the radiolysis of water with high-linear energy transfer (LET) radiation, which is distinct from low-LET radiation wherein O2 radiolytic yield is negligible. Since O2 is a powerful radiosensitizer, this fact is of practical relevance in cancer therapy with energetic heavy ions, such as carbon ions. It has recently been discovered that large doses of ionizing radiation delivered to tumors at very high dose rates (i.e., in a few milliseconds) have remarkable benefits in sparing healthy tissue while preserving anti-tumor activity compared to radiotherapy delivered at conventional, lower dose rates. This new method is called "FLASH radiotherapy" and has been tested using low-LET radiation (i.e., electrons and photons) in various pre-clinical studies and recently in a human patient. Although the exact mechanism(s) underlying FLASH are still unclear, it has been suggested that radiation delivered at high dose rates spares normal tissue via oxygen depletion. In addition, heavy-ion radiation achieves tumor control with reduced normal tissue toxicity due to its favorable physical depth-dose profile and increased radiobiological effectiveness in the Bragg peak region. To date, however, biological research with energetic heavy ions delivered at ultra-high dose rates has not been performed and it is not known whether heavy ions are suitable for FLASH radiotherapy. Here we present the additive or even synergistic advantages of integrating the FLASH dose rates into carbon-ion therapy. These benefits result from the ability of heavy ions at high LET to generate an oxygenated microenvironment around their track due to the occurrence of multiple (mainly double) ionization of water. This oxygen is abundant immediately in the tumor region where the LET of the carbon ions is very high, near the end of the carbon-ion path (i.e., in the Bragg peak region). In contrast, in the "plateau" region of the depth-dose distribution of ions (i.e., in the normal tissue region), in which the LET is significantly lower, this generation of molecular oxygen is insignificant. Under FLASH irradiation, it is shown that this early generation of O2 extends evenly over the entire irradiated tumor volume, with concentrations estimated to be several orders of magnitude higher than the oxygen levels present in hypoxic tumor cells. Theoretically, these results indicate that FLASH radiotherapy using carbon ions would have a markedly improved therapeutic ratio with greater toxicity in the tumor due to the generation of oxygen at the spread-out Bragg peak.

FIG. 1.

Time dependence of the O₂ yields calculated from our IONLYS-IRT Monte Carlo track chemistry simulations of the radiolysis of pure, air-free liquid water at 25°C, in the interval of 10⁻¹²−10⁻⁶ s, for the three incident carbon ions considered here: 4.1 (with and without multiple ionization of water molecules), 290 and 400 MeV per nucleon (LET: ~330, 11.3, and 10 keV/μm, respectively). Note that multiple ionization plays no significant role on the values of G(O₂) for the lower-LET 290 and 400 MeV/nucleon ¹²C⁶⁺ ions (represented by dash-dot and dot-dot lines, respectively). The short-dot line corresponds to our calculated G(O₂) values for 300-MeV protons (which mimic the low-LET limiting case of ⁶⁰Co γ or fast electron irradiation, LET ~ 0.3 keV/μm) and is shown here for comparison. Radiation chemical yields are expressed in units of molecule per 100 eV. For conversion into SI units (mol/J), 1 molecule/100 eV ≈ 0.10364 μmol/J (7, 8). MI = multiple ionization.

FIG. 2.

Three-dimensional representations of track segments for the following impacting ions: (panel A) 4.1-MeV/nucleon ¹²C⁶⁺ (LET ~ 330 keV/μm, 2-μm track length), (panel B) 300-MeV/nucleon ¹²C⁶⁺ (LET ~ 11 keV/μm, 30-μm track length), and (panel C) 300-MeV ¹H⁺ (LET ~ 0.3 keV/μm, 30-μm track length) traversing through liquid water at 25°C, calculated (at ~10⁻¹³ s) with our IONLYS Monte Carlo simulation code. Ions are generated at the origin and start traveling along the y-axis. Each dot represents an interaction where energy deposition occurred. Surrounding the “core” of the track is a much larger region (named the “penumbra”) in which all of the energy is deposited by energetic secondary electrons (δ rays) that result from knock-on collisions with the primary carbon ion.

FIG. 3.

Time dependence of the corresponding track concentrations of O₂ (in mM) (with and without multiple ionization of water molecules) calculated as explained in the text for the three incident carbon ions under consideration, using the G(O₂) values reported in Fig. 1. As in Fig. 1, the [O₂] values for the lower-LET 290 and 400 MeV/nucleon ¹²C⁶⁺ ions are represented by the dash-dot and dot-dot lines, respectively. The short-dot line corresponds to our calculated [O₂] values for 300-MeV protons (which mimic the low-LET limiting case of ⁶⁰Co γ or fast electron irradiation, LET ~ 0.3 keV/μm), shown in the figure for comparison. Typical O₂ concentrations in normal human cells (~30 μM) are indicated by the arrow on the right side. MI = multiple ionization.

FIG. 4.

Changes in LET with the penetration depth in liquid water at 25°C for carbon ions at the three energies considered in this study, as obtained using the SRIM software (43). Total ions calculated = 1,000. The arrows on the left side show the entry LET of the ions: ~330, 11.3 and 10 keV/μm, corresponding to the incident ion energies of 4.1, 290 and 400 MeV per nucleon, respectively.