Adaptation of stochastic microdosimetric kinetic model to hypoxia for hypo-fractionated multi-ion therapy treatment planning

Abstract

For hypo-fractionated multi-ion therapy (HFMIT), the stochastic microdosimetric kinetic (SMK) model had been developed to estimate the biological effectiveness of radiation beams with wide linear energy transfer (LET) and dose ranges. The HFMIT will be applied to radioresistant tumors with oxygen-deficient regions. The response of cells to radiation is strongly dependent on the oxygen condition in addition to radiation type, LET and absorbed dose. This study presents an adaptation of the SMK model to account for oxygen-pressure dependent cell responses, and develops the oxygen-effect-incorporated stochastic microdosimetric kinetic (OSMK) model. In the model, following assumptions were made: the numbers of radiation-induced sublethal lesions (double-strand breaks) are reduced due to lack of oxygen, and the numbers of oxygen-mediated lesions are reduced for radiation with high LET. The model parameters were determined by fitting survival data under aerobic and anoxic conditions for human salivary gland tumor cells and V79 cells exposed to helium-, carbon-, and neon-ion beams over the LET range of 18.5–654.0 keV μm−1. The OSMK model provided good agreement with the experimental survival data of the cells with determination coefficients >0.9. In terms of oxygen enhancement ratio, the OSMK model reproduced the experimental data behavior, including slight dependence on particle type at the same LET. The OSMK model was then implemented into the in-house treatment planning software for the HFMIT to validate its applicability in clinical practice. A treatment plan with helium- and neon-ion beams was made for a pancreatic cancer case assuming an oxygen-deficient region within the tumor. The biological optimization based on the OSMK model preferentially placed the neon-ion beam to the hypoxic region, while it placed both helium- and neon-ion beams to the surrounding normoxic region. The OSMK model offered the accuracy and usability required for hypoxia-based biological optimization in HFMIT treatment planning.

Spot‐scanning hadron arc (SHArc) therapy: A proof of concept using single‐ and multi‐ion strategies with helium, carbon, oxygen, and neon ions

“…Neon ions, in conventional delivery settings, surpass LET d levels > 90-100 keV/μm and according to models, may prove useful for combating hypoxia. 8 Particularly for higher beam energies, LET d in the Bragg peak will reduce due to energy straggling and fragmentation processes occurring with higher penetration depths (Figure S-1A), resulting in increased low dose-halo (Figure S-1B) compared to carbon and oxygen ions, as well as increased entrance-to-peak ratios. These attributes were historically considered during modality selection, which ultimately led to widespread use of carbon ions in Japan and Europe.…”

“…The multi-ion optimization approach aimed to produce more homogenous biophysical target distributions. In contrast, Inaniwa et al 8 applies MIT in an effort to combat hypoxia-related radio-resistance, with Ne primarily covering the GTV and auxiliary beams of helium supplement target coverage of the PTV-GTV shell. Similarly, other works combat tumor hypoxia via LET kill-painting, which requires biological informed planning for oxygen status and pattern of oxygenation gradient within the tumor.…”

“…Helium and carbon ions provide moderate to high linear energy transfer (LET) values within the target volume but for larger target sizes, due to overlapping entrance channel (low LET), the full effect of the higher LET may be mitigated with ideal target LET values often localized laterally and beyond the distal end of the target volume 6 . Oxygen and neon ions are under consideration for increasing target LET beyond the capabilities of carbon ions and have been shown to potentially mitigate hindrances on clinical outcome caused by radio‐resistance factors 7,8 . For higher penetration depths, the sharp relative biological effectiveness (RBE) gradients, reduced entrance‐to‐peak ratio and subsequent fragmentation tail may be less favorable than carbon ion therapy for single field arrangements.…”

“…6 Oxygen and neon ions are under consideration for increasing target LET beyond the capabilities of carbon ions and have been shown to potentially mitigate hindrances on clinical outcome caused by radio-resistance factors. 7,8 For higher penetration depths, the sharp relative biological effectiveness (RBE) gradients, reduced entrance-to-peak ratio and subsequent fragmentation tail may be less favorable than carbon ion therapy for single field arrangements. Nonetheless, scientific programs at the National Insti-tute of Radiological Sciences (NIRS, Chiba, Japan) are investigating pre-clinical beams like oxygen and neon ions for the purpose of multi-ion therapy (MIT) regimes and/or hypofractionated treatments.…”

Charge Evolution for N2 + Ion Passing Through Ag Target

“…Interaction between energetic ion beams with target has been subject of research for a wide area from fast ignition inertial fusion to medical therapy [1][2][3][4][5][6]. Due to fast molecular ion can deposit more energy in a small region of the target, which arouses the interest and has become a new potential tool to replace traditional atomic ion [7][8][9][10].…”