An investigation of kV mini-GRID spatially fractionated radiation therapy: dosimetry and preclinical trial

Abstract

Objective: To develop and characterize novel methods of extreme spatially fractionated kV radiation therapy (including mini-GRID therapy) and to evaluate efficacy in the context of a pre-clinical mouse study. Approach: Spatially fractionated GRIDs were precision-milled from 3 mm thick lead sheets compatible with mounting on a 225 kVp small animal irradiator (X-Rad). Three pencil-beam GRIDs created arrays of 1 mm diameter beams, and three ‘bar’ GRIDs created 1x20 mm rectangular fields. GRIDs projected 20x20 mm2 fields at isocenter, and beamlets were spaced at 1, 1.25, and 1.5 mm, respectively. Peak-to-valley ratios and dose distributions were evaluated with Gafchromic film. Syngeneic transplant tumors were induced by intramuscular injection of a soft tissue sarcoma cell line into the gastrocnemius muscle of C57BL/6 mice. Tumor-bearing mice were randomized to four groups: unirradiated control, conventional irradiation of entire tumor, GRID therapy, and hemi-irradiation (half-beam block, 50% tumor volume treated). All irradiated mice received a single fraction of 15 Gy. Results: High peak-to-valley ratios were achieved (bar GRIDs: 11.9±0.9, 13.6±0.4, 13.8±0.5; pencil-beam GRIDs: 18.7±0.6, 26.3±1.5, 31.0±3.3). Pencil-beam GRIDs could theoretically spare more intra-tumor immune cells than bar GRIDs, but they treat less tumor tissue (3-4% vs 19-23% area receiving 90% prescription, respectively). Bar GRID and hemi-irradiation treatments significantly delayed tumor growth (P<0.05), but not as much as a conventional treatment (P<0.001). No significant difference was found in tumor growth delay between GRID and hemi-irradiation. Significance: High peak-to-valley ratios were achieved with kV grids: two-to-five times higher than MV grids in literature. GRID irradiation and hemi-irradiation delayed tumor growth, but neither was as effective as conventional whole tumor uniform dose treatment. Single fraction GRID therapy could not initiate an anti-cancer immune response strong enough to match conventional RT outcomes, but follow-up studies will evaluate the combination of mini-GRID with immune checkpoint blockade.

Development and characterization of a versatile mini‐beam collimator for pre‐clinical photon beam irradiation

“…Although slightly different X‐ray beams were used for irradiation, the trends of an increasing valley dose and decreasing peak dose, as well as the resulting steadily decreasing PVDR are similar. Additionally, the findings of increasing FWHM and ctc with increasing depth agree with previous studies, where the same trend was observed 26 …”

“…When comparing the behavior of dose as a function of depth for the peak and valley doses (Figure 5), the obtained results are in agreement with previous publications. 9,16,25,26 Although slightly different X-ray beams were used for irradiation, the trends of an increasing valley dose and decreasing peak dose, as well as the resulting steadily decreasing PVDR are similar. Additionally, the findings of increasing FWHM and ctc with increasing depth agree with previous studies, where the same trend was observed.…”

“…Additionally, the findings of increasing FWHM and ctc with increasing depth agree with previous studies, where the same trend was observed. 26 Decreasing the SCD enabled the increase of dose rate, reaching even ultra-high dose rates to combine these with mini-beam irradiation, a relatively new field in radiotherapy proposing the question of these effects superimpose. 27 Decreasing the SCD, however, imposes the challenge of adapting the mini-beam collimator to the beam divergence.…”

Development and optimisation of grid inserts for a preclinical radiotherapy system and corresponding Monte Carlo beam simulations

“…The output factor in this study is comparable to those in the work by Johnson et al (2022), although slightly larger due to the larger hole radii employed in our grid design. The PVDR, which mainly depends on the open area ratio in an inverse relationship, is larger in our grid configuration compared to their 2 mm spacing grid.…”

“…Grid therapy operates on radiobiological principles that exploit the spatial fractionation of radiation to minimise the irradiated volume of normal tissue, enabling unirradiated cells to migrate into damaged regions. Although the tumour volume also experiences reduced irradiation, the effectiveness of grid therapy persists due to non-targeted effects and other radiobiological factors such as bystander effects, alterations in tumour vasculature, and immune responses (Moghaddasi et al 2022) In a previous study by Johnson et al (2022), physical attenuating grids were developed for use in a preclinical beam setting. These mini-grids were made of lead and featured non-diverging hexagonal array cylindrical holes.…”