Purpose: To develop and implement novel methods of extreme spatially fractionated radiation therapy (including GRID therapy) and subsequent evaluation in pre-clinical mice trials investigating the potential of novel radiation treatments that more effectively promote anti-cancer immunogenic response.
Methods: Spatially fractionated GRIDs were designed and precision-milled from 3mm thick lead sheets compatible with mounting on a 225 kVp small animal irradiator (X-Rad). Three pencil-beam GRIDs created arrays of 1mm diameter beams, and three “bar” GRIDs created 1x20mm rectangular fields. GRIDs projected 20x20mm fields at isocenter and beamlets were spaced at 1, 1.25, and 1.5mm, respectively. Output factors, peak-to-valley ratios, and dose distributions were determined with Gafchromic film. The bar GRID with 1mm beamlet spacing (50:50 open:closed ratio) was selected for the pre-clinical trial. Soft-tissue sarcoma (p53/MCA) was transplanted into C57BL/6 mice’s flanks. Four treatment arms were compared: unirradiated control (n=14), conventional radiation therapy (n=8), GRID therapy (n=12), and hemi-irradiation (n=10) where one-half of the beam was blocked. All irradiated mice received a single fraction of 15 Gy to irradiated regions.
Results: Very high peak-to-valley ratios were achieved (bar GRIDs: 11.9±0.9, 13.6±0.4, 13.7±0.5; pencil-beam GRIDs: 18.7±0.6, 26.3±1.5, 31.0±3.3). Pencil-beam GRIDs spared twice the number of intra-tumor immune cells as bar GRIDs but left more of the tumor untreated (2-3% vs 14-17% area receiving 95% prescription, respectively). Penumbra was halved when GRIDs were 50% closer to treatment isocenter. The GRID selected for mouse trials was capable of sparing approximately 30% of intra-tumor CD8+ and CD4+ T cells. Preliminary results indicate mean times to tumor quintupling were: 9, 12, 12, and 24 days for unirradiated, GRID, hemi-irradiated, and conventional treatment groups, respectively.
Conclusion: Peak-to-valley ratios with kV grids were substantially superior to MV grids. In data collected to date, GRID did not control tumors as effectively as conventional treatment at the same dose level.