Evaluation of Equivalent Toxicity and Associated Tumor Control for Broad-Beam and Ultra-High Dose Rate Spatially-Fractionated Radiotherapy on a Kilovoltage X-Ray Source
Abstract
Purpose
To establish a preclinical x-ray platform for delivering broad-beam (BB) and spatially-fractionated radiotherapy (SFRT) at conventional (CONV) and ultra-high dose rates (UHDR), and to determine the capacity for SFRT to maintain tumor control at doses eliciting BBRT-equivalent skin toxicity in immunocompetent mice.
Methods
A high-power x-ray tube adapted for UHDR delivery, and a divergence-matched 3D-printed multi-slit collimator (MSC) were developed to enable mini-beam SFRT. Radiochromic film dosimetry was used to characterize in-phantom and in-vivo field-averaged dose rates (DRavg) for the 123kVp 1x2.6cm2 broad-beam (CONV,UHDR) or MSC-collimated fields (SFRT), comprising eleven 560μmx2.6cm planar mini-beams for which peak-to-valley dose-ratios (PVDR) were also calculated. A dose-escalation trial with 126 8-week-old male C57BL/6 mice was conducted using 16 dose-modality combinations (N≥6). Skin toxicity was scored over 8 weeks on a 5-grade scale to calculate the dose (TD50) where 50% of mice achieved dose-limiting toxicity (erythema). Subcutaneous D4M melanoma hindlimb tumors were subsequently treated to TD50 using UHDR or UHDR-SFRT (N=8;5 sham) to evaluate tumor control and survival over 162 days.
Results
Significant toxicity differences (p<0.007) were only found between CONV (DRmean,avg=0.62Gy/s) and UHDR (DRavg=31.7Gy/s) for the 32.5Gy dose groups; the estimated TD50 ratio (TDUHDR/TD50CONV) was 1.07. Meanwhile, field-averaged SFRT doses (DRpeak=27.5Gy/s,DRavg= 13.1Gy/s;PVDR=11.7) required for BBRT-equivalent toxicity were significantly increased. The TD50 for UHDR-SFRT and UHDR-BBRT was estimated to be 55.7 and 35.8Gy (TD50SFRT/TD50UHDR=1.6), respectively. Tumor-bearing mice treated to TD50 showed robust tumor control with no significant difference in survival between modalities.
Conclusion
UHDR-SFRT was successfully implemented on a kilovoltage x-ray source. Higher average SFRT doses were required to induce equivalent normal-tissue toxicity compared with BBRT. Results for UHDR-SFRT treatment of subcutaneous melanoma tumors demonstrated intact tumor control despite extreme dose non-uniformity. Ongoing work will evaluate the relative efficacy of SFRT at lower doses and identify opportunities for increasing the therapeutic index through UHDR-SFRT.