Optimizing the MLC-based Spatially Fractionated Radiotherapy (SFRT) Technique: Investigating the Radiobiological Response of Indirect Cell Kill Mechanisms in SFRT Treatment of Large and Bulky Tumors (Radiation Medicine and Markey Cancer Center Collaborative Bench to Bedside pilot) (RPA Pilot / Seed Project)

"Radiation therapy traditionally strives to deliver a homogeneous daily dose to tumors, but spatially fractionated radiotherapy (SFRT) breaks from that tradition and aims to deliver a highly heterogenous dose distribution to large and bulky tumors. SFRT, traditionally known as GRID therapy, is a single high radiation
dose (15–18 Gy) delivery method employed to treat unresectable, large, and bulky (≥ 6 cm) tumors while respecting skin toxicity. This is achieved with either a GRID-like or spherical/ lattice-like dose pattern. SFRT treatments prescribed with a large single dose to advanced site-specific bulky tumors have shown great clinical response of mass reduction (62% to 91%) followed by conventionally fractionated radiation therapy
(RT) in the curative setting. Additionally, in the palliative setting, a 78% response rate in pain relief and 73% rate of mass reduction after SFRT with/without conventional RT has been reported. The utility of SFRT treatments has been hypothesized to arise from the indirect cell kill (in addition to direct DNA double
strands break) being induced from the highly heterogenous spatial dose patterns. Although SFRT has shown great clnical response, there is still a big unknown of the optimal dosing patterns and what best practices are for SFRT treatments? Currently, we utilize a multi-leaf collimators (MLC)-based crossfire method that generates a spatial dose pattern of high dose cylindrical distribution of 1 cm diameter and 2 cm center-tocenter spacing within the large tumor while sparing adjacent critical organs including skin. However, this may not be the most optimal pattern or shape that could provide the greatest tumor mass reduction while minimizing dose to normal tissue also known as therapeutic ratio. We will examine the potential enhanced therapeutic ratio utilizing differential high dose patterns for site-specific SFRT treatments. By optimizing the highly heterogenous dose distributions, this could change the radiobiological response of tumor cells
kill potentially increasing the indirect cell kill component. Preclinical investigation will be performed using cancer cell line exposures. Based on the preclinical results, we will demonstrate the feasibility, efficacy, and
safety of utilizing optimal patterns including spherical dose distributions in the clinical setting on our new EDGE linac (with 2.5 mm width MLC) for enhancing treatments for future SFRT patients. Another unknown is how to prescribe and evaluate these SFRT plans. Currently, we prescribe 15 Gy nominal dose for these SFRT plans. Additionally, we utilize departmental metrics for evaluating these
plans which consists of the peak-to-valley dose ratio (PVDR=D10/D90), mean dose to the target and volume of the target receiving 50% of the prescription dose as well as maximum dose to adjacent critical organs. Little research has been conducted that investigates the correlation and utility of these dose metrics with current clinical outcomes, thus we will fill this knowledge gap. Lastly, due to the highly heterogenous dose distribution, the radiobiological response of these SFRT treatments is not completely characterized, yet. Currently, clinically used Linear-Quadratic (LQ) biological model only takes into consideration of direct cell kill mechanism, but the utility of SFRT is highly contributed to indirect cell death as well that isn’t factored in the classical LQ model. The development of a clinically available and explainable radiobiological model that accounts both direct and indirect cell kill mechanisms will aid tremendous value in evaluating and prescribing SFRT treatments leading to improved clinical outcomes in the future."