Spatially Fractionated Radiation Therapy

Spatially fractionated radiation therapy, often called GRID therapy, is a mode of external beam radiation treatment characterized by highly non-uniform dose distributions. Large dose gradients can be achieved using a sieve-like filter, creating a grid pattern.

Historically, low-dose shadows were introduced intentionally and were useful in the days of kilovoltage (kV) to partially spare the skin, a major limitation in kilovoltage radiotherapy for deep-seated tumors at the time. GRID therapy differs from conventional radiation therapy in which the targeted dose to the tumor is uniform.

Spatially Fractionated Dose Distribution via NCBI

 

There are several different ways to achieve this heterogenous dose distribution in the tumor volume. The most common in historical context is 2D GRID therapy, which is achieved by passing an open field through a high-density grid filter.

Employed in three dimensions, lattice therapy was designed to modernize GRID therapy and to improve conformality and high doses to surrounding normal tissues. In 3D lattice radiotherapy, the goal is to create small high dose spheres, called vertices, within the tumor and keep lower dose regions closer to the periphery of the tumor in order to spare healthy tissue. These vertices are spaced strategically depending on the tumor size, shape, and location in normal tissue. 3D lattice radiotherapy has been used clinically and has resulted in improved local control, with no increased toxicity.

Example of a GRID used for GRID Therapy via NCBI

Smaller apertures are used in proton minibeam radiation therapy (pMBRT), which uses beams in the range of 500-700µm spaced by 1-3mm to create dose peaks and troughs to cover the tumor. The use of protons further decreases the amount of dose to the surrounding normal tissue, leveraging the Bragg peak phenomenon inherent to protons. Pre-clinical investigation into kV photon microbeam radiation therapy (MRT) is ongoing, according to Nolan Esplen at the University of Victoria, whose recent work focuses on the design of a multi-slit collimator for use in small animal irradiation.

 

Choi, et al. used spatially fractionated GRID therapy, SFGRT, to treat head and neck cancers along with traditional external beam radiation. Therapy was delivered in a single fraction of 15-20Gy using a 6MV or 18MV beam. The results of this analysis show that SFGRT can be a useful clinical tool to palliatively and definitively treat unresectable head and neck tumors, without exposing patients to unnecessary toxicity.

Investigating the use of 3D lattice radiotherapy on patients with bulky non-small cell lung cancer, Amendola, et al. showed no associated mortality and no increased toxicity in a small cohort of 10 patients that received the lattice therapy as an adjunct to conventional radiation, in which 18Gy at the lattice vertices, central in the tumor, and of 3Gy at the periphery of the tumor. The mean decrease in tumor size following treatment at a median follow-up time of six months was 42%.

Dose Distribution of 3D Lattice Radiotherapy via NCBI

 

Studies have also been conducted on animals to investigate the use of pMBRT in treating high-grade gliomas. Results showed non-glioma bearing rats treated with pMBRT gained weight on par with untreated rats and developed no skin damage from their irradiation. Glioma bearing rats treated with the pMBRT showed good local tumor control and did not display some side effects associated with standard proton therapy. These results show promise for pMBRT if it is to be adapted for human treatments.

 

How is it possible that the variability in dose of GRID therapy is able to achieve results without complete tumor coverage? Current understanding of the radiobiological mechanisms suggest that the low dose regions in tumors are still affected because of the bystander effect, vascular damage, and anti-tumor immune response.

A review of SFRT by Billena and Khan explains that the bystander effect is triggered by certain cytokines being expressed or downregulated due to proximity of highly irradiated cells. Vascular damage via endothelial apoptosis can be caused in low dose SFRT regions due to local travel of soluble radiation byproduct. This damage inhibits tumor growth and sustainability. In the absence of high dose there is an anti-tumor response from the immune system that aids in cancerous cell death in the low dose region. It is also possible that this could trigger a more distant abscopal effect.

 

Spatially fractionated radiation therapy has historical roots in kilovoltage therapy, which was developed to counter skin toxicity for deep seated tumors. But new research continues to vet the use of GRID therapy for applications in megavoltage radiotherapy such as tumor debulking and palliative care, but novel methods and indications continue to grow with continued research.