On the horizon: Grid Therapy

Learning Objectives

To understand about spatially fractionated radiotherapy.
Review biological principles underlying the response to such radiotherapy.
Overview of the technical considerations for implementation.
Review of the clinical outcomes.

Historical Origins

Started in the orthovoltage era (First reported by Kohler in 1909).
Initially started as a way to reduce skin toxicity for large tumors which required palliative radiotherapy
Orthovoltage grids were variable:
- 40% -50% open area
- 1 - 1.5 cm open areas
- Overall treatment time 28 - 45 days ( 600 - 1200 r per day - total dose 12,000 - 24,000 r at air per portal)> Note total doses are 2.5 times that would be treated with conventional open fields.
Matching done at the skin.
The areas covered by grid would serve as “centers” for epithelial regeneration.

Initial Clinical outcomes

Areas in the open experienced brisk dermatitis.
However healing took place even when grid doses as high as 12000 r were administered.
Grid pattern of healing was maintained but in the longer run late changes like atrophy, telengiectasia and scarrring were seen.
Hypothesized that the first 3 - 4 cm of the tissue under the grid were destroyed by the radiation and were replaced by fibrosis.
Ideal locations : Large tumors, superficial away from significant critical structures. Radiation necrosis of the deep seated structures and myelitis / perforation etc were known complications

With advent of megavoltage radiation and its advantages of skin sparing, bone sparing , better depth dose and reduced scatter interest in grid therapy waned.

Megavoltage Grid therapy

First described by Mohiuddin et al from the Department of Radiation Medicine, University of Kentucky School of Medicine.
Described outcomes of 22 patients treated with this therapy in 1990.
Mix of cases 9 sarcoma, 6 GI and 3 massive liver mets among others.
Single field treatment with a 50% open grid comprising of 141 holes. Total doses 10 - 15 Gy
Palliative treatment had 89% response for pain, 80% for mass effect, and 100% for edema and bleeding.

Hexaboard Arrray Grid (Mohiuddin et al. Cancer, 1990)

Biology: Bystander effects

In grid therapy, areas of tumor which are under the grid can be considered as “bystander cells”.
Bystander effect is likely as it is noted that after high dose grid therapy, tumors tend to regress uniformly.
High dose irradiation results in induction of Tumor necrosis factor ⍺ and ceramide as well as downregulation of transforming growth factor 𝛃1 which probably mediates the bystander effect.
Additionally, gene expression changes have been documented in in-vitro experiments in DNA damage and cellular stress response signaling pathways.

Biology: Microvascular changes

Radiation induces apoptosis in endothelial cells via the ceramide pathway. This pathway is independent of the p53 dependent apoptotic pathway.
Knockout mice with deficient acid sphingomyelinase do not undergo radiation induced apoptosis as this enzyme is necessary for production of ceramide.
In a study by Sathishkumar et al, patients responding to GRID therapy had a significantly increased ASM and Ceramide expression.

Serum ceramide concentrations between patient with CR in PR (Sathishkumar et al, Cancer Biology and Therapy, 2005)

Biology: Immunomodulation

While lymphocytes are highly radiosensitive, it is also known that after high dose RT CD8 lymphocytes infiltrate tumors.
In a in-vivo murine model increased tumor growth delay has been observed when partial tumor irradiation was performed.
This has been accompanied with differential lymphocyte infiltration in the tumor.

Change in T cell infiltration in the irradiated (left) and non-irradiated tumor(right) after SFRT. (Kanagavelu et al. Radiation Research 2014)

Technical aspects

Grid therapy is a two dimensional concept where high dose “cylinders” are created inside the tumor volume.
Irradiation of these cylinders can be accomplished using a grid or using IMRT approaches.
In case of IMRT virtual cylindrical volumes are created inside the tumor to affect the irradiation.

Using MLCs to create a grid pattern. (Zhang et al Radiation Research 2010)

3dimensional representation of the grid doses (Zhang et al Radiation Research 2010)

Key Terms in Grid Dosimetry

Usual grid therapy will result in high dose irradiation of about 50% of the tumor volume.
Aperture size of commercially available grid collimators is such that field size is about 1cm²
Doses in the grid have nearly the same depth of Dmax as open fields.
The ratio of the doses at the peaks and the valleys is called as the peak:valley ratio (PVR).

Depth Dose Profiles

PDD at different depths along the beam profile (Zhang et al Radiation Research 202)

Radial and Transvers beam profiles (Zhang et al Radiation Research 2020)

Key Dosimetric Parameters

Nominal dose : Dose delivered at the dose profile peak
Valley to Peak Dose Ratio (VPDR): Ratio of dose in the valley to that of the peak. Usually represented as ratio of D90/D10 doses.
Peak width: Width of the peak dose defined at 50% of max peak dose.
Peak to Peak distance: Distance between two peaks

Equivalent Uniform Dose

LQ model has limitations in the high dose fractionation employed for grid therapy.
Hence a modified LQ model has been proposed by Zhang et al
Using this model an approximate EUD conversion formula for doses > 5 Gy is as follows:

\[ EUD_{grid} = 2.47 + 0.089 * D_{nominal} \qquad(1)\]

An important corollary from this EUD formalism is that for durable control whole tumor control is necessary after Grid therapy !

EUD for different dose fractions and different tumor sizes for GRID therapy (Zhang et al Medical Physics 2014)

Lattice (3d Grid)

This approach relies on creation of three dimensional hot spots in the target volume which are then irradiated.
Unlike cylinders in grid high dose volumes are spherical.
Allows greater flexibility in dose distribution using IMRT at the cost of lower valley to peak ratios.

Example of Lattice Dose distribution (Ahmed et al Semin Rad Onc 2024)

Lattice Radiotherapy Planning

Spheres of 1 - 1.5 cm placed in an array.
Typically separated by 1 - 2 cm from each other as well as from critical structures
Peak doses of 10 - 20 Gy are prescribed
Valley doses are constrained to about 5 Gy or less.

Lattice SBRT planning example (Kavanaugh et al Radiotherapy Oncology 2022)

Clinical Outcomes

Author	N / FU	Dose	Outcomes
Mohiuddin	87 ( 3 - 42 m)	15 Gy	91% response rate. 1 fatal carotid blowout
Huhn	27	15 Gy	93% control rate; poor wound healing in 3 and 4 fibrosis limiting neck movement
Neuner	79	15 Gy	Pain response rate 95%, Mas effect response rate 84%
Amendola	56	NA	8 patients alive without disease at a median FU of 47 months

Most studies have reported a very heterogneous population of patients and while they had voluminous tumors selection bias and impact of post therapy care cannot be removed.

Conclusions

Spatially fractionated (GRID) radiotherapy is an exciting approach.
Dosimetry and commissioning is very complex and clinical results are sparse.
Needs properly conducted clinical trials before wider adoption.
Exciting potential for synergism between immunological modulation and systemic therapy