Computer Simulation Can Help Plan Brain Cancer Treatment

A computer simulation, NovoTAL, that optimizes therapeutic delivert in two orthogonal directions to the gross tumor volume (GTV) and proximal peri-tumorial brain zone (PBZ) may help plan treatment for patients likely to experience contiguous recurrence of glioblastoma, according to findings presented at the 2016 American Society for Radiation Oncology (ASTRO) Annual Meeting.

The device uses tumor treating fields (TTF) and employs a personalized transducter array, delivering electric field (EF) intensities that exceeded therapeutic intensities in three different tumor locations.

Since the EF intensity cannot be easily measured inside the human head, a computational model was used to study EF distribution to determine the influence of TTF treatment planning and resultant EF intensity in the GTV, PBZ, subventricular zone (SVZ) regions and contralateral lobe (CL). Tumor models included sites that were cortex restricted (CTX+) and involved the SVZ+.

“Tumors that involve the subventricular zone tend to be more invasive, so we see more distal recurrences when this zone is involved by the primary tumor,” said Uri Weinberg, M.D., M.P.H., vice president, Research and Development at Novocure, the manufacturer of NovoTAL. “We wanted to test whether layout planning of the transducer arrays may effectively cover the relevant zones of each tumor. The output of the system is a map that indicates how to apply the transducer array in a specific layout according to the physical characteristics of the patient.”

There are challenges associated with the use of TTF, notably its large wavelength and uneven distribution throughout the brain, resulting in regions that receive higher or lower field intensities. Predicting field intensities in an actual patient would be difficult because it can only be done during surgery, said Weinberg. “Using a simulation, we can test and predict the field intensities,” he said.

NovoTAL is a software that allows physicians to plan the array layout through measurements using MRI scans. In the simulation, MRI scans for three different tumor locations — the frontal-parietal (cortex restricted+/subventricular zone-), the posterior parietal (CTX+/SVZ-) and the large frontal parietal (CTX+/SVZ+) — were integrated into a realistic head model (Colin27), which includes scalp, skull, grey matter, white matter, cerebrospinal fluid (CSF) and ventricles.

The size and location of the ellipsoids were chosen to match the size and location of the three tumors that were tested. The ellipsoids were assigned properties to simulate three different tumor types: solid tumor mass; a tumor with a necrotic core (tumor comprises a solid margin surrounding a necrotic center); and a resection cavity (tumor has been surgically removed, and the cavity filled with fluid similar to CSF). Standard TTF treatment planning was performed using the patient’s MRIs to generate transducer array layouts maps using the NovoTAL System planning software. Planning was performed using the T1 post-contrast sequences, following methods described previously.

The NovoTAL-generated transducer array layouts were used to guide placement of simulated arrays on the scalp of the realistic head models; array configuration is specific to tumor location and cranial morphometry. Two orthogonal fields, left-right, and antero-posterior at field frequency of 200 kHz were employed for all simulations. Boundary conditions were prespecified to mimic therapeutic parameters; dielectric properties were assigned to all tissue types including assumptions for solid tumor properties, necrotic cores and resection cavity fluid.

“By modifying the placement of the transducer arrays, we can position the alternating fields towards the tumor bed,” said Weinberg. “By applying TTF to cover large areas of the brain, we can affect tumor cells that are located distally.”

The threshold of therapeutic EF intensity is about 1V/cm, and EF intensities more than 2V/cm have been observed to completely arrest cellular proliferation in GB cell lines. GB is heterogeneous, highly proliferative and invasive into the normal brain. The majority of GB will recur contiguously or at the margin of a resection cavity or within the proximal PBZ with fewer cases recurring at distal sites.

There is some evidence to suggest that the heterogeneity in patient survival and recurrence patterns observed in GB may be related to the origin of tumor cells and the involvement of the SVZ, a region containing neural progenitor cells. GB stem-like cells represent a minority of cells in the tumor that may be responsible for aggressive tumor characteristics such as self-renewal and radioresistance. Retrospective studies suggest that GB patients with SVZ tumor involvement are most likely to present with multifocal lesions and may have more rapid progression and decreased overall survival.