Enhancing predicted efficacy of tumor treating fields therapy of glioblastoma using targeted surgical craniectomy: A computer modeling study

OBJECTIVE:The present work proposes a new clinical approach to TTFields therapy of glioblastoma. The approach combines targeted surgical skull removal (craniectomy) with TTFields therapy to enhance the induced electrical field in the underlying tumor tissue. Using computer simulations, we explore the potential of the intervention to improve the clinical efficacy of TTFields therapy of brain cancer. METHODS:We used finite element analysis to calculate the electrical field distribution in realistic head models based on MRI data from two patients: One with left cortical/subcortical glioblastoma and one with deeply seated right thalamic anaplastic astrocytoma. Field strength was assessed in the tumor regions before and after virtual removal of bone areas of varying shape and size (10 to 100 mm) immediately above the tumor. Field strength was evaluated before and after tumor resection to assess realistic clinical scenarios. RESULTS:For the superficial tumor, removal of a standard craniotomy bone flap increased the electrical field strength by 60-70% in the tumor. The percentage of tissue in expected growth arrest or regression was increased from negligible values to 30-50%. The observed effects were highly focal and targeted at the regions of pathology underlying the craniectomy. No significant changes were observed in surrounding healthy tissues. Median field strengths in tumor tissue increased with increasing craniectomy diameter up to 50-70 mm. Multiple smaller burr holes were more efficient than single craniectomies of equivalent area. Craniectomy caused no significant field enhancement in the deeply seated tumor, but rather a focal enhancement in the brain tissue underlying the skull defect. CONCLUSIONS:Our results provide theoretical evidence that small and clinically feasible craniectomies may provide significant enhancement of TTFields intensity in cerebral hemispheric tumors without severely compromising brain protection or causing unacceptable heating in healthy tissues. A clinical trial is being planned to validate safety and efficacy

Topographical effect of craniectomy after tumor resection.

<p><b>A.</b> Topographical maps of field strength distributions (coronal, axial, and sagittal from left to right, colorbar 0–300 V/m) with and without craniectomy and for both electrode pairs as indicated. <b>B</b>. Paired difference between craniectomy and no craniectomy scenarios, i.e. Δ|<b>E</b>| = |<b>E</b>|_craniectomy—|<b>E</b>|_{no craniectomy}, for both electrode pairs. Leftmost panels show a rotated surface view of the resection cavity and the surrounding region of pathology. Craniectomy produced a marked and focal increase in electrical field strength in the peritumoral region underlying the craniectomy, while leaving the healthy tissues largely unaffected.</p

MRI data from study Subject 1 and corresponding 3D head model.

<p><b>A.</b> Coronal (left), axial (middle) and sagittal (right) views of original Gadolinium enhanced T1 MRI patient data showing left parietal glioblastoma (radiological orientation). <b>B.</b> Volume reconstruction of gray matter (gray), white matter (white), tumor tissue (yellow), and a peritumoral region (blue). <b>C.</b> Surface reconstruction of patient skull rotated to present the craniectomy boneflap outlined as a darkened area above the tumor (left). The rightmost image shows the same view, but with the bone flap removed to display the underlying tumor and peritumoral region. <b>D.</b> Surface reconstruction of the head model showing the optimized electrode layout used for simulation (NovoTAL ^™). Electrodes are paired orange with white and gray with blue.</p

MRI data from study Subject 2 and corresponding 3D head model.

<p><b>A.</b> Coronal (left), axial (middle) and sagittal (right) views of original T2 MRI patient data showing a deeply seated WHO III astrocytoma (radiological orientation). The tumor was non-enhancing on T1 with Gadolinium enhancement. <b>B.</b> Volume reconstruction of gray matter (gray), white matter (white), tumor tissue (yellow), and a peritumoral region of interest (blue). <b>C.</b> Surface reconstruction of patient skull rotated to present the circular 50 mm craniectomy boneflap outlined as a darkened area above the tumor on the right side. The rightmost image shows the same view, but with the bone flap removed to display the underlying cortical surface. <b>D.</b> Surface reconstruction of the head model showing the optimized electrode layout used for simulation (NovoTAL^™). Electrodes are paired orange with white and gray with blue.</p

Topographical effect of craniectomy for a deeply seated tumor.

<p><b>A.</b> Field strength distributions with and without craniectomy (coronal, axial, and sagittal sections from left to right, colorbar 0–300 V/m). <b>B</b>. Paired difference between craniectomy and no craniectomy scenarios, i.e. Δ|<b>E</b>| = |<b>E</b>|_craniectomy—|<b>E</b>|_{no craniectomy}, for both electrode pairs. Leftmost panels show a surface view of the region of pathology. Craniectomy caused no considerable changes in electrical field strength in the regions of pathology, but rather induced a significant increase in field strength in the healthy tissues immediately underlying the skull defect.</p

Effect of craniectomy on current density.

<p><b>A.</b> Current density distribution (color indication 0–180 A/m²) on the brain surface with and without craniectomy (no resection). The skin surface (with placed electrodes) is shown for orientation. Craniectomy significantly increases the current density in the region of pathology underlying the craniectomy (black ellipse, <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0164051#pone.0164051.g001" target="_blank">Fig 1C</a>). This in turn leads to increased field strength in the affected region. <b>B</b>. Topographical distribution of the current density on the skin surface with and without craniectomy (range 0–250 A/m²). Craniectomy causes the current to be shunted through the skull defect thereby lowering the current density in the skin region between the active electrodes. The figure also shows how individual electrodes in the arrays contribute differently in the two situations.</p

Topographical effect of craniectomy without tumor resection.

<p><b>A.</b> Field strength distributions with and without craniectomy (coronal, axial, and sagittal sections from left to right, colorbar 0–300 V/m). <b>B</b>. Paired difference between craniectomy and no craniectomy scenarios, i.e. Δ|<b>E</b>| = |<b>E</b>|_craniectomy—|<b>E</b>|_{no craniectomy}, for both electrode pairs. Leftmost panels show a rotated surface view of the region of pathology. Craniectomy produced a marked and focal increase in electrical field strength in the regions of pathology underlying the craniectomy, while healthy tissues were largely unaffected.</p

Effect of craniectomy size and configuration on field distribution.

<p><b>A.</b> Median and 99^th percentile field strengths (<i>ordinate</i>) in the tumor and peritumoral tissues at different craniectomy diameters (<i>abscissa</i>). Results are shown for both the L/R (red line) and A/P (black line) array pairs. Asterisk symbols represent equivalent results obtained using a model with four 15 mm burr holes located above the tumor region. The results are displayed at 30 mm craniectomy diameter as these configurations had the same total area. <b>B.</b> Equivalent results as displayed in A but after resection of the tumor. <b>C.</b> Surface view of selected craniectomies and the corresponding field distributions obtained before tumor resection. Color bar represent the range of field strengths displayed.</p

Effect of craniectomy without tumor resection.

<p>Percentage of tissue exposed to field strengths above the corresponding value on the abscissa (craniectomy—stippled line; no craniectomy—solid line). Rows represent different tissues and columns the L/R and A/P electrode pairs, as indicated. Craniectomy significantly increased the electrical field strengths in tumor tissue and the peritumoral region compared to no craniectomy. The distributions of field strengths in healthy tissues were largely unaffected.</p