Electronic Thesis and Dissertation Repository

Thesis Format

Integrated Article

Degree

Doctor of Philosophy

Program

Medical Biophysics

Supervisor

Wong, Eugene

2nd Supervisor

Peters, Terry

Co-Supervisor

Abstract

The use of anti-cancer non-ablative electric fields is an expanding area of research that includes clinically available external devices for the treatment of glioblastoma (GBM), and a pre-clinical internal system called Intratumoural Modulation Therapy (IMT). IMT uses multiple electrodes implanted within the tumour to apply low intensity electric fields (~1 V/cm) focused on the target region, anywhere in the brain, with no externally visible devices. In this thesis, multi-electrode spatiotemporally dynamic IMT is investigated through computer simulation, numerical optimization, brain phantom and in vitro validation methods. These planning and validation strategies are hypothesized to improve tumour coverage with the necessary electric field and improving treatment efficiency through minimizing number of electrodes, power consumption, and manual planning time.

The development of an IMT optimization algorithm that considers the placement of multiple electrodes, voltage amplitude and phase shift of input waveforms showed that human scale tumours are coverable with anti-cancer electric fields. Additionally, maximally separating the relative phase shifts of sinusoidal voltage waveforms applied to the electrodes, induces rotating electric fields that cover the tumour over time, with spatially homogeneous time averaged fields. A treatment planning system designed specifically for IMT considered optimizable electrode trajectories and patient images to create custom field plans for each patient, which was validated using robotic electrode implantation on a brain phantom. These custom fields can be optimized to conform to patient-specific tumour size, shape, or location. The efficacy of spatiotemporally dynamic fields was validated by developing a purpose-built in vitro device to deliver multi-electrode IMT to patient derived GBM cells. Cell viability was reduced when subjected to these rotating electric fields, supporting the optimality criteria derived analytically.

The IMT optimization algorithm and planning system, supporting phantom validation and in vitro data, together with an accompanying planning system user guide support the move to clinical trials in the future. Overall, IMT technology has been advanced in this thesis to include patient-specific treatment planning optimization, a development that holds significance towards the future clinical implementation of IMT and treatment goals.

Summary for Lay Audience

A recent advancement in brain cancer research is the use of electric fields to control the disease. These electric fields can be applied either externally in the form of an electrode cap, or internally with implanted electrodes. The former is available clinically, and the latter is the topic of this thesis. Electric fields delivered directly using electrodes surgically placed within the brain tumour is a method called Intratumoural Modulation Therapy (IMT). Computerized optimization allows us to determine the ideal treatment settings to best cover the tumour with the prescribed electric field. In this thesis, anti-cancer electric fields are optimized for brain cancer treatment, through the development of an IMT optimization algorithm, a patient-specific IMT treatment planning system, and in vitro validation of optimized rotating electric fields.

It was found through computer simulations and a custom designed optimization algorithm that human scale tumours can be covered with sufficient anti-cancer electric fields from multiple electrodes placed in the tumour at optimized locations. The settings of the applied voltage waveforms to each electrode resulted in fields that moved over time to cover the entire tumour. A treatment planning system was then developed that incorporates this optimization algorithm. Patient images are used in conjunction with treatment goals including electric field dose and number of electrodes, where the treatment provider can run the simulator and optimizer to design a patient-specific treatment plan. The planning system was validated by performing an electrode implantation on a brain phantom using a robotic insertion technique. Finally, the rotating electric fields found to have the best coverage were investigated in vitro, where a device was designed to deliver reliable reproducible stimulation to multiple wells simultaneously. The results of this study found rotating fields effective at reducing the viability of brain cancer cells, where the strength of the electric field was the main driver of cell death. The optimization strategies applied in the planning system were found to be impactful with more tumour cell kill observed in trials using optimized settings. Overall, the discoveries made in this thesis are significant in the development of IMT and patient-specific treatment planning.

Creative Commons License

Creative Commons Attribution-Noncommercial-No Derivative Works 4.0 License
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 4.0 License.

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