Hepatocellular carcinoma (HCC) is the most common form of primary liver cancer and the second-highest leading cause of cancer-related deaths. Effective and site-specific strategies for the administration of therapeutic drugs are urgently needed, especially for patients with unresectable tumors.
Unresectable HCC can be treated by transarterial chemoembolization (TACE) or radioembolization (TARE). During these therapies, the patient is catheterized through the femoral artery and the catheter is advanced via the aorta towards the liver (Figure 1, panels a-b). Microspheres are injected in the proper hepatic artery or, ideally, closer to the tumor (Figure 1, panel c). In TACE, these microspheres carry drug particles and are used to permanently damage the tumor tissue by a combined embolic (occlusive) and chemotherapeutic effect. In TARE, the embolic effect is only of secondary importance- the main pathway by which tumor tissue is damaged, is through local emission of high-intensity radiation.
Figure 1: The workflow for transarterial therapies (TACE, TARE). A catheter is inserted in the femoral artery and navigated towards the liver. Damaging microspheres are injected as close as possible to the tumor to maximize the target-specificity of the treatment.
The overall goal is to steer the damaging microspheres towards the tumor tissue to (i) maximize drug delivery to the tumor, and (ii) limit the amount of toxicity delivered to healthy tissue. This method of delivery for these transarterial therapies stand out against unspecific drug delivery, such as conventional intravenous chemotherapy, where drugs pass through the systemic circulation and severe side-effects (e.g. nausea, hair loss) may occur as a result of unwanted toxicity at the level of the healthy tissue.
Because it is often challenging to navigate catheters inside the smaller arteries and release particles close to the tumor, easily accessible, upstream locations are instead used to release particles. There, the problem arises how microspheres can be steered through the bloodstream towards the tumor. A range of parameters that are variable in clinical practice (e.g. particle size, particle density, injection velocity, injection location, catheter type, catheter tip orientation, etc.) may have a large impact on where particles eventually end up. However, as of now, this impact is unclear. A limited range of studies in simplified geometries have been performed, but the impact is likely to depend highly on the patient-specific geometry used.
If certain parameters prove to be highly impactful on the downstream particle distribution, they can be used in a patient-specific optimization workflow to increase the target-specificity of the eventual treatment (e.g. selecting the most optimal injection location and catheter type for each patient independently.)
The workflow of this thesis can be divided in several succinct steps.
(i) Literature study, in which the student(s) will explore the problem setting and identify relevant research questions.
(ii) Segmentation and meshing of the arterial network of the liver. Practically, imaging data (e.g. CT, MRI) of the liver vasculature of a cohort of patients will be used to create 3D models for simulation geometries (Figure 2).
Figure 2: Two examples of patient-specific liver geometries which were extracted from micro-CT images.
(iii) Modelling and analysis of vascular flow dynamics. From a modelling point of view, this transport problem can be translated in a dispersion of discrete phase particles (drug carriers) in a continuous fluid phase (blood). Simulations of the blood circulation and drug carrier transport in the liver will be performed in order to gain more insight in the parameters influencing treatment efficacy.
(iv) Post-processing. E.g. Particle Release Maps (PRMs) are projections of particle fate on the injection plane (Figure 3). Here, it can be seen that by carefully controlling the location of the in-plane catheter tip, particles can be steered towards specific outlet branches.
Figure 3: Particle Release Maps (PRMs) show where particles need to be injected in the injection plane to reach certain targeted exit branches.
(v) Validation. For validation purposes, a patient-inspired in-vitro model using a 3D print of patient-specific hepatic arterial geometry connected to a perfusion pump will allow to experimentally simulate targeted drug delivery (Figure 4, panel b). Similarly, validation can be done by overlapping numerical results with SPECT-CT images. The radioactive hotspots show where microspheres deposited in the tissue during the (pre-)treatment, which should correspond with particle deposition as predicted by the model (Figure 4, panel a).
Figure 4: Two examples of patient-specific validation. a) SPECT-CT imaging b) in vitro experimental method