Progress in the field of functional imaging will possibly lead to more specific tumor targeting and personalized treatment, increasing tumor control and improving quality of life.

No abstract

Glioblastomas (GBM) are notorious for their high fatality rate. Boron Neutron Capture Therapy (BNCT) being a biochemically targeted type of radiotherapy is a potent modality for GBM. In the current work, a BNCT treatment modelling framework for GBM was developed. Optimal Clinical Target Volume (CTV) margins for GBM-BNCT and the BNCT efficacy have been investigated. The model integrated a cell-based dosimetry model, an in-house-developed epithermal neutron beam model and previously-developed Microscopic Extension Probability (MEP) model. The system was defined as a cubic ICRP-brain phantom divided into 20 μm side voxels. The corresponding 10B concentrations in GBM and normal brain cells were applied. The in-silico model was irradiated with the epithermal neutron beam using 2 and 2.5 cm CTV margins. Results from the cell-based dosimetry and the MEP models were combined to calculate GBM cell survival fractions (SF) post BNCT and compared to x-ray radiotherapy (XRT) SFs. Compared to XRT, the SF within the beam decreased by five orders of magnitudes and the total SF was reduced three times following BNCT. CTV extension by 0.5 cm reduced the SF by additional (53.8 ± 0.3)%. In conclusion, BNCT results in a more efficient cell kill. The extension of the CTV margin, however, may not increase the treatment outcome significantly.

The model provides a quantitative tool for evaluation of different CTV margins in terms of cell kill efficacy. Cellular platform of the tool allows future incorporation of cellular properties of GBM.

No abstract

The continuously evolving field of radiotherapy aims to devise and implement techniques that allow for greater tumour control and better sparing of critical organs. Investigations into the complexity of tumour radiobiology confirmed the high heterogeneity of tumours as being responsible for the often poor treatment outcome. Hypoxic subvolumes, a subpopulation of cancer stem cells, as well as the inherent or acquired radioresistance define tumour aggressiveness and metastatic potential, which remain a therapeutic challenge. Non-conventional irradiation techniques, such as spatially fractionated radiotherapy, have been developed to tackle some of these challenges and to offer a high therapeutic index when treating radioresistant tumours. The goal of this article was to highlight the current knowledge on the molecular and radiobiological mechanisms behind spatially fractionated radiotherapy and to present the up-to-date preclinical and clinical evidence towards the therapeutic potential of this technique involving both photon and proton beams.

Clinical target volume (CTV) determination may be complex and subjective. In this work a microscopic-scale tumour model was developed to evaluate current CTV practices in glioblastoma multiforme (GBM) external radiotherapy. Previously, a Geant4 cell-based dosimetry model was developed to calculate the dose deposited in individual GBM cells. Microscopic extension probability (MEP) models were then developed using Matlab-2012a. The results of the cell-based dosimetry model and MEP models were combined to calculate survival fractions (SF) for CTV margins of 2.0 and 2.5 cm. In the current work, oxygenation and heterogeneous radiosensitivity profiles were incorporated into the GBM model. The genetic heterogeneity was modelled using a range of α/β values (linear-quadratic model parameters) associated with different GBM cell lines. These values were distributed among the cells randomly, taken from a Gaussian-weighted sample of α/β values. Cellular oxygen pressure was distributed randomly taken from a sample weighted to profiles obtained from literature. Three types of GBM models were analysed: homogeneous-normoxic, heterogeneous-normoxic, and heterogeneous-hypoxic. The SF in different regions of the tumour model and the effect of the CTV margin extension from 2.0-2.5 cm on SFs were investigated for three MEP models. The SF within the beam was increased by up to three and two orders of magnitude following incorporation of heterogeneous radiosensitivities and hypoxia, respectively, in the GBM model. However, the total SF was shown to be overdominated by the presence of tumour cells in the penumbra region and to a lesser extent by genetic heterogeneity and hypoxia. CTV extension by 0.5 cm reduced the SF by a maximum of 78.6  ±  3.3%, 78.5  ±  3.3%, and 77.7  ±  3.1% for homogeneous and heterogeneous-normoxic, and heterogeneous hypoxic GBMs, respectively. Monte-Carlo model was developed to quantitatively evaluate SF for genetically heterogeneous and hypoxic GBM with two CTV margins and three MEP distributions. The results suggest that photon therapy may not provide cure for hypoxic and genetically heterogeneous GBM. However, the extension of the CTV margin by 0.5 cm could be beneficial to delay the recurrence time for this tumour type due to significant increase in tumour cell irradiation.

A growing proportion of head and neck cancers (HNC) result from HPV infection. Between HNC aetiological groups (HPV positive and HPV negative) clinical evidence demonstrates significantly better treatment response among HPV positive cancers. Cancer stem cells (CSCs) are identified in HNC tumour populations as agents of treatment resistance and a target for tumour control. This study examines dynamic responses in populations of a CSC phenotype in HNC cell lines following X-irradiation at therapeutic levels, and comparing between HPV statuses. Variations in CSC density between HPV groups showed no correlation with better clinical outcomes seen in the HPV positive status. CSC populations in HPV positive cell lines ranged from 1.9 to 4.8%, and 2.6 to 9.9% for HPV negative. Following 4 Gy X-irradiation however, HPV negative cell lines demonstrated more frequent and significantly greater escalation in CSC proportions, being 3-fold that of the HPV positive group at 72 hours post irradiation. CSC proportions of tumour populations are not fixed but subject to change in response to radiation at therapeutic dose levels. These findings imply a potential effect of aetiology on radio-responsiveness in CSCs, illustrating that clonogen treatment response may be more informative of therapy outcomes than inherent population density alone.