Imaging and radiotherapy physics – Proposal for PhD 

degree

Supervisors: Assoc. Professor Kathrine Røe Redalen and PhD candidates Franziska Knuth
and Kajsa Fridström. Contact: kathrine.redalen@ntnu.no, office D4-164

There has been a huge expansion in the use of medical imaging in cancer diagnostics,
and treatment evaluation, where particularly magnetic resonance imaging (MRI) is being
increasingly used due to the method’s ability to provide high-resolution images without
the use of ionizing radiation. Anatomical MRI is important in the diagnostic work-up in
many cancer types, where it allows visualisation of zonal anatomy and detailed
evaluation of local disease extent, regional metastasis and general anatomy. Further,
functional MRI comprises sequences reflecting functional / biological tissue properties,
such as tissue structure and cell density (diffusion-weighted MRI), metabolism (MR
spectroscopy) and various features of tumour vascularity (dynamic contrast-enhanced
(DCE) MRI and dynamic susceptibility contrast (DSC) MRI). These techniques have
shown potential to also capture important features of the tumour microenvironment
relevant for radiotherapy efficacy. We are investigating how these techniques may be
optimally utilised in order to provide pre-treatment measures of whole-tumour
radiosensitivity that may be aid planning of individualised radiotherapy strategies. In
addition, we are investigation how these techniques may be used both for early
monitoring and end-of- therapy evaluation of radiotherapy outcome.

Figure 1: Functional MR images of rectal cancer acquired on a 1.5 T MR scanner. (A) T2-weighted morphologic
image, (B) diffusion-weighted (DW) image with b-value of 500 s/mm 2, (C) Parametric bmax map from DW image
overlaid the T2-weighted image, (D) multi-echo T2*-weighted image, (E) T1-weighted image before injection of
contrast agent, (F) T1-weighted image after injection of contrast agent, (G) Parametric blood perfusion map from
dynamic contrast-enhanced image overlaid the T2-weighted image, (H) Spectra from in vivo MR spectroscopy.
In a study entitled “OxyTarget – Functional MRI of hypoxia-mediated rectal cancer
aggressiveness” functional MR data from 180 patients are collected to investigate
whether functional MR images (or a combination of several images – multiparametric
MRI) can identify the radiosensitivity of tumours. The study also includes collection of
histology/immunohistochemistry of surgical specimens, clinicopathologic outcome
parameters, radiotherapy plans and patient survival which allows broad cross-
investigations as well as interpretation of the biology behind the MR images. Example
functional MR images from a patient in this study are shown in Figure 1.

Below are presented some proposals for project- and master theses. Candidates may
also take contact for discussion of alternative proposals.

Proposal 1: DW-MRI and DCE MRI for tumour perfusion imaging

Estimates on tumour blood perfusion is commonly acquired by voxel-wise kinetic
modelling of contrast-enhancement curves from T1-weighted DCE MRI, which requires
injection of a contrast agent. We have in a small pilot study recently shown that
alternative estimates on tumour blood perfusion may be acquired through so-called
intravoxel incoherent modelling (IVIM) of diffusion-weighted (DW) MRI data (Bakke et
al, 2017), which does not require injection of a contrast agent, and which were shown
to both predict radiotherapy response and patient survival.

Figure 2: Map of kep, a perfusion marker estimated from DCE MRI. Made by
project student in 2017, Tina S. Evensen. The image shows that perfusion is
heterogeneous in the tumour.

In this proposal, the candidate will use Matlab (or a similar tool) to estimate
blood perfusion parameters from both DW MRI and DCE MRI and thereafter perform
immunohistochemical analysis of tumour perfusion in tissue (the surgical specimen) in
order to explain the MRI findings. We have surgical specimens stained with the
endothelial marker CD34 available for this project.

Proposal 2: T2*-weighted MR imaging for hypoxia detection

T2* relaxation refers to decay of transverse magnetisation caused by spin-spin
relaxation or magnetic field inhomogeneity. T2*-weighted MR images may be acquired
by gradient echo MRI with multiple echo-times (TE) or by DSC MRI. The inverse T2* is
R2* and is in
theory a measure of the oxygen saturation in the tissue. Oxygen (or oxygen deficiency;
hypoxia) is an important determinant for radiotherapy response and outcome in patients
with solid cancer.

Figure 3: An R2* peak tumour map from one patient with rectal cancer. This figure
was part of our publication in Journal of Magnetic Resonance Imaging (by E. Grøvik et
al, 2017;46(1):194-206). In this study, we found that the R2* peak could predict
whether the patient had benign or malignant lymph nodes, which is an important
prognostic factor for patient outcome.

In this proposal, the candidate is expected to use Matlab (or a similar tool) to
estimate R2* tumour maps from both multi-TE MRI and DSC MRI data acquired both
before and after chemoradiotherapy. Thereafter, the candidate will evaluate the
potential of these measures to assess tumour radiosensitivity and their correlation to
tumour hypoxia by comparison with immunohistochemical analysis of tumour hypoxia in
tissue. We specimens stained with the hypoxia-inducible factor 1 alpha (HIF-1 alpha)
and carbonic anhydrase (CAIX). Depending on the candidate’s competences and
interests the generated MR data may also be further used to simulate various
approaches of delivering radiotherapy based on the R2* tumour maps, for instance
through dose- painting or radiation boosting techniques.

Proposal 3: MRI-based texture analysis

It is acknowledged that solid tumours are heterogeneous and that mean tumour values
of estimated MR parameters do not reflect the heterogeneous information contained in
the tumours. One way to capture tumour heterogeneity is through texture analysis. The
term texture refers to specific properties of the internal structure of image regions, for
example rough versus smooth or oriented versus randomly dispersed (among others).
In medical image analysis, texture-based methods are very useful to classify tissue
types, typically by first extracting texture features and then feeding these features into a
classifier. However, investigations on the potential of texture-based methods of imaging
data in the context of radiotherapy is poorly investigated, and particularly the potential
value of texture-based analysis of functional imaging data in the context of
radiotherapy. In this proposal, the candidate will use various functional MR images from
the OxyTarget data set and explore how texture analysis may provide added value in
detection of tumour radiosensitivity and radiotherapy outcome compared to mean
parameter values. The candidate will start with lower-order histogram features (such as
kurtosis, entropy and skewness) and may proceed to more advanced texture analysis
based on for instance local binary patterns (BNP), gray-level co-occurrence matrix
(GLCM), filtering approaches (e.g. Gabor filters) and various classifiers and multi-
channel visualisation methods.

Proposal 4: Automated image segmentation for radiotherapy

Due to rapid advances in radiation therapy, especially image-guidance and treatment
adaptation, a fast and accurate segmentation of medical images is a very important part
of the treatment. Manual delineation of target volumes and organs at risk is still the
standard routine, even though it is time-consuming and prone to intra- and
interobserver variations. Automated segmentation methods seek to exploit machine-
learning algorithms to reduce delineation workload and unify the organ boundary
definition. In radiotherapy, CT is currently the most common imaging modality,
however, there is a rapid shift to more frequent use of MRI, which provides superior soft
tissue contrast. This is particularly relevant also due to the introduction of the combined
MRI-linear accelerator (MRI-Linac). The improved soft tissue contrast provided by MRI
enables better identification of various tissue structures, which may enable improved
performance of segmentation algorithms.

Figure 4: Rectal tumour delineated on anatomical T2-weighted MR image. The

illustration was made by project student in 2017, Tina S. Evensen.

In this project, we aim to explore different MRI-based segmentation methods

based on machine-learning and by combining anatomical with functional MR images to
see what approaches performs better. We will compare the results to tumor delineations
already made by two independent radiologists.

Proposal 5: MR-based radiotherapy dose-painting: modelling studies

Radiotherapy dose-painting strategies relies on the use of medical images that
reflects radiobiological tumour properties. These images are used to prescribe an
inhomogeneous tumour dose in order to increase the local control compared to
conventional radiotherapy with a homogenous tumour dose. Two dose-painting
approaches exist: dose-painting by contours (DPBC) and dose-painting by numbers
(DPBN). In DPBC the most aggressive sub-volume within the tumour is delineated
and subsequently dose-escalated to a homogenous dose, while in DPBN each
tumour voxel is given a dose according to the voxel value in the corresponding
biological image.
 Figure 5: Left: example standard
radiotherapy plan, right; illustration of the
concept of dose- painting by increasing the
dose > 2 Gy in some voxels and decreasing
the dose > 2 Gy in other voxels. This
strategy relies on functional imaging of
radiobiological properties. In our projects we
investigate whether functional MRI is useful
for this purpose.

In rectal cancer, DPBC may be an alternative in two different scenarios: 1) to

increase the probability of obtaining a better tumour response to preoperative
chemoradiotherapy in aggressive, poor-responding tumours in order to enable
subsequent surgery, and 2) to increase the probability of obtaining a complete
response to chemoradiotherapy and thereby omit the surgery to achieve an
improved quality of life with sparing of normal tissue structures (no colostomy).
This project includes modelling studies where you will estimate the tumour
control probability (TCP) based on utilising MR-data to plan the DPBC for one or
both of the situations 1 and 2 above. Standard TCP models assume uniform tumour
cell density across the tumour. Our aim is to develop an individualised TCP model
by including functional MR information. MR-data that can be used is apparent
diffusion coefficient (ADC) maps from DWI MRI to extract tumour cell density
distributions and R2* maps from T2*-weighted MRI to extract hypoxia distributions
across the tumour. The number of cells
/ initial amount of hypoxia within imaging voxel can be explored by different approaches
by using the ADX maps; linear, binary and sigmoid relations. The TCP models will be
based on linear-quadratic (LQ) cell survival curves with appropriate alpha/beta values.
The aim is to develop a method that can be evaluated prospectively in clinical studies.

Proposal 6: Quantitative tumour histology analysis

The purpose of this project is to describe the intratumoural network through image
analysis of histological sections. This information is useful both to describe the
aggressiveness of a tumour and to understand how therapies have or will work. The
tumour vasculature is characterized by complexity, irregularities and poorly regulated
growth. Fractal analysis has been used to establish that tumour vasculature has a
different network architecture from that of the normal arteriovenous system or the
capillary network. The vasculature is responsible for the transportation of oxygen to
tumour cells. Hypoxia (oxygen deficiency) is a challenge in treatment of cancer, both
through its indirect biological effects, such as on cell cycle progression, but also through
direct chemical effects. In particular, the oxygen effect reduces the effectiveness of
radiation
therapy. Furthermore, the network morphology relates to many other parameters as
well, such as the angiogenic and the metastatic capability of the cancer. This raises the
possibility of using image analysis, and fractal analysis in particular, to quantify different
aspects of the network morphology.
In this project, tissue sections stained with the endothelial marker CD34 as well
as with the hypoxia markers HIF-1 alpha and CAIX will be available. The impact of the
immune system and its response may also be included through stains with the markers
CD3 and CD8. You will quantitatively assess parameters mainly through fractal analysis
and syntactic structure analysis. Some parameters, such as the number of vessels, the
size of the vessels, the total vascular area, and cumulative histograms of distances to
the nearest vessel, can be obtained directly from the images. The results will be
compared with the patients’ clinical outcome data in order to also identify whether some
of the parameters are associated to diagnosis, treatment outcome or survival.

Figure 6: CD34 images depicting the endothelium (blood

vessels) of two different tumours. We can see different vessel
size, area coverages and micro vessel densities (MVD).

Figure 7: Illustration of a potential methodology to quantify vascular

features. A) Individual vessel characterisation: endothelial area (red),
luminal area (blue), vessel/vascular area (red + blue), vessel perimeter
(stapled green), width (diameter of imposed yellow circle), skeleton (black
line), branching points (yellow markers), convex hull (interior of stapled
black line, i.e. vessel + gray). B) Contextual vasculature characterisation:
centre of vessel (yellow markers), neighbouring vessels according to the
Gabriel’s Graph criterion (blue lines), i.e. all connections between vessels
such that no other vessel centres are found within the circle spanned by the
connecting line (see blue circle).

Both figures are from Mikalsen et al., 2013.