PhD Projects

Random subspace decision forest support for markerless stereotatic body radiotherapy.

PhD student: Camille Raets, Msc
Promotors: Prof. Dr. Mark De Ridder & Prof. dr. Kurt Barbé

Project Summary

In the field of dosimetry, clinicians define the correct dose of radiotherapy to treat cancer of their patients. In this research, we examine and design the potential of random forest for the dose calculation. In a first stage we work at the optimization of the random forest to predict the regression grade of rectal cancer after preoperative chemotherapy where the radiomics of CT-scan are used together with some blood values and questionary data. We want to achieve a random forest model where both training and validation data are predicted well. This way we can conclude that the data can be generalized to the real world, where external patients might be added. The research has some challenging problems that needs to be solved in order to obtain the most optimal random subspace decision forest model. In order to construct the random forest model, least discriminant analysis is used which was developed in 1936 and has since then be modified and optimized by many different researchers. We also investigate the possibility of using a penalized least discriminant analysisin order to be able to classify both patients that resample the training data well as well as the patients that are more special and/or show deviations from a standard patient pathology. 

About Camille Raets

Camille Raets was born on July 25, 1995 in Antwerp, Belgium. She graduated from the Sint-Rita College in Kontich in the year 2013 after which she went to went to study at the University of Antwerp (UA). There she started the Bachelor in Mathematics where her interest of biostatistics was triggered and became larger within the years. For this reason she choose to continue her university studies with a Master of Financial and Applies Mathematics after graduating in the Bachelor. The master was a collaboration with the University of Antwerp and the Free University of Brussels (VUB). In 2019, Camille graduated at the university cum laude. Her Master thesis entitled “Random Forests” spiked het interest to start a career in the research. In October 2019, she started working at the VUB in the research group Biostatistics and Medical Informatics (BISI). In this research group she got the opportunity to take the first steps in the academic world as well as the first steps in teaching as a PhD student. Together with the University Hospital of Brussels (UZB) she continued to for on the Random Forest algorithm in order to predict the response of cancer after preoperative chemotherapy. To this day she is still active as a PhD student at the VUB/UZB.


Societal cost of radiation-induced morbidities in cancer survivors (SCORA)

PhD student: Eva Kimpe
Promotors: Prof. Dr. Mark De Ridder & Prof. DR. Koen Putman

Project Summary

Radiotherapy is used as a part of cancer treatment for many patients. Research demonstrated the benefit of radiotherapy in increasing disease-free survival, and prolonging the life of cancer patients. However, despite improved radiotherapeutic strategies, irradiation is not limited to tumorous tissue. Damage to healthy tissue -for example to the heart and lungs- relates to radiation-induced inflammation, and possibly results in comorbidities such as cardiovascular diseases and secondary non-breast cancers or contralateral breast cancers. Therefore, on the long term, radiotherapy might contribute to a rise in non-cancer-related death rates in cancer survivors. Furthermore, treatment of morbidities is accompanied by an increased use of healthcare resources and additional productivity loss in cancer survivors. The use of healthcare resources and productivity loss reflect on direct and indirect healthcare costs. Hence, in order to estimate the societal cost of cancer, the cost of the primary cancer treatment should be supplemented with costs related to radiation-induced comorbidities. SCORA (Societal Cost of Radiation-induced morbidities in cancer survivors) delivers socio-economic evaluations where the societal perspective is adopted. Taking long-term effects into account, SCORA provides a methodology to evaluate strategies which are contributing to a reduction in the burden of disease in cancer survivors.

About

Eva Kimpe was born on November 18th, 1989. She obtained her bachelor’s degree in ‘Nutrition & Dietetics’ in 2011. After combining her full time job as a clinical dietician with her master studies, she graduated as MSc in ‘Health Care Management & Policy’ in 2018. Eva has worked at the Vrije Universiteit Brussel since 2019. In January 2020, she joined the ‘Interuniversity Centre for Health Economics Research’. Currently, she works as doctoral researcher and teaching assistant at the Faculty of Medicine & Pharmacy. Eva is involved in performing socio-economic evaluations within the SRP. Hence, she is supervised by Prof. Koen Putman & Prof. Mark De Ridder. Her research focusses on the societal burden of radiation-induced long-term effects in cancer survivors.


Radiomics in cancer radiotherapy: unraveling the biology to optimize treatment

PhD student: Amir Rifi
Promotors: PROF. DR. MARK DE RIDDER & PROF. DR. KURT BARBÉ

Project Summary

Non-invasive medical imaging can be used to sample entire tumors non-invasively and on demand. These images may be able to capture the biological variation within tumors, which molecular characterization of a random sample of tumor might fail to represent. Here, radiomics, defined as the high-throughput extraction of quantitative data from medical images with the subsequent analysis of it, can be used to provide valuable information for personalized cancer therapy. In contrast to the other omics strategies, it does not require any additional intervention on the patients as the required input for radiomics (i.e. medical images) part is of the standard diagnostic procedure, which facilitates its application in the clinic. However, the high dimensionality of radiomics renders a huge data set with many quantitative variables extracted from medical images. Although some machine learning approaches can cope with high dimensional data, their predictions are a black box system. In this project, we will break in into the black box. By dedicated animal trials, we will track the biological interpretation of radiomics variables.

About Amir Rifi

Amir L. Rifi studied the biomedical research at the Vrije Universiteit Brussel and graduated magna cum laude in 2021. His master thesis titled “Derivation of an adverse outcome pathway network for in vitro hepatotoxicity predictive testing” was performed in the In Vitro Toxicology and Dermato-Cosmetology (IVTD) department of the Vrije Universiteit Brussel.

In that same year, he enrolled as a PhD candidate in the lab of Translational Oncology, Radiation and Physics (TROP) under the supervision of Prof. Dr. Mark De Ridder and Prof. Dr. Kurt Barbé, with focus on the clinical translation of radiomics to support personalized cancer therapy.



Free radicals in radiosensitization

PhD student: Febe Geirnaert
PROMOTORS: PROF. DR. MARK DE RIDDER & DR. INES DUFAIT

Project Summary

In most solid tumors, hypoxia occurs due to several factors, including the rapid growth rate of cancer cells and the highly disorganized vasculature. The amount of oxygen present influences a tumor’s susceptibility to radiation damage with hypoxia being the main cause of radioresistance in solid tumors. Decades of research into this topic led to limited clinical success. Administration of free radicals improved radiosensitivity drastically in experimental settings, however this could not be administered systemically to cancer patients due to its high toxicity and severe side effects. Local administration of free radicals to the patient’s tumor is extremely painful and therefore, not an appropriate alternative. As such, the research direction of translating free radicals to the clinic has been largely discarded. Previously in our lab, we developed a method to endogenously produce free radical nitric oxide (NO) at the tumor site as an alternative to exogeneous administration, which resulted in significant radiosensitizing effects without inducing severe toxicities. Another potent radiosensitizer in vitro is hydrogen peroxide (H2O2). Recent advances have been made to enable the use H2O2 in clinical settings for enhancing radiotherapy response without causing critical side-effects. Nonetheless, the underlying mechanisms remain to be determined.

We aim to compare the radiomodulating effects of exogeneous administration of free radicals against endogenous production of free radicals at the tumor site. Secondly, we aim to unravel the underlying mechanisms of NO and H2O2 on an experimental level. Hereby, we aim to contribute to a better understanding and optimized use of free radicals in a clinical setting.

About Febe Geirnaert

Febe Geirnaert was born on September 9th 1998. Her interest in radiotherapy was sparked during a summer internship at the International Atomic Energy Agency in Vienna before starting her academic career at the Vrije Universiteit Brussel in 2016. During her masters she performed several research internships. The first internship was performed at the laboratory of Skin Immunology and Immune Tolerance (SKIN, Vrije Universiteit Brussel) on the topic of atopic dermatitis, followed by a virtual internship on the topic of autophagy as a strategy to overcome therapy resistance in lung cancer at the Laboratory for Medical and Molecular Oncology (LMMO, Vrije Universiteit Brussel). Her master thesis at the Reproduction and Genetics Research group (REGE, Vrije Universiteit Brussel) focused on the topic of chromosomal aberrations in human embryonic stem cells and included an optimization of transfection-based CRISPR-Cas9 on these cells. She finished her master’s in Biomedical Sciences in 2021, magna cum laude. In October 2021, Febe started a PhD in the lab of Translational Oncology, Radiation and Physics (TROP) under the supervision of Prof. Dr. De Ridder and Dr. Inès Dufait. The research focuses on the use of endogenous and exogenous production of free radicals as radiosensitizers. Simultaneously, the underlying mechanisms of KORTUC, a novel radiosensitizer with H2O2 as active ingredient, is going to be investigated on an experiment level.

Value-based radiotherapy

PhD student: Sara-Lise Busschaert
PROMOTORS: PROF. DR. MARK DE RIDDER & PROF. DR. KOEN PUTMAN

Project Summary

Cancer is a major cause of mortality and morbidity worldwide and is set to become the leading cause of death among Europeans in 2035 (European Commission, 2021). Expenditure on cancer care has risen substantially and is expected to rise even further, and the high financial burden cannot be solely attributed to the rising number of cancer patients, because the expenditure growth for cancer therapies exceeds the increase in cancer incidence (Hofmarcher, Lindgren, Wilking, & Jönsson, 2020). Although rising costs per cancer patient can partly be justified by the fast pace of innovation in oncology which has helped more patients profit from superior treatments, a source of cost escalation also lies in the overuse and misuse of cancer treatments (Grilli & Chiesa, 2018; Nass, Patlak, & Balogh, 2013; Schleicher, Bach, Matsoukas & Korenstein, 2018), a problem that can at least partially be traced back to misaligned reimbursement schemes that often give physicians an incentive to provide more treatments and to choose the costliest options (Mitchell et al., 2019). Escalating costs, notably the costs of oncologic drugs, have brought the financial sustainability of healthcare systems into jeopardy and threaten patient access to high-quality cancer care.

Radiotherapy is a core component of the comprehensive management of cancer, and approximately one in two cancer patients has an indication for radiotherapy. This cornerstone of cancer care is, however, underfunded and underutilised. Closing the worldwide gap to radiotherapy by 2035 would allow to save one million lives annually, prevent the pain and suffering of numerous other cancer patients and would stimulate economic growth by curtailing productivity losses (Atun et al., 2015). Furthermore, although radiotherapy is frequently misperceived as expensive, it represents only about 7% of all cancer-related costs in European countries (Lievens et al., 2020). Nevertheless, increasing pressure on healthcare budgets requires that costs and benefits are balanced in investment decisions. New technologies, treatment schedules and techniques are continuously introduced into the ever-evolving field of radiation oncology (Lievens, 2017). These innovations hold the promise of saving more lives with fewer side effects, but never come without a price tag and it is therefore indispensable that investments are based on solid evidence. There is, however, a dearth of high-quality economic evidence for radiotherapy interventions and previous studies do not capture the actual costs of delivering these treatments (Lievens, Borras, & Grau, 2015).

Value-based healthcare (VBHC), a framework to improve patient outcomes while simultaneously keeping the costs of care under control, offers a promising approach to address the leading challenges in oncology. In this doctoral project, VHBC will be implemented in radiotherapy departments. The central goal of VBHC is to maximize patient value, which is defined as the patient-relevant outcomes achieved per unit cost expended over the entire cycle of care. A successful implementation of VBHC requires an accurate and systematic measurement of outcomes and costs at the patient level. As has been recommended by the International Consortium for Health Outcomes Measurement, we will use patient reported outcomes. With respect to costs, time-driven activity-based costing (TD-ABC) has been put forward as the gold standard (Kaplan & Porter, 2011). Essentially, TD-ABC can be described as a micro-costing costing methodology that calculates the costs of resources consumed to treat a patient’s medical condition over a complete cycle of care (Keel et al., 2017). By providing detailed and accurate insights into costs incurred at the patient level TD-ABC unveils a surfeit of value-creating opportunities. TD-ABC can, for example, be used to optimize resource capacity utilization, streamline care processes, decrease redundancy or variability in care delivery and can assist providers in deciding on future investments (Kaplan & Porter, 2011).

This doctoral project aims to fill the aforementioned research gap in the field of radiation oncology by using TD-ABC to precisely determine the costs of radiotherapeutic treatments. In addition, this study will extend previous research in this area by examining the financial consequences of future investments in the radiotherapy department. The research will be first performed at the radiotherapy department of the University Hospital Brussels (UZ Brussel). The department is internationally recognized as a leader in the field of radiation oncology and its various ongoing research programs as well as national and international collaborations ensure that it remains at the forefront of scientific research and innovation. In a following step international partners will be included, which will allow us to compare different care facilities.

By implementing VBHC in radiotherapy departments, this research can make headway in overcoming the key challenges in radiation oncology. The TD-ABC analysis of radiotherapeutic treatments will give insight into the real costs of radiation therapy, information which is essential to update present outdated reimbursement systems and to support policymaking. The international comparison will enrich our understanding of these costs and potential differences between care institutions. Moreover, our analysis of the financial consequences of investments can assist organisations in pinpointing investment priorities with the result that every cancer patient can be granted access to state-of-the-art radiation therapy such as Stereotactic Body Radiotherapy (SBRT). In this way, this PhD project will contribute to the Strategic Research Programme “Societal Benefit of Markerless Stereotactic Body Radiotherapy: a Statistical Support based on Quantitative Imaging”, an interdisciplinary research programme that aims to improve the efficiency of SBRT and to increase patient access to this advanced type of radiation therapy.

About Sara-Lise Busschaert

Sara-Lise Busschaert obtained a master’s degree in Experimental Psychology and an additional master’s degree in General Economics from the University of Ghent. After graduation, she worked as a research executive at Ipsos, a leading global market and opinion research company, and co-authored a book with Professor Johan Albrecht. She joined I-CHER in June 2021 to work on the Strategic Research Programme “Societal Benefit of Markerless Stereotactic Body Radiotherapy: a Statistical Support based on Quantitative Imaging”. For her PhD, she uses time-driven activity-based costing to accurately assess the costs of radiotherapy treatments and to examine the financial consequences of future investments in radiotherapy departments.

Targeting the redox homeostasis: a promising strategy to improve the radiosensitivity of colorectal cancer.

PhD student: Lisa Kerhove
PromotorS: Prof. Dr. Mark De RiddER & DR. INES DUFAIT

Project Summary

Colorectal cancer (CRC) accounts for approximately 10% of cancer-related mortality in the western world. Radiotherapy (RT) is a cornerstone treatment of CRC, unfortunately a subset of patients does not sufficiently respond. Conventional (Conv) RT, as used in the clinic, mainly targets DNA via the production of reactive oxygen species (ROS). FLASH-RT, a novel RT modality, also utilizes ROS, however the precise working mechanisms are not elucidated yet. Cancer cells heavily rely on the antioxidant system to sustain the delicate balance between ROS production and scavenging. Hence, targeting the redox homeostasis is an attractive strategy to tackle radioresistance. In this project, we aim to enhance the overall response in CRC by combining cytotoxic and radiosensitizing strategies in both Conv and FLASH-RT by exploring a novel clinically relevant combinatorial treatment regimen. Since epigenetic processes are considered valuable therapeutic targets in numerous anticancer investigations and the treatment of cancer cells with several HDAC inhibitors (HDACi) has been linked with the generation of ROS. The first drug used in this project will be an HDACi. Furthermore, an xCT inhibitor will be added to the novel regimen, since it inhibits glutathione (GSH), which is considered the most important antioxidant. Furthermore, HDACi have the potential to induce ROS via inhibition of the antioxidant thioredoxin, which is upregulated by the cells as a response to reduced GSH levels. Both inhibitors are clinically available drugs and possess intrinsic cytotoxic properties. In summary, we hypothesize that by combining a HDACi and a xCT inhibitor, the ROS homeostasis in cancer cells will be disrupted sufficiently to obtain lethal ROS levels upon irradiation, with respect to both conv and FLASH-RT. 

About Lisa Kerkhove

Lisa Kerkhove was born on March 13th 1997. Her career at the VUB started in 2015, when she started studying Biomedical Sciences. During her master she performed two different research internships. The first one at the laboratory of Biology of the Testis (BITE, Vrije Universiteit Brussel), on the topic of Klinefelter Syndrome and the second one at the laboratory of Translational Oncology, Radiation and Physics (TROP, Vrije Universiteit Brussel), on the topic of repurposing biguanides as radiosensitizers. She finished her master in Biomedical Sciences in 2020, magna cum laude, at the Vrije Universiteit Brussel. She performed her master thesis at the Center for Medical Genetics (UZ Brussel) on the topic of cortical malformations. The subject of her master thesis was presented, on the basis of a poster, on the Belgium Society in Human Genetics (BSHG) Conference 2020. 

In October 2020, she started a PhD in the lab of Translational Oncology, Radiation and Physics (TROP) under the supervision of Prof. Dr. De Ridder and Dr. Inès Dufait. The research is focussed on the radiosensitization of colorectal cancer via targeting of the redox homeostasis.

Lisa Kerkhove was born on March 13th 1997. Her career at the VUB started in 2015, when she started studying Biomedical Sciences. During her master she performed two different research internships. The first one at the laboratory of Biology of the Testis (BITE, Vrije Universiteit Brussel), on the topic of Klinefelter Syndrome and the second one at the laboratory of Translational Oncology, Radiation and Physics (TROP, Vrije Universiteit Brussel), on the topic of repurposing biguanides as radiosensitizers. She finished her master in Biomedical Sciences in 2020, magna cum laude, at the Vrije Universiteit Brussel. She performed her master thesis at the Center for Medical Genetics (UZ Brussel) on the topic of cortical malformations. The subject of her master thesis was presented, on the basis of a poster, on the Belgium Society in Human Genetics (BSHG) Conference 2020. 

In October 2020, she started a PhD in the lab of Translational Oncology, Radiation and Physics (TROP) under the supervision of Prof. Dr. De Ridder and Dr. Inès Dufait. The research is focussed on the radiosensitization of colorectal cancer via targeting of the redox homeostasis.