Research Dirk Verellen

Abstract

Positioning of Project Adaptive radiotherapy (ART) was introduced in the late 20th century to adjust treatment margins based on imaging. Since then, technological advances have enabled the development of new treatment plans, either offline or in real-time (online ART). Offline ART modifies treatment plans between sessions, while online ART adapts the plan in real-time, keeping the patient on the treatment couch. This approach enhances tumor coverage and spares organs at risk (OAR) by adapting to anatomical changes such as tumor shrinkage or weight loss. Online ART systems are based on magnetic resonance or high-resolution cone-beam CT (CBCT) imaging to guide the adaptive process. They necessitate specialized linear accelerators, limiting their wider application. Robust planning, initially developed for proton therapy, challenges the traditional Planning Target Volume model by integrating organ motion and setup uncertainties directly into the treatment plan. This method optimizes plans across multiple deformed CTs, offering a more accurate approach than fixed-margin models. Although routinely used in proton therapy to address setup uncertainties, its use in photon therapy is underexplored. This research aims to: 1. Develop offline ART on non-specialized linear accelerators. Currently, no standardized guidelines or workflows exist for offline ART using CBCT imaging. This project will establish these guidelines, including automatic triggers for adaptation, and create a practical workflow for medical physicists based on imaging, surface scanning, and dose tracking. 2. Explore robust planning in photon therapy. Despite its potential to reduce the need for adaptation, robust planning has not been fully investigated in photon therapy. This study will bridge that gap by developing new methods for photon therapy planning. Methodology 1. ART Workflow Development and QA - Create, automate, and validate the ART workflow on a non-specialized linear accelerator. - Identify clinical scenarios where ART is most beneficial, incorporating CBCT, deformable registration, and dose calculation. - Perform Failure Mode and Effects Analysis (FMEA) for the online ART workflow and establish QA guidelines for Medical Physics Experts (MPEs). - Implement the ART workflow in clinical practice. 2. Identifying Patient Populations - Conduct a retrospective dosimetric analysis of patient cohorts, recalculating treatment plans under various scenarios: non-adapted, offline adapted, online adapted, and robustly planned. 3. Defining Adaptation Triggers - Determine key parameters (dose-related) that should trigger adaptation by analyzing data from patient positioning, plan complexity, and anatomical changes tracked via CBCT.

Researcher(s)

• Promoter: Verellen Dirk

Research team(s)

• Center for Oncological Research (CORE)

Project type(s)

• Research Project

Abstract

In high-income countries, more than 50% of cancer patients receive one or several courses of radiotherapy. Despite recent technological advances, especially in precision, tumour targeting and dose distribution, normal tissue exposure to ionizing radiation can be responsible for irreversible and debilitating long term side effects. Moreover, the sensibility of these organs at risk can substantially limit the dose escalation necessary to treat certain radiation resistant tumours, limiting the therapeutic impact of radiotherapy. For these reasons, preclinical research in radiotherapy has been focusing on new treatments and technologies that can prevent, mitigate or reverse radiation-induced side effects, without impairing antitumor efficacy. In this framework, recent observations made with the use of ultra-high dose rate (UHDR) "FLASH" radiotherapy (FLASH-RT), have shown the possibility to spare normal tissues from radiation-induced side effects. Indeed, the exposure of healthy tissues to radiation doses delivered at UHDR (> 100 Gy/s) was shown to induce significantly less side effects compared to conventional dose rate radiotherapy currently used in the clinics, while retaining a similar killing effect on tumour cells. This observation has since been coined the "FLASH effect". This normal tissue preservation was observed on multiple invertebrate and vertebrate organisms, including murine preclinical models of cerebral, skin, lung, gut, muscle, bone and hematopoietic toxicities but also on minipig skin. Moreover, veterinary clinical trials on cats and dogs domestic pets have shown promising results. These results led to the development of – currently 4, clinical trials in Switzerland and in the USA. This new technology raises multiple challenges in different disciplines: physics, chemistry, biology and clinics. Despite the publication of a large number of studies showing the advantages of FLASH radiotherapy, the lack of knowledge concerning the biological mechanisms explaining the FLASH effects drastically slows down its clinical translation. Similarly, the development of UHDR beams (protons, photons, electrons or ions) raises technological challenges concerning the production of such beams, dose measurement (dosimetry), dose distribution, treatment planning or radiation protection. Fundamental and translational research on UHDR FLASH-RT is blooming globally, and Belgium has become a major actor in this field. To our knowledge, at least 7 research institutes in Belgium are currently involved in UHDR research, including 4 centres equipped with dedicated UHDR beams, and one centre currently involved in a clinical trial. The impressive number of challenges and research questions related to this research field necessitate the development of close collaborations, in each discipline respectively, but also multidisciplinary actions, in order to reach a clinical application quicker and more efficiently. Some of these collaborations already exist (in physics for example) which allowed to create an initial network of research centres, willing to actively participate in the development of a better coordinated research activity.

Researcher(s)

• Promoter: Verellen Dirk

Research team(s)

• Center for Oncological Research (CORE)

Project type(s)

• Research Project

Abstract

Ultra-short pulsed high dose rate radiation therapy, known as FLASH, has recently created a serious ripple effect in the radiation oncology community. Pre-clinical data has shown single-pulse doses above certain thresholds to decrease normal tissue radiotoxicity with a factor of nearly two, and as such increasing the differential response between healthy and tumour tissue. The effect had already been described by Hornsey et al. in 1966, but a recent series of publications by the Franco-Swiss team from the Institut Curie (France) and Centre Hospitalier Universitaire Vaudois (CHUV, Switzerland) has revived the interest prompting various reviews and a special edition of the Radiotherapy and Oncology Journal dedicated to the topic [Vol 139, 2019]. Radiation oncology has been improved over the last century in a series of distinct evolutions from increasing photon energy from kV to MV, introducing proton therapy, the implementation of CT and 3D conformal radiation therapy including increasingly more accurate dose calculation algorithms, intensity-modulated radiation therapy, biological conformal radiation therapy, stereotactic (body) radiation therapy, and image-guided radiation therapy; all of which caused stepwise improvements in treatment outcome and toxicity. FLASH, once confirmed by independent pre-clinical research & clinical trials, has on the contrary the potential to cause a genuine revolution in the field. In all of this, precise dose-measurement is of tremendous importance to monitor and evaluate radiation delivery, which is essential for performing quality assurance in radiation oncology by monitoring, benchmarking and comparing treatment outcomes. This, up to now, is not yet available for FLASH-delivered radiation therapy. At this moment, there are still many questions to be addressed before we will be able to apply the FLASH effect in clinical practice. The radiobiological mechanism underlying the FLASH effect is still unknown and requires substantial pre-clinical research, which is not the primary focus of this project proposal. In addition, the dosimetry of FLASH beams poses considerable challenges due to the ultra-high dose rates (UHDR) per pulse. Modern radiation therapy operates at typical dose rates of 1 to 25 Gy per minute, whereas FLASH operates between 40 and 1000 Gy per second. Moreover, preliminary results indicate that the dose per pulse is more relevant than the average dose per (mili)second to induce this FLASH effect. Secondary standard ionization chambers, typically used for absolute dosimetry in a clinical setting, suffer from significant limitations and require large correction factors for charge collection inefficiencies in FLASH regimes. It comes to no surprise that dosimetric characteristics of these previous reports on the FLASH effect were based on alanine EPR and radiochromic dose assessments, both off-line solutions and presenting considerable uncertainties. The current project aims roexplore and identify the dosimetric challenges related to FLASH and contribute to standardized codes of practice in absolute dosimetry and dose reporting. With none of the available dosimetry techniques being developed to be operational within the extreme exposure conditions as faced with UHDR radiotherapy, it is the goal of this PhD project to - Challenge the existing dosimetry systems and further develop/improve them to have accurate and reliable dosimetry techniques for FLASH radiotherapy - Establish a UHDR-dedicated dosimetry protocol for both reference and online dosimetry

Researcher(s)

• Promoter: Verellen Dirk

Research team(s)

• Center for Oncological Research (CORE)

Project type(s)

• Research Project