Development of a novel fibre optic beam profile and dose monitor for very high energy electron radiotherapy at ultrahigh dose rates.

Objective. Very high energy electrons (VHEE) in the range of 50-250 MeV are of interest for treating deep-seated tumours with FLASH radiotherapy (RT). This approach offers favourable dose distributions and the ability to deliver ultra-high dose rates (UHDR) efficiently. To make VHEE-based FLASH treatment clinically viable, a novel beam monitoring technology is explored as an alternative to transmission ionisation monitor chambers, which have non-linear responses at UHDR. This study introduces the fibre optic flash monitor (FOFM), which consists of an array of silica optical fibre-based Cherenkov sensors with a photodetector for signal readout.Approach. Experiments were conducted at the CLEAR facility at CERN using 200 MeV and 160 MeV electrons to assess the FOFM's response linearity to UHDR (characterised with radiochromic films) required for FLASH radiotherapy. Beam profile measurements made on the FOFM were compared to those using radiochromic film and scintillating yttrium aluminium garnet (YAG) screens.Main results. A range of photodetectors were evaluated, with a complementary-metal-oxide-semiconductor (CMOS) camera being the most suitable choice for this monitor. The FOFM demonstrated excellent response linearity from 0.9 Gy/pulse to 57.4 Gy/pulse (R2= 0.999). Furthermore, it did not exhibit any significant dependence on the energy between 160 MeV and 200 MeV nor the instantaneous dose rate. Gaussian fits applied to vertical beam profile measurements indicated that the FOFM could accurately provide pulse-by-pulse beam size measurements, agreeing within the error range of radiochromic film and YAG screen measurements, respectively.Significance. The FOFM proves to be a promising solution for real-time beam profile and dose monitoring for UHDR VHEE beams, with a linear response in the UHDR regime. Additionally it can perform pulse-by-pulse beam size measurements, a feature currently lacking in transmission ionisation monitor chambers, which may become crucial for implementing FLASH radiotherapy and its associated quality assurance requirements.

Mini-GRID radiotherapy on the CLEAR very-high-energy electron beamline: collimator optimization, film dosimetry, and Monte Carlo simulations.

Objective.Spatially-fractionated radiotherapy (SFRT) delivered with a very-high-energy electron (VHEE) beam and a mini-GRID collimator was investigated to achieve synergistic normal tissue-sparing through spatial fractionation and the FLASH effect.Approach.A tungsten mini-GRID collimator for delivering VHEE SFRT was optimized using Monte Carlo (MC) simulations. Peak-to-valley dose ratios (PVDRs), depths of convergence (DoCs, PVDR ≤ 1.1), and peak and valley doses in a water phantom from a simulated 150 MeV VHEE source were evaluated. Collimator thickness, hole width, and septal width were varied to determine an optimal value for each parameter that maximized PVDR and DoC. The optimized collimator (20 mm thick rectangular prism with a 15 mm × 15 mm face with a 7 × 7 array of 0.5 mm holes separated by 1.1 mm septa) was 3D-printed and used for VHEE irradiations with the CERN linear electron accelerator for research beam. Open beam and mini-GRID irradiations were performed at 140, 175, and 200 MeV and dose was recorded with radiochromic films in a water tank. PVDR, central-axis (CAX) and valley dose rates and DoCs were evaluated.Main results.Films demonstrated peak and valley dose rates on the order of 100 s of MGy/s, which could promote FLASH-sparing effects. Across the three energies, PVDRs of 2-4 at 13 mm depth and DoCs between 39 and 47 mm were achieved. Open beam and mini-GRID MC simulations were run to replicate the film results at 200 MeV. For the mini-GRID irradiations, the film CAX dose was on average 15% higher, the film valley dose was 28% higher, and the film PVDR was 15% lower than calculated by MC.Significance.Ultimately, the PVDRs and DoCs were determined to be too low for a significant potential for SFRT tissue-sparing effects to be present, particularly at depth. Further beam delivery optimization and investigations of new means of spatial fractionation are warranted.

Understanding the challenges of delivering radiotherapy in low- and middle-income countries in Africa.

BACKGROUND: Access to high quality radiotherapy (RT) continues to be a major issue across Africa with Africa having just 34% of its optimal capacity. METHODS: We co-developed a survey with clinical, academic and policy stakeholders designed to provide a structured assessment of the barriers and enablers to RT capacity building in Africa. The survey covered nine key themes including funding, procurement, education and training. The survey was sent to RT professionals in 28 countries and the responses underwent qualitative and quantitative assessment. RESULTS: We received completed questionnaires from 26 African countries. Funding was considered a major issue, specifically the lack of a ring fenced funds from the Ministry of Health for radiotherapy and the consistency of revenue streams which relates to a lack of prioritisation for RT. In addition to a significant shortfall in RT workforce disciplines, there is a general lack of formal education and training programmes. 13/26 countries reported having some IAEA support for RT for education and training. Solutions identified to improve access to RT include a) increasing public awareness of its essential role in cancer treatment; b) encouraging governments to simplify procurement and provide adequate funding for equipment; c) increasing training opportunities for all radiotherapy disciplines and d) incentivizing staff retention. CONCLUSION: This survey provides unique information on challenges to delivering and expanding radiotherapy services in Africa. The reasons are heterogonous across countries but one key recommendation would be for national Cancer Control plans to directly consider radiotherapy and specifically issues of funding, equipment procurement, servicing and training. POLICY SUMMARY: The study demonstrates the importance of mixed methods research to inform policy and overcome barriers to radiotherapy capacity and capability in LMICs.

Collaboration: The Force That Makes the Impossible Possible.

Over the last three decades, the landscape of cancer treatment with radiotherapy has never stopped improving. ENLIGHT - the European Network for Light Ion Hadron Therapy - has been an active participant in the huge changes that have taken place, in particular in Europe. At the end of the 90s when I arrived at CERN, it appeared clear that an improvement in communication, sharing and exchange, while keeping a common goal, was needed to bring together international experts from accelerator physics, imaging, medical physics, radiobiology and clinical medicine. ENLIGHT network was most aptly launched at CERN, since CERN is renowned as a place for global collaboration. The network has come a long way since the kick-off meeting at CERN in 2002 when only about 70 specialists from different disciplines took part and continues to grow and flourish with now over 1000 participants, accounting for over 100 institutions, from around 40 countries around the globe.

Clinical use and future requirements of relative biological effectiveness: Survey among all European proton therapy centres.

BACKGROUND AND PURPOSE: The relative biological effectiveness (RBE) varies along the treatment field. However, in clinical practice, a constant RBE of 1.1 is assumed, which can result in undesirable side effects. This study provides an accurate overview of current clinical practice for considering proton RBE in Europe. MATERIALS AND METHODS: A survey was devised and sent to all proton therapy centres in Europe that treat patients. The online questionnaire consisted of 39 questions addressing various aspects of RBE consideration in clinical practice, including treatment planning, patient follow-up and future demands. RESULTS: All 25 proton therapy centres responded. All centres prescribed a constant RBE of 1.1, but also applied measures (except for one eye treatment centre) to counteract variable RBE effects such as avoiding beams stopping inside or in front of an organ at risk and putting restrictions on the minimum number and opening angle of incident beams for certain treatment sites. For the future, most centres (16) asked for more retrospective or prospective outcome studies investigating the potential effect of the effect of a variable RBE. To perform such studies, 18 centres asked for LET and RBE calculation and visualisation tools developed by treatment planning system vendors. CONCLUSION: All European proton centres are aware of RBE variability but comply with current guidelines of prescribing a constant RBE. However, they actively mitigate uncertainty and risk of side effects resulting from increased RBE by applying measures and restrictions during treatment planning. To change RBE-related clinical guidelines in the future more clinical data on RBE are explicitly demanded.

Availability of technology for managing cancer patients in the Southeast European (SEE) region.

Background: The Southeast European (SEE) region of 10 countries and about 43 million people differs from Western Europe in that most SEE countries lack active cancer registries and have fewer diagnostic imaging devices and radiotherapy (RT) units. The main objective of this research is to initiate a common platform for gathering SEE regional cancer data from the ground up to help these countries develop common cancer management strategies. Methods: To obtain detailed on-the-ground information, we developed separate questionnaires for two SEE groups: a) ONCO - oncologists regarding cancer treatment modalities and the availability of diagnostic imaging and radiotherapy equipment; and b) REG - national radiation protection and safety regulatory bodies regarding diagnostic imaging and radiotherapy equipment in SEE facilities. Results: Based on responses from 13/17 ONCO participants (at least one from each country) and from 9/10 REG participants (all countries but Albania), cancer incidence rates are higher in those SEE countries that have greater access to diagnostic imaging equipment while cancer mortality-to-incidence (MIR) ratios are higher in countries that lack radiotherapy equipment. Conclusion: By combining unique SEE region information with data available from major global databases, we demonstrated that the availability of diagnostic imaging and radiotherapy equipment in the SEE countries is related to their economic development. While immediate diagnostic imaging and radiation therapy capacity building is necessary, it is also essential to develop both national and SEE-regional cancer registries in order to understand the heterogeneity of each country's needs and to establish regional collaborative strategies for combating cancer.

Patients With Cancer in the Countries of South-East Europe (the Balkans) Region and Prospective of the Particle Therapy Center: South-East European International Institute for Sustainable Technologies (SEEIIST).

PURPOSE: A recent initiative was launched for establishing the South-East European International Institute for Sustainable Technologies (SEEIIST), which will provide a cutting-edge Hadron radiation therapy treatment and research institute for treating cancer patients with Hadron therapy (HT). To justify the initiative for building the SEEIIST facility, a study was conducted to estimate the number of patients with cancer from the SEE region that would be eligible for HT. METHODS AND MATERIALS: Two different methods for projecting the future annual cancer incidence have been applied: (1) using the International Agency on Research on Cancer@World Health Organization's (WHO) Globocan model which uses country's demographic factors, and (2) averaging the crude incidence data of 3 SEE countries with available national cancer registries, using a linear regression model of combined incidence per 100,000, and applying it to the entire SEE region. Cancer epidemiology data were collected and studied by using the countries' cancer datasheets from WHO. The top 10 cancers were presented for the SEE region. Studies of other countries were used to develop a primordial model for estimating the number of SEE patients who could be treated most successfully with HT upon SEEIIST commissioning in 2030. RESULTS: A model was developed to estimate the number of eligible patients for HT from SEE. It is estimated that 2900 to 3200 patients per year would be eligible for HT in the new SEEIIST facility in 2030. CONCLUSIONS: After commissioning, SEEIIST will initially treat approximately 400 patients per year, progressing toward 1000. Creation of SEEIIST dedicated patient selection criteria will be both necessary and highly challenging.

Achieving flexible competence: bridging the investment dichotomy between infectious diseases and cancer.

Today's global health challenges in underserved communities include the growing burden of cancer and other non-communicable diseases (NCDs); infectious diseases (IDs) with epidemic and pandemic potential such as COVID-19; and health effects from catastrophic 'all hazards' disasters including natural, industrial or terrorist incidents. Healthcare disparities in low-income and middle-income countries and in some rural areas in developed countries make it a challenge to mitigate these health, socioeconomic and political consequences on our globalised society. As with IDs, cancer requires rapid intervention and its effective medical management and prevention encompasses the other major NCDs. Furthermore, the technology and clinical capability for cancer care enables management of NCDs and IDs. Global health initiatives that call for action to address IDs and cancer often focus on each problem separately, or consider cancer care only a downstream investment to primary care, missing opportunities to leverage investments that could support broader capacity-building. From our experience in health disparities, disaster preparedness, government policy and healthcare systems we have initiated an approach we call flex-competence which emphasises a systems approach from the outset of program building that integrates investment among IDs, cancer, NCDs and disaster preparedness to improve overall healthcare for the local community. This approach builds on trusted partnerships, multi-level strategies and a healthcare infrastructure providing surge capacities to more rapidly respond to and manage a wide range of changing public health threats.

Union of light ion therapy centers in Europe (ULICE EC FP7) - Objectives and achievements of joint research activities.

Under the umbrella of the European Network for Light Ion Therapy (ENLIGHT), the project on Union of Light Ion Centers in Europe (ULICE), which was funded by the European Commission (EC/FP7), was carried out from 2009 to 2014. Besides the two pillars on Transnational Access (TNA) and Networking Activities (NA), six work packages formed the pillar on Joint Research Activities (JRA). The current manuscript focuses on the objectives and results achieved within these research work packages: "Clinical Research Infrastructure", "Biologically Based Expert System for Individualized Patient Allocation", "Ion Therapy for Intra-Fractional Moving Targets", "Adaptive Treatment Planning for Ion Radiotherapy", "Carbon Ion Gantry", "Common Database and Grid Infrastructures for Improving Access to Research Infrastructures". The objectives and main achievements are summarized. References to either publications or open access deliverables from the five year project work are given. Overall, carbon ion radiotherapy is still not as mature as photon or proton radiotherapy. Achieved results and open questions are reflected and discussed in the context of the current status of carbon ion therapy and particle and photon beam therapy. Most research topics covered in the ULICE JRA pillar are topical. Future research activities can build upon these ULICE results. Together with the continuous increase in the number of particle therapy centers in the last years ULICE results and proposals may contribute to the further growth of the overall particle therapy field as foreseen with ENLIGHT and new joint initiatives such as the European Particle Therapy Network (EPTN) within the overall radiotherapy community.

Overview of research and therapy facilities for radiobiological experimental work in particle therapy. Report from the European Particle Therapy Network radiobiology group.

Particle therapy (PT) as cancer treatment, using protons or heavier ions, can provide a more favorable dose distribution compared to X-rays. While the physical characteristics of particle radiation have been the aim of intense research, less focus has been placed on the actual biological responses arising from particle irradiation. One of the biggest challenges for proton radiobiology is the RBE, with an increasing concern that the clinically-applied generic RBE-value of 1.1 is an approximation, as RBE is a complex quantity, depending on both biological and physical parameters, such as dose, LET, cellular and tissue radiobiological characteristics, as well as the endpoints being studied. Most of the available RBE data derive from in vitro experiments, with very limited in vivo data available, especially in late-reacting tissues, which provide the main constraints and influence the quality of life endpoints in radiotherapy. There is a need for systematic, large-scale studies to thoroughly establish the biology of particle radiation in a number of different experimental models in order to refine biophysical mathematical models that can potentially be used to guide PT. The overall objective of the European Particle Therapy Network (EPTN) WP6 is to form a network of research and therapy facilities in order to coordinate and standardize the radiobiological experiments, to obtain more accurate predictive parameters than in the past. Coordinated research is required in order to obtain the most appropriate experimental data. The aim in this paper is to describe the available radiobiology infrastructure of the centers involved in EPTN WP6.

ENLIGHT: European network for Light ion hadron therapy.

The European Network for Light Ion Hadron Therapy (ENLIGHT) was established in 2002 following various European particle therapy network initiatives during the 1980s and 1990s (e.g. EORTC task group, EULIMA/PIMMS accelerator design). ENLIGHT started its work on major topics related to hadron therapy (HT), such as patient selection, clinical trials, technology, radiobiology, imaging and health economics. It was initiated through CERN and ESTRO and dealt with various disciplines such as (medical) physics and engineering, radiation biology and radiation oncology. ENLIGHT was funded until 2005 through the EC FP5 programme. A regular annual meeting structure was started in 2002 and continues until today bringing together the various disciplines and projects and institutions in the field of HT at different European places for regular exchange of information on best practices and research and development. Starting in 2006 ENLIGHT coordination was continued through CERN in collaboration with ESTRO and other partners involved in HT. Major projects within the EC FP7 programme (2008-2014) were launched for R&D and transnational access (ULICE, ENVISION) and education and training networks (Marie Curie ITNs: PARTNER, ENTERVISION). These projects were instrumental for the strengthening of the field of hadron therapy. With the start of 4 European carbon ion and proton centres and the upcoming numerous European proton therapy centres, the future scope of ENLIGHT will focus on strengthening current and developing European particle therapy research, multidisciplinary education and training and general R&D in technology and biology with annual meetings and a continuously strong CERN support. Collaboration with the European Particle Therapy Network (EPTN) and other similar networks will be pursued.

A general method for motion compensation in x-ray computed tomography.

Motion during data acquisition is a known source of error in medical tomography, resulting in blur artefacts in the regions that move. It is critical to reduce these artefacts in applications such as image-guided radiation therapy as a clearer image translates into a more accurate treatment and the sparing of healthy tissue close to a tumour site. Most research in 4D x-ray tomography involving the thorax relies on respiratory phase binning of the acquired data and reconstructing each of a set of images using the limited subset of data per phase. In this work, we demonstrate a motion-compensation method to reconstruct images from the complete dataset taken during breathing without recourse to phase-binning or breath-hold techniques. As long as the motion is sufficiently well known, the new method can accurately reconstruct an image at any time during the acquisition time span. It can be applied to any iterative reconstruction algorithm.

Monte Carlo Calculations Supporting Patient Plan Verification in Proton Therapy.

Patient's treatment plan verification covers substantial amount of the quality assurance (QA) resources; this is especially true for Intensity-Modulated Proton Therapy (IMPT). The use of Monte Carlo (MC) simulations in supporting QA has been widely discussed, and several methods have been proposed. In this paper, we studied an alternative approach from the one being currently applied clinically at Centro Nazionale di Adroterapia Oncologica (CNAO). We reanalyzed the previously published data (Molinelli et al. (1)), where 9 patient plans were investigated in which the warning QA threshold of 3% mean dose deviation was crossed. The possibility that these differences between measurement and calculated dose were related to dose modeling (Treatment Planning Systems (TPS) vs. MC), limitations on dose delivery system, or detectors mispositioning was originally explored, but other factors, such as the geometric description of the detectors, were not ruled out. For the purpose of this work, we compared ionization chambers' measurements with different MC simulation results. It was also studied that some physical effects were introduced by this new approach, for example, inter-detector interference and the delta ray thresholds. The simulations accounting for a detailed geometry typically are superior (statistical difference - p-value around 0.01) to most of the MC simulations used at CNAO (only inferior to the shift approach used). No real improvement was observed in reducing the current delta ray threshold used (100 keV), and no significant interference between ion chambers in the phantom were detected (p-value 0.81). In conclusion, it was observed that the detailed geometrical description improves the agreement between measurement and MC calculations in some cases. But in other cases, position uncertainty represents the dominant uncertainty. The inter-chamber disturbance was not detected for the therapeutic protons energies, and the results from the current delta threshold are acceptable for MC simulations in IMPT.

Medical Applications at CERN and the ENLIGHT Network.

State-of-the-art techniques derived from particle accelerators, detectors, and physics computing are routinely used in clinical practice and medical research centers: from imaging technologies to dedicated accelerators for cancer therapy and nuclear medicine, simulations, and data analytics. Principles of particle physics themselves are the foundation of a cutting edge radiotherapy technique for cancer treatment: hadron therapy. This article is an overview of the involvement of CERN, the European Organization for Nuclear Research, in medical applications, with specific focus on hadron therapy. It also presents the history, achievements, and future scientific goals of the European Network for Light Ion Hadron Therapy, whose co-ordination office is at CERN.

Introduction to the EC's Marie Curie Initial Training Network Project: The European Training Network in Digital Medical Imaging for Radiotherapy (ENTERVISION).

Between 2011 and 2015, the ENTERVISION Marie Curie Initial Training Network has been training 15 young researchers from a variety of backgrounds on topics ranging from in-beam Positron Emission Tomography or Single Particle Tomography techniques, to adaptive treatment planning, optical imaging, Monte Carlo simulations and biological phantom design. This article covers the main research activities, as well as the training scheme implemented by the participating institutes, which included academia, research, and industry.

Introduction to the EC's Marie Curie Initial Training Network (MC-ITN) project: Particle Training Network for European Radiotherapy (PARTNER).

PARTNER (Particle Training Network for European Radiotherapy) is a project funded by the European Commission's Marie Curie-ITN funding scheme through the ENLIGHT Platform for 5.6 million Euro. PARTNER has brought together academic institutes, research centres and leading European companies, focusing in particular on a specialized radiotherapy (RT) called hadron therapy (HT), interchangeably referred to as particle therapy (PT). The ultimate goal of HT is to deliver more effective treatment to cancer patients leading to major improvement in the health of citizens. In Europe, several hundred million Euro have been invested, since the beginning of this century, in PT. In this decade, the use of HT is rapidly growing across Europe, and there is an urgent need for qualified researchers from a range of disciplines to work on its translational research. In response to this need, the European community of HT, and in particular 10 leading academic institutes, research centres, companies and small and medium-sized enterprises, joined together to form the PARTNER consortium. All partners have international reputations in the diverse but complementary fields associated with PT: clinical, radiobiological and technological. Thus the network incorporates a unique set of competencies, expertise, infrastructures and training possibilities. This paper describes the status and needs of PT research in Europe, the importance of and challenges associated with the creation of a training network, the objectives, the initial results, and the expected long-term benefits of the PARTNER initiative.

Feasibility study for a biomedical experimental facility based on LEIR at CERN.

In light of the recent European developments in ion beam therapy, there is a strong interest from the biomedical research community to have more access to clinically relevant beams. Beamtime for pre-clinical studies is currently very limited and a new dedicated facility would allow extensive research into the radiobiological mechanisms of ion beam radiation and the development of more refined techniques of dosimetry and imaging. This basic research would support the current clinical efforts of the new treatment centres in Europe (for example HIT, CNAO and MedAustron). This paper presents first investigations on the feasibility of an experimental biomedical facility based on the CERN Low Energy Ion Ring LEIR accelerator. Such a new facility could provide beams of light ions (from protons to neon ions) in a collaborative and cost-effective way, since it would rely partly on CERN's competences and infrastructure. The main technical challenges linked to the implementation of a slow extraction scheme for LEIR and to the design of the experimental beamlines are described and first solutions presented. These include introducing new extraction septa into one of the straight sections of the synchrotron, changing the power supply configuration of the magnets, and designing a new horizontal beamline suitable for clinical beam energies, and a low-energy vertical beamline for particular radiobiological experiments.