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INfraStructure in Proton International REsearch

Periodic Reporting for period 2 - INSPIRE (INfraStructure in Proton International REsearch)

Reporting period: 2019-09-01 to 2021-02-28

Proton Beam Therapy (PBT) is a new type of advanced radiotherapy capable of delivering and conforming a targeted dose of radiation to the tumour while causing minimal damage to the surrounding healthy tissue.
INSPIRE comprises 17 European centres to form a highly specialised research infrastructure in high-energy PBT. The consortium is made up of internationally leading research and clinical facilities, industry including an SME. INSPIRE collaborates internally with EU Networks (ARIE) and with other EU projects (UHDPulse).
The activities of INSPIRE are grouped into 3 areas: Networking Activities (NA), Transnational Access (TNA) and Joint Research Activities (JRA) and arranged in 10 interconnecting Work Packages (WP). WP1 Project Management; NA includes WP2 Access Gateway, QA and Standards; WP3 Training users and inspiring the Next Generation; WP4 Communication and Dissemination; WP5 Innovation and Sustainability. WP6 is TNA. JRA comprises of 4 WPs: WP7 Radiobiology; WP8 Patient selection and data sharing; WP9 Mathematical simulation and modelling for proton therapy and WP10 Dosimetry, robustness and uncertainties.
During RP2, time has been spent on:
• Budget and continuous progress monitoring of Tasks, Milestones and Deliverables described in the Grant Agreement
• Coordination of INSPIRE, NA, TNA and JRA together with individual WP meetings
• Developed INSPIRE web site
• 3 audit inter-comparison studies started linking in to JRA WP7, 8 and 10. 1 standard phantom for 3D printing.
• Online training for INSPIRE Fellows (3 days)
• Online proton schools at CHRIS/ UNIMAN and PSI
• Flash radiotherapy and Particle Therapy (FRPT) Conference organised in collaboration with EMPIR UHDPulse
• 2 secondments to GSI from UNIMAN and LSMU
• INSPIRE Open days will take place when Covid19 restrictions relax. Series of INSPIRE webinars will complement Open Days
• Data Management plan uploaded
• 56 open-access INSPIRE publications
• 4 INSPIRE Newsletters, 5th in preparation
• Fact sheets on PBT on web site in different languages
• Open Nights at IFJ-PAN with 1000 participants online
• FRPT Dec 2021; AU to host ESTRO in 2022
• IBA and UMCG have increased the number of NTCP models in the database (CAPTAIN) which is now available Open Source.
• VARIAN has developed new detector technology (WP10) for FLASH PBT. A first full beam monitor system has been tested on a clinical gantry and is being used in the world’s first FLASH PBT clinical trial FAST-01. A commercial product “FLEX”, has been developed for FLASH PBT research. VARIAN are now developing a product through INSPIRE’s Innovation Gateway (WP5) with AU that can be used clinically at both FLASH and conventional dose rates. Varian worked with PTW-Freiburg via UHDpulse on modified dosimetry equipment for ultra-high dose rate proton beams. Varian also worked with GSI and THM Gießen on 3D printed range modulators for the delivery of Bragg peak FLASH.
• TUD has been working with SME ADVACAM (WP5) and UHDPulse. Initial experiments were successful and further experiments are planned.
• 1 activity from INSPIRE has patent approved. 2 further applications are currently being filed.
• Two hundred and sixty seven beam time hours used and a further 677 beam hours approved by independent User Selection Panel
• All TNA providers in INSPIRE have demonstrated that they are capable of delivering FLASH beams

• Radiobiology inter-comparison experiment is underway using a phantom designed by GSI.
• The radiobiology capabilities of INSPIRE and how these are being enhanced through JRA has been published in Frontiers.
• UNamur are developing a device for irradiating small animals on a clinical machine with a gantry. This is the subject of a patent application.
• I-SEE has developed a web app for collecting and sharing data
• UNIMAN/CHRIS have developed a customised hypoxia end station with robotic arm for high throughput radiobiology experiments.
• GSI has developed a new small portable hypoxia chamber for in vitro irradiations in acute hypoxia.
• Drug radiation experiments have been undertaken by IFJ-PAN and LSMU. At IFJ-PAN the work has led to a patent application.
• Secondment from UNIMAN to GSI developed new multi-scale models and published a review of mathematical modelling in immunotherapy
• The CAPTAIN database of NTCP models has been developed and is now available online. These have been used at AU and will be translated EU wide.
• PSI has initiated a project to study inter-centre variability in PBT planning of head and neck cancers.
• The Malthus model of radiotherapy demand has been adapted to analyse the impact of Covid-19.
• UNIMAN /CHRIS have used Malthus to investigate the impact of waiting times for cancer treatment.
• PSI has published a comprehensive benchmarking of PBT treatment planning

• UNIMAN/CHRIS DNA damage and repair models now include anomalous diffusion and geometrical developments using a HiC model to give realistic DNA conformations. Available Open Access via TOPAS n-Bio.
• TUD led an international benchmarking study which harmonised LET calculations. This has the potential to lead to a harmonized variable RBE dose prescription in PBT.
• At TUD and SKANDION high LET and RBE values are being spatially correlated with observed toxicity areas.
• Incorporation of normal tissue effects in the models in WP9 as part of the LET benchmarking exercise, this feeds in to NTCP models in WP8.
• VARIAN has developed new detector technology for FLASH PBT. This is described in WP5.
• UNIMAN/ CHRIS are investigating the parameter space for FLASH. This is now being integrated with PBT spot scanning and treatment planning. PSI are working on FLASH treatment planning and a new model of spatially varying dose-rate.
• INSPIRE dosimetry audit led by NPI-CAS is underway. 3 different types of detector are being used. This will feed in to WP2.
• SKANDION are also involved in an audit coordinated by MedAustron this will allow comparison with NPI-CAS audit
• Zoomorphic phantoms have been developed UNIMAN /CHRIS and used for an in vivo dosimetry audit. The designs will be shared via the web site.
• TUD has extended their the first-in-human validation of a prompt gamma device to 5 head and neck treatments.
• IFJ-PAN has developed a personalized 3D printed PBT compensator and used on paediatric patients.
• SKANDION has made measurements to characterise the field of secondary neutrons and gamma photons from clinically relevant irradiation.
A new technology (FLASH) that has the potential to transform radiotherapy, is included in INSPIRE’s JRA WP10. In FLASH a higher dose typically > 10 Gy is delivered typically at dose rates >40 Gy/s. FLASH appears to spare normal tissues while still maintaining tumour control.
In RP2 VARIAN has continued to develop new detector technology for FLASH PBT in WP10. This has been used in the world’s first PBT FLASH clinical trial FAST 01, together with a commercially available research product FLEX being developed and the testing of a clinical prototype at AU. Through JRA all TNA providers can now provide FLASH beams for TNA. INSPIRE is working closely with EU project UHDPulse on a conference FRPT. VARIAN and PTW-Freiburg (from UHDPulse) are working on dosimetry equipment for FLASH PBT. GSI, VARIAN and THM Gießen are working on Bragg peak FLASH.
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