Periodic Reporting for period 3 - SIRMIO (Small animal proton Irradiator for Research in Molecular Image-guided radiation-Oncology)
Reporting period: 2021-02-01 to 2022-12-31
Radiation therapy (RT) is a cost-effective and efficient treatment strategy against cancer, already applied in more than 50% of all cancer patients. Hence, improvements of RT may have a significant clinical and socio-economic impact.
Understanding radiation response in tumour and normal tissue models mimicking clinical scenarios is key for investigating new therapeutic approaches and support their translation into next generation of radio-oncological treatments. Small animal radiation research can unravel complex radiation damage mechanisms and assess the efficacy of novel therapeutic strategies. However, a main challenge is to precisely target tiny structures of small animals.
For the widely established X-rays, several small animal RT platforms were recently developed and commercialized. Conversely, especially at the time of the project proposal and its beginning, such platforms did not exist for protons, despite the increasing adoption of proton RT due to its superior ability to target the tumour and spare normal tissue. Although meanwhile a few small animal proton irradiators were developed at selected centres, they are typically limited to X-ray based anatomical image guidance, which introduces additional uncertainties for proton irradiation, challenging precise dose targeting in small animals. Moreover, they only employ passive beam delivery, which compromises the achievable beam quality, produces many undesired secondary neutrons close to the irradiated target and is progressively phased out in clinical practice.
SIRMIO aimed at filling this research gap by realizing and showcasing an innovative portable system to enable precision image-guided small animal proton irradiation at existing beamlines of clinical proton therapy facilities. The modular SIRMIO system realized within the project combines a dedicated beamline for precise dose application with advanced solutions specific to proton RT for image guidance and in-situ in-vivo verification of the actual treatment delivery.
Understanding radiation response in tumour and normal tissue models mimicking clinical scenarios is key for investigating new therapeutic approaches and support their translation into next generation of radio-oncological treatments. Small animal radiation research can unravel complex radiation damage mechanisms and assess the efficacy of novel therapeutic strategies. However, a main challenge is to precisely target tiny structures of small animals.
For the widely established X-rays, several small animal RT platforms were recently developed and commercialized. Conversely, especially at the time of the project proposal and its beginning, such platforms did not exist for protons, despite the increasing adoption of proton RT due to its superior ability to target the tumour and spare normal tissue. Although meanwhile a few small animal proton irradiators were developed at selected centres, they are typically limited to X-ray based anatomical image guidance, which introduces additional uncertainties for proton irradiation, challenging precise dose targeting in small animals. Moreover, they only employ passive beam delivery, which compromises the achievable beam quality, produces many undesired secondary neutrons close to the irradiated target and is progressively phased out in clinical practice.
SIRMIO aimed at filling this research gap by realizing and showcasing an innovative portable system to enable precision image-guided small animal proton irradiation at existing beamlines of clinical proton therapy facilities. The modular SIRMIO system realized within the project combines a dedicated beamline for precise dose application with advanced solutions specific to proton RT for image guidance and in-situ in-vivo verification of the actual treatment delivery.
For dose delivery, degradation and focusing of the lowest energy clinical beam are achieved by a dedicated beamline consisting of passive (degraders/collimators) and active (permanent magnet quadrupoles) components. For positioning and treatment planning, three solutions of proton imaging at different levels of technology readiness have been investigated. The first two feature spatially resolved detection of individual or integral proton energy deposition in commercial thin pixelated detectors. The last one relies on in-house built gas detectors for single particle tracking with residual range measurement. For range monitoring at isochronous cyclotron/synchrotron-based facilities, a dedicated in-beam positron emission tomography (PET) scanner of high spatial resolution and sensitivity has been developed, while ionoacoustics (i.e. sensing of thermoacoustic emissions) has been investigated for application at intense pulsed beams from synchrocyclotrons. Treatment planning is based on a research system from RaySearch Laboratories AB, tailored to the specificities of the SIRMIO beam and thoroughly validated against Monte Carlo simulations.
In the recently concluded experiments at the Danish Centre for Particle Therapy (DCPT), we could show the ability of the SIRMIO system to degrade and focus the incoming clinical proton beam with the lowest energy of 70 MeV and perform precision, image-guided delivery to homogenous and heterogeneous, mice-mimicking phantoms. For image guidance, proton radiography and tomography was successfully deployed and compared to prior X-ray cone beam computed tomography from an X-ray irradiator, while on-line monitoring of the treatment delivery was achieved with our dedicated in-beam PET scanner.
The objectives of the project could be fulfilled and future work will aim at automation/acceleration of the entire workflow of image-guided planning and delivery. The unique features of the newly developed system will pave the way to a new class of small animal experiments which we are currently planning with biologists. The project contributed to 38 BSc/MSc/PhD thesis (30 already completed) and over 50 contributions of peer reviewed papers and presentations at national and international conferences (with a few publications still in the pipeline). Moreover, we are currently exploring patenting and technology transfer possibilities with commercial key players in small animal radiation research. This has the twofold purpose to make the SIRMIO technologies available to more centres for advancing precision image-guided proton irradiation, as well as to explore possible application of some developments in the broader field of small animal irradiation with different beam qualities. Finally, the SIRMIO in-beam PET scanner will also serve as the key detector for in-vivo investigations with radioactive ion beams in the framework of another ERC project (BARB, grant agreement 883425, PI Prof. Marco Durante from GSI Darmstadt).
In the recently concluded experiments at the Danish Centre for Particle Therapy (DCPT), we could show the ability of the SIRMIO system to degrade and focus the incoming clinical proton beam with the lowest energy of 70 MeV and perform precision, image-guided delivery to homogenous and heterogeneous, mice-mimicking phantoms. For image guidance, proton radiography and tomography was successfully deployed and compared to prior X-ray cone beam computed tomography from an X-ray irradiator, while on-line monitoring of the treatment delivery was achieved with our dedicated in-beam PET scanner.
The objectives of the project could be fulfilled and future work will aim at automation/acceleration of the entire workflow of image-guided planning and delivery. The unique features of the newly developed system will pave the way to a new class of small animal experiments which we are currently planning with biologists. The project contributed to 38 BSc/MSc/PhD thesis (30 already completed) and over 50 contributions of peer reviewed papers and presentations at national and international conferences (with a few publications still in the pipeline). Moreover, we are currently exploring patenting and technology transfer possibilities with commercial key players in small animal radiation research. This has the twofold purpose to make the SIRMIO technologies available to more centres for advancing precision image-guided proton irradiation, as well as to explore possible application of some developments in the broader field of small animal irradiation with different beam qualities. Finally, the SIRMIO in-beam PET scanner will also serve as the key detector for in-vivo investigations with radioactive ion beams in the framework of another ERC project (BARB, grant agreement 883425, PI Prof. Marco Durante from GSI Darmstadt).
SIRMIO can open new avenues in small animal proton RT research. The novel beamline reduces neutron background and provides preclinical irradiation conditions emulating modern clinical treatments. For pre-treatment imaging, the developments of proton imaging alone or in combination with prior X-ray computed tomography allow reducing limitations of current X-ray based solutions for beam range estimation in treatment planning. SIRMIO features a unique preclinical in-vivo range verification capability, enabling unprecedented accuracy in targeting small animal structures. This has been shown possible with the novel in-beam PET scanner of high sensitivity and sub-millimeter spatial resolution. We could successfully demonstrate the SIRMIO platform capabilities by planning and delivering complex irradiation plans to homogeneous and heterogeneous, mouse mimicking phantom a few months after the project end in March 2023 at the Danish Centre for Particle Therapy, due to delays because of the pandemic and beamtime availability. The SIRMIO system is expected to be used at the Danish proton therapy center to support in-vivo studies of the local physics and biology teams. Moreover, via the partnership established during the project with a leading industrial provider of treatment planning solutions and the ongoing exploration of technology transfer possibilities with key companies in small animal radiation research, SIRMIO can contribute to a commercial system, thus potentially benefiting the rapidly growing small animal proton RT research community. Given the modularity and cost-effectiveness, we also expect some of the SIRMIO components to find application in enhancing the performance of other small animal irradiators currently under development for protons or even other radiation qualities.