Periodic Reporting for period 2 - SIRMIO (Small animal proton Irradiator for Research in Molecular Image-guided radiation-Oncology) Reporting period: 2019-05-01 to 2021-01-31 Summary of the context and overall objectives of the project 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, typically tumour-bearing mice. For the widely established X-ray radiation, several small animal RT platforms were recently developed and commercialized. Conversely, especially at the time of the project proposal and its start, such platforms were not existing for protons, despite their increasing use in RT due to their superior ability to target the tumour and spare normal tissue. Although meanwhile a couple of small animal proton irradiators were developed at few selected centers, they are still limited to X-ray based anatomical image guidance, which cannot guarantee precise dose targeting in small animals. Moreover, they only employ passive beam delivery, which compromises the achievable beam quality and produces many undesired secondary neutrons close to the irradiated target. SIRMIO aims at filling this research gap by realizing and demonstrating an innovative portable system to make precision image-guided small animal proton irradiation possible at existing clinical proton therapy facilities. This will be achieved by combining a dedicated beamline with proton RT-specific image guidance and in-vivo verification of the actual treatment delivery. Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far The design of the several SIRMIO platform components is almost completed.Relevant parameters of the lowest energy proton beams at clinical facilities were collected as input to the beamline optimization. The final beamline design features an adjustable degrader and collimator, followed by a triplet of permanent magnet quadrupoles focusing the beam to sub-millimeter sigma spot sizes at the focal point where the tumour will be positioned with a dedicated, in-house printed mouse holder. For pre-treatment imaging, two proton-based solutions are investigated for target alignment and determination of relative (to water) stopping power ratio (RSP) for treatment planning. A prototype proton computed tomography scanner is being developed to enable single-particle tracking by combining Micromegas tracking detectors with a range telescope based on a time-projection-chamber with thin Mylar absorbers. Thorough Monte Carlo (MC) simulations suggested an achievable RSP accuracy better than 1% and sub-millimeter spatial resolution. First detector components were successfully realized in-house and tested, and the system is now under production. The second approach relies on a CMOS integrating detector and multiple probing proton beam energies, for usage at facilities, e.g. synchrocyclotron-based, where the instantaneous beam current exceeds detection capabilities for single-particle tracking. Due to scattering in the object, the expected spatial resolution is inferior to single-particle tracking, yet MC studies still support sub-mm spatial resolution. First experimental campaigns were performed and data are currently being analyzed. For in-vivo beam range verification during irradiation, two non-exclusive approaches are studied for application at either pulsed beams of high instantaneous beam currents, e.g. synchrocyclotrons, or continuous wave cyclotrons and (slowly cycling) synchrotrons facilities. The former approach aims at sensing thermoacoustic emissions induced by the pulsed proton energy deposition (so called ionoacoustics), naturally enhanced at the end of range. The major challenge is the low-frequency and low-amplitude of the signal, preventing the usage of conventional ultrasound (US) technologies. A simulation framework was developed to study in-silico the signal dependence on different beam characteristics and media, to identify the optimal ultrasonic sensor design and positioning. Moreover, we are experimentally investigating different transducers developed in-house and by international collaborators, to identify the best candidate for application in SIRMIO, ideally co-registered to conventional US imaging of the mouse anatomy. As a more general solution not restricted to pulsed beams, we are developing a dedicated in-beam positron-emission-tomography scanner to measure the irradiation-induced beta+-activity, correlated to the beam range. This system could also provide imaging of injected tracers for novel means of biologically-guided delivery. Different detector materials, shapes and geometrical arrangements were studied to optimize sensitivity and spatial resolution, resulting in the final design of a spherical-like assembly of novel detectors developed in collaboration with the National Institute of Radiological Sciences (Japan). Simulations show promising sub-millimeter spatial resolution and detection efficiency within ca. 10% in the relevant region where the tumor will be located. Finally, we reached a license agreement with RaySearch Laboratories AB, a major provider of treatment planning solutions, to use their research small animal treatment planning system in SIRMIO. Thereby we could perform first treatment planning studies on computed tomography images of mice provided by the collaborating LMU university hospital to guide the optimization of the beamline design. In a joint effort we are now working on validating and expanding the capabilities of the planning system to devise an adaptive workflow for future experiments at the SIRMIO platform, taking advantage of its novel integration of several imaging modalities. Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far) SIRMIO will advance small animal proton RT research. The novel beamline will reduce neutron background and possibly outperform passive designs in terms of beam quality and transmission, eventually providing scanning abilities for similar irradiation conditions as modern clinical treatment. For pre-treatment imaging, two original prototypes of proton imaging will overcome limitations of current X-ray based solution for beam range estimation in planning. Also, SIRMIO will provide for the first time preclinical in-vivo range verification, enabling unprecedented accuracy in targeting small animal structures. Moreover, via the partnership with an industrial provider of treatment planning solutions, it will contribute to the improvement of an eventual commercial system, thus potentially benefiting the rapidly growing small animal proton RT research community. By the project end we will demonstrate the SIRMIO platform capabilities in a mouse mimicking phantom. 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 proton irradiators currently under development. Schematics of the SIRMIO platform and related workpackages (source: Parodi et al, Acta Oncol 2019)
