Towards a novel small animal proton irradiation platform: the SIRMIO project

Background: Precision small animal radiotherapy research is a young emerging field aiming to provide new experimental insights into tumor and normal tissue models in different microenvironments, to unravel complex mechanisms of radiation damage in target and non-target tissues and assess efficacy of novel therapeutic strategies. For photon therapy, modern small animal radiotherapy research platforms have been developed over the last years and are meanwhile commercially available. Conversely, for proton therapy, which holds potential for an even superior outcome than photon therapy, no commercial system exists yet. Material and methods: The project SIRMIO (Small Animal Proton Irradiator for Research in Molecular Image-guided Radiation-Oncology) aims at realizing and demonstrating an innovative portable prototype system for precision image-guided small animal proton irradiation, suitable for installation at existing clinical treatment facilities. The proposed design combines precise dose application with in-situ multi-modal anatomical image guidance and in-vivo verification of the actual treatment delivery. Results and conclusions: This manuscript describes the status of the different components under development, featuring a dedicated beamline for degradation and focusing of clinical proton beams, along with novel detector systems for in-situ imaging and range verification. The foreseen workflow includes pre-treatment proton transmission imaging, complemented by ultrasonic tumor localization, for treatment planning and position verification, followed by image-guided delivery with on-site range verification by means of ionoacoustics (for pulsed beams) and positron-emission-tomography (PET, for continuous beams). The proposed compact and cost-effective system promises to open a new era in small animal proton therapy research, contributing to the basic understanding of in-vivo radiation action to identify areas of potential breakthroughs for future translation into innovative clinical strategies

Magnetic resonance imaging-guided radiation therapy using animal models of glioblastoma

Glioblastoma is the most aggressive and most common malignant primary brain tumour in adults and has a high mortality and morbidity. Because local tumour control in glioblastoma patients is still elusive in the majority of patients, there is an urgent need for alternative treatment strategies. However, to implement changes to the existing clinical standard of care, research must be conducted to develop alternative treatment strategies. A novel approach in radiotherapy is the introduction of pre-clinical precision image-guided radiation research platforms. The aim of this review is to give a brief overview of the efforts that have been made in the field of radiation research using animal models of glioblastoma. Because MRI has become the reference imaging technique for treatment planning and assessment of therapeutic responses in glioblastoma patients, we will focus in this review on small animal radiotherapy combined with MRI

A novel data management platform to improve image-guided precision preclinical biological research

Objective: Preclinical biological research is mandatory for developing new drugs to investigate the toxicity and efficacy of the drug. In this paper, the focus is on radiobiological research as an example of advanced preclinical biological research. In radiobiology, recent technological advances have produced novel research platforms which can precisely irradiate targets in animals and use advanced onboard image-guidance, mimicking the clinical radiotherapy environment. These platforms greatly facilitate complex research combining several agents simultaneously (in our example, radiation and non-radiation agents). Since these modern platform can produce a large amount of wide-ranging data, one of the main impediments in preclinical research platforms is a proper data management system for preclinical studies. Methods: A preclinical data management system, inspired by current radiotherapy clinical data management systems was designed. The system was designed with InterSystems technology, i.e. a programmable Enterprise Service Bus solution. New DICOM animal imaging standards are used such as DICOM suppl. 187 for storing small animal acquisition context and the DICOM second generation course model. Results: A small animal big data warehouse environment for research is designed to work with modern image-guided precision research platforms. Its modular design includes (1) a study workflow manager, (2) a data manager, and (3) a storage manager. The system provides interfaces to, e.g. preclinical treatment planning systems and data analysis plug-ins, and guides the user efficiently through the many steps involved in preclinical research. The system manages various data source locations, and arranges access to the data centrally. Conclusion: A novel preclinical data management system can be designed to improve preclinical workflow, facilitate data exchange between researchers, and support translation to clinical trials. Advances in knowledge: A preclinical data management system such as the one proposed here would greatly benefit preparation, execution and analysis of biological experiments, and will eventually facilitate translation to clinical trials

MRI-only based radiotherapy treatment planning for the rat brain on a Small Animal Radiation Research Platform (SARRP)

Computed tomography (CT) is the standard imaging modality in radiation therapy treatment planning (RTP). However, magnetic resonance (MR) imaging provides superior soft tissue contrast, increasing the precision of target volume selection. We present MR-only based RTP for a rat brain on a small animal radiation research platform (SARRP) using probabilistic voxel classification with multiple MR sequences. Six rat heads were imaged, each with one CT and five MR sequences. The MR sequences were: T1-weighted, T2-weighted, zero-echo time (ZTE), and two ultra-short echo time sequences with 20 mu s (UTE1) and 2 ms (UTE2) echo times. CT data were manually segmented into air, soft tissue, and bone to obtain the RTP reference. Bias field corrected MR images were automatically segmented into the same tissue classes using a fuzzy c-means segmentation algorithm with multiple images as input. Similarities between segmented CT and automatic segmented MR (ASMR) images were evaluated using Dice coefficient. Three ASMR images with high similarity index were used for further RTP. Three beam arrangements were investigated. Dose distributions were compared by analysing dose volume histograms. The highest Dice coefficients were obtained for the ZTE-UTE2 combination and for the T1-UTE1-T2 combination when ZTE was unavailable. Both combinations, along with UTE1-UTE2, often used to generate ASMR images, were used for further RTP. Using 1 beam, MR based RTP underestimated the dose to be delivered to the target (range: 1.4%-7.6%). When more complex beam configurations were used, the calculated dose using the ZTE-UTE2 combination was the most accurate, with 0.7% deviation from CT, compared to 0.8% for T1-UTE1-T2 and 1.7% for UTE1-UTE2. The presented MR-only based workflow for RTP on a SARRP enables both accurate organ delineation and dose calculations using multiple MR sequences. This method can be useful in longitudinal studies where CT's cumulative radiation dose might contribute to the total dose

Optimizing dual energy cone beam CT protocols for preclinical imaging and radiation research

Objective: The aim of this work was to investigate whether quantitative dual-energy CT (DECT) imaging is feasible for small animal irradiators with an integrated cone-beam CT (CBCT) system. Methods: The optimal imaging protocols were determined by analyzing different energy combinations and dose levels. The influence of beam hardening effects and the performance of a beam hardening correction (BHC) were investigated. In addition, two systems from different manufacturers were compared in terms of errors in the extracted effective atomic numbers (Z(eff)) and relative electron densities (rho(e)) for phantom inserts with known elemental compositions and relative electron densities. Results: The optimal energy combination was determined to be 50 and 90kVp. For this combination, Z(eff) and r rho(e) can be extracted with a mean error of 0.11 and 0.010, respectively, at a dose level of 60cGy. Conclusion: Quantitative DECT imaging is feasible for small animal irradiators with an integrated CBCT system. To obtain the best results, optimizing the imaging protocols is required. Well-separated X-ray spectra and a sufficient dose level should be used to minimize the error and noise for Z(eff) and rho(e). When no BHC is applied in the image reconstruction, the size of the calibration phantom should match the size of the imaged object to limit the influence of beam hardening effects. No significant differences in Z(eff) and rho(e) errors are observed between the two systems from different manufacturers. Advances in knowledge: This is the first study that investigates quantitative DECT imaging for small animal irradiators with an integrated CBCT system

Commissioning and performance characteristics of a pre-clinical image-guided radiotherapy system

Characteristics of a small-animal radiotherapy device, the X-RAD SmART, are described following commissioning of the device for pre-clinical radiotherapy research. Performance characteristics were assessed using published standards and compared with previous results published for similar systems. Operational radiation safety was established. Device X-ray beam quality and output dose-rate were found to be consistent with those reported for similar devices. Output steadily declined over 18 months though remained within tolerance levels. There is considerable variation in output factor across the international installations for the smallest feld size (varying by more than 30% for 2.5 mm diameter felds). Measured depth dose and profle data was mostly consistent with that published, with some diferences in penumbrae and generally reduced fatness. Target localisation is achieved with an imaging panel and with automatic corrections for panel fex and device mechanical instability, targeting within 0.2 mm is achievable. The small-animal image-guided radiotherapy platform has been implemented and assessed and found to perform as specifed. The combination of kV energy and high spatial precision make it suitable for replicating clinical dose distributions at the small-animal scale, though dosimetric uncertainties for the narrowest felds need to be acknowledged

Towards Laser Driven Hadron Cancer Radiotherapy: A Review of Progress

It has been known for about sixty years that proton and heavy ion therapy is a very powerful radiation procedure for treating tumours. It has an innate ability to irradiate tumours with greater doses and spatial selectivity compared with electron and photon therapy and hence is a tissue sparing procedure. For more than twenty years powerful lasers have generated high energy beams of protons and heavy ions and hence it has been frequently speculated that lasers could be used as an alternative to RF accelerators to produce the particle beams necessary for cancer therapy. The present paper reviews the progress made towards laser driven hadron cancer therapy and what has still to be accomplished to realise its inherent enormous potential.Comment: 40 pages, 24 figure