Development and Implementation of an End-To-End Test for Absolute Dose Verification of Small Animal Preclinical Irradiation Research Platforms.

PURPOSE: Lack of standardization and inaccurate dosimetry assessment in preclinical research is hampering translational opportunities for new radiation therapy interventions. The aim of this work was to develop and implement an end-to-end dosimetry test for small animal radiation research platforms to monitor and help improve accuracy of dose delivery and standardization across institutions. METHODS AND MATERIALS: The test is based on a bespoke zoomorphic heterogeneous mouse and WT1 Petri dish phantoms with alanine as a reference detector. Alanine measurements within the mouse phantom were validated with Monte Carlo simulations at 0.5 mm Cu x-ray reference beam. Energy dependence of alanine in medium x-ray beam qualities was taken into consideration. For the end-to-end test, treatment plans considering tissue heterogeneities were created in Muriplan treatment planning systems (TPS) and delivered to the phantoms at 5 institutions using Xstrahl's small animal irradiation platforms. Mean calculated dose to the pellets were compared with alanine measured dose. RESULTS: Monte Carlo simulations and in phantom alanine measurements in NPL's reference beam were in excellent agreement, validating the experimental approach. At 1 institute, initial measurements showed a larger than 12% difference between calculated and measured dose caused by incorrect input data. The physics data used by the calculation engine were corrected, and the TPS was recommissioned. Subsequent end-to-end test measurements showed differences <5%. With an anterior field, 4 of the participating institutes delivered dose within 5% to both phantoms. CONCLUSIONS: An end-to-end dosimetry test was developed and implemented for dose evaluation in preclinical irradiation with small animal irradiation research platforms. The test was capable of detecting treatment planning commissioning errors and highlighted critical elements in dose calculation. Absolute dosimetry with alanine in relevant preclinical irradiation conditions showed reasonable levels of accuracy compared with TPS calculations. This work provides an independent and traceable dosimetric validation in preclinical research involving small animal irradiation.

The influence of lack of reference conditions on dosimetry in pre-clinical radiotherapy with medium energy x-ray beams.

Despite well-established dosimetry in clinical radiotherapy, dose measurements in pre-clinical and radiobiology studies are frequently inadequate, thus undermining the reliability and reproducibility of published findings. The lack of suitable dosimetry protocols, coupled with the increasing complexity of pre-clinical irradiation platforms, undermines confidence in preclinical studies and represents a serious obstacle in the translation to clinical practice. To accurately measure output of a pre-clinical radiotherapy unit, appropriate Codes of Practice (CoP) for medium energy x-rays needs to be employed. However, determination of absorbed dose to water (Dw) relies on application of backscatter factor (Bw) employing in-air method or carrying out in-phantom measurement at the reference depth of 2 cm in a full backscatter (i.e. 30 × 30 × 30 cm3) condition. Both of these methods require thickness of at least 30 cm of underlying material, which are never fulfilled in typical pre-clinical irradiations. This work is focused on evaluation the effects of the lack of recommended reference conditions in dosimetry measurements for pre-clinical settings and is aimed at extending the recommendations of the current CoP to practical experimental conditions and highlighting the potential impact of the lack of correct backscatter considerations on radiobiological studies.

Development of an anatomically correct mouse phantom for dosimetry measurement in small animal radiotherapy research.

Significant improvements in radiotherapy are likely to come from biological rather than technical optimization, for example increasing tumour radiosensitivity via combination with targeted therapies. Such paradigms must first be evaluated in preclinical models for efficacy, and recent advances in small animal radiotherapy research platforms allow advanced irradiation protocols, similar to those used clinically, to be carried out in orthotopic models. Dose assessment in such systems is complex however, and a lack of established tools and methodologies for traceable and accurate dosimetry is currently limiting the capabilities of such platforms and slowing the clinical uptake of new approaches. Here we report the creation of an anatomically correct phantom, fabricated from materials with tissue-equivalent electron density, into which dosimetry detectors can be incorporated for measurement as part of quality control (QC). The phantom also allows training in preclinical radiotherapy planning and cross-institution validation of dose delivery protocols for small animal radiotherapy platforms without the need to sacrifice animals, with high reproducibility. Mouse CT data was acquired and segmented into soft tissue, bone and lung. The skeleton was fabricated using 3D printing, whilst lung was created using computer numerical control (CNC) milling. Skeleton and lung were then set into a surface-rendered mould and soft tissue material added to create a whole-body phantom. Materials for fabrication were characterized for atomic composition and attenuation for x-ray energies typically found in small animal irradiators. Finally cores were CNC milled to allow intracranial incorporation of bespoke detectors (alanine pellets) for dosimetry measurement.

Evaluation of four different small animal radiation plans on tumour and normal tissue dosimetry in a glioblastoma mouse model.

OBJECTIVE:: Small animal radiotherapy research platforms such as XStrahl's SARRP enable more precise irradiation of tumours and normal tissues in pre-clinical models of cancer. Using an orthotopic G7 glioblastoma xenograft model we studied the impact of four different radiotherapy plans on tumour and normal tissue dosimetry. METHODS:: Plans were created using four different approaches (single beam, parallel opposed pair, single plane arcs, couch rotation arcs) and dose volume histograms (DVH) for the tumour and the relevant organs at risk (OARs) (mouth, ipsilateral brain, contralateral brain, brain stem) were compared for a sample mouse subject. To evaluate the accuracy of delivery, treatment plans were recreated in solid-water phantoms and delivered to radiochromic film. RESULTS:: Favourable tumour dosimetry was achieved by all plans. DVH analysis showed that different plans could be used to spare specific OARs depending on the objectives of the study. The delivery accuracy of the various treatments was better than 2%/2mm (dose difference/distance to agreement) in terms of global γ analysis. CONCLUSION:: Small animal radiotherapy research platforms are an exciting addition to the pre-clinical research environment. Such systems improve the conformality of irradiation of tumours and OARs while maintaining a high degree of accuracy and enable investigators to optimise experiments in terms of tumour coverage and inclusion or exclusion of relevant OARs. ADVANCES IN KNOWLEDGE:: This study confirms the utility of the SARRP in terms of the accuracy of plan delivery, and informs decisions on treatment planning to optimise the clinical relevance and scientific value of experiments.

Small field dosimetry for the small animal radiotherapy research platform (SARRP).

BACKGROUND: Preclinical radiation biology has become increasingly sophisticated due to the implementation of advanced small animal image guided radiation platforms into laboratory investigation. These small animal radiotherapy devices enable state-of-the-art image guided therapy (IGRT) research to be performed by combining high-resolution cone beam computed tomography (CBCT) imaging with an isocentric irradiation system. Such platforms are capable of replicating modern clinical systems similar to those that integrate a linear accelerator with on-board CBCT image guidance. METHODS: In this study, we present a dosimetric evaluation of the small animal radiotherapy research platform (SARRP, Xstrahl Inc.) focusing on small field dosimetry. Physical dosimetry was assessed using ion chamber for calibration and radiochromic film, investigating the impact of beam focus size on the dose rate output as well as beam characteristics (beam shape and penumbra). Two film analysis tools) have been used to assess the dose output using the 0.5 mm diameter aperture. RESULTS: Good agreement (between 1.7-3%) was found between the measured physical doses and the data provided by Xstrahl for all apertures used. Furthermore, all small field dosimetry data are in good agreement for both film reading methods and with our Monte Carlo simulations for both focal spot sizes. Furthermore, the small focal spot has been shown to produce a more homogenous beam with more stable penumbra over time. CONCLUSIONS: FilmQA Pro is a suitable tool for small field dosimetry, with a sufficiently small sampling area (0.1 mm) to ensure an accurate measurement. The electron beam focus should be chosen with care as this can potentially impact on beam stability and reproducibility.