Roadmap for precision preclinical x-ray radiation studies.

This Roadmap paper covers the field of precision preclinical x-ray radiation studies in animal models. It is mostly focused on models for cancer and normal tissue response to radiation, but also discusses other disease models. The recent technological evolution in imaging, irradiation, dosimetry and monitoring that have empowered these kinds of studies is discussed, and many developments in the near future are outlined. Finally, clinical translation and reverse translation are discussed.

Molecular Detection of Venous Thrombosis in Mouse Models Using SPECT/CT.

The efficacy of thrombolysis is inversely correlated with thrombus age. During early thrombogenesis, activated factor XIII (FXIIIa) cross-links α2-AP to fibrin to protect it from early lysis. This was exploited to develop an α2-AP-based imaging agent to detect early clot formation likely susceptible to thrombolysis treatment. In this study, this imaging probe was improved and validated using 111In SPECT/CT in a mouse thrombosis model. In vitro fluorescent- and 111In-labelled imaging probe-to-fibrin cross-linking assays were performed. Thrombus formation was induced in C57Bl/6 mice by endothelial damage (FeCl3) or by ligation (stenosis) of the infrarenal vena cava (IVC). Two or six hours post-surgery, mice were injected with 111In-DTPA-A16 and ExiTron Nano 12000, and binding of the imaging tracer to thrombi was assessed by SPECT/CT. Subsequently, ex vivo IVCs were subjected to autoradiography and histochemical analysis for platelets and fibrin. Efficient in vitro cross-linking of A16 imaging probe to fibrin was obtained. In vivo IVC thrombosis models yielded stable platelet-rich thrombi with FeCl3 and fibrin and red cell-rich thrombi with stenosis. In the stenosis model, clot formation in the vena cava corresponded with a SPECT hotspot using an A16 imaging probe as a molecular tracer. The fibrin-targeting A16 probe showed specific binding to mouse thrombi in in vitro assays and the in vivo DVT model. The use of specific and covalent fibrin-binding probes might enable the clinical non-invasive imaging of early and active thrombosis.

Inter-observer variability of organ contouring for preclinical studies with cone beam Computed Tomography imaging.

BACKGROUND AND PURPOSE: In preclinical radiation studies, there is great interest in quantifying the radiation response of healthy tissues. Manual contouring has significant impact on the treatment-planning because of variation introduced by human interpretation. This results in inconsistencies when assessing normal tissue volumes. Evaluation of these discrepancies can provide a better understanding on the limitations of the current preclinical radiation workflow. In the present work, interobserver variability (IOV) in manual contouring of rodent normal tissues on cone-beam Computed Tomography, in head and thorax regions was evaluated. MATERIALS AND METHODS: Two animal technicians performed manually (assisted) contouring of normal tissues located within the thorax and head regions of rodents, 20 cases per body site. Mean surface distance (MSD), displacement of center of mass (ΔCoM), DICE similarity coefficient (DSC) and the 95th percentile Hausdorff distance (HD95) were calculated between the contours of the two observers to evaluate the IOV. RESULTS: For the thorax organs, right lung had the lowest IOV (ΔCoM: 0.08 ±â€¯0.04 mm, DSC: 0.96 ±â€¯0.01, MSD:0.07 ±â€¯0.01 mm, HD95:0.20 ±â€¯0.03 mm) while spinal cord, the highest IOV (ΔCoM:0.5 ±â€¯0.3 mm, DSC:0.81 ±â€¯0.05, MSD:0.14 ±â€¯0.03 mm, HD95:0.8 ±â€¯0.2 mm). Regarding head organs, right eye demonstrated the lowest IOV (ΔCoM:0.12 ±â€¯0.08 mm, DSC: 0.93 ±â€¯0.02, MSD: 0.15 ±â€¯0.04 mm, HD95: 0.29 ±â€¯0.07 mm) while complete brain, the highest IOV (ΔCoM: 0.2 ±â€¯0.1 mm, DSC: 0.94 ±â€¯0.02, MSD: 0.3 ±â€¯0.1 mm, HD95: 0.5 ±â€¯0.1 mm). CONCLUSIONS: Our findings reveal small IOV, within the sub-mm range, for thorax and head normal tissues in rodents. The set of contours can serve as a basis for developing an automated delineation method for e.g., treatment planning.

Automatic contouring of normal tissues with deep learning for preclinical radiation studies.

Objective.Delineation of relevant normal tissues is a bottleneck in image-guided precision radiotherapy workflows for small animals. A deep learning (DL) model for automatic contouring using standardized 3D micro cone-beam CT (µCBCT) volumes as input is proposed, to provide a fully automatic, generalizable method for normal tissue contouring in preclinical studies.Approach.A 3D U-net was trained to contour organs in the head (whole brain, left/right brain hemisphere, left/right eye) and thorax (complete lungs, left/right lung, heart, spinal cord, thorax bone) regions. As an important preprocessing step, Hounsfield units (HUs) were converted to mass density (MD) values, to remove the energy dependency of theµCBCT scanner and improve generalizability of the DL model. Model performance was evaluated quantitatively by Dice similarity coefficient (DSC), mean surface distance (MSD), 95th percentile Hausdorff distance (HD95p), and center of mass displacement (ΔCoM). For qualitative assessment, DL-generated contours (for 40 and 80 kV images) were scored (0: unacceptable, manual re-contouring needed - 5: no adjustments needed). An uncertainty analysis using Monte Carlo dropout uncertainty was performed for delineation of the heart.Main results.The proposed DL model and accompanying preprocessing method provide high quality contours, with in general median DSC > 0.85, MSD < 0.25 mm, HD95p < 1 mm and ΔCoM < 0.5 mm. The qualitative assessment showed very few contours needed manual adaptations (40 kV: 20/155 contours, 80 kV: 3/155 contours). The uncertainty of the DL model is small (within 2%).Significance.A DL-based model dedicated to preclinical studies has been developed for multi-organ segmentation in two body sites. For the first time, a method independent of image acquisition parameters has been quantitatively evaluated, resulting in sub-millimeter performance, while qualitative assessment demonstrated the high quality of the DL-generated contours. The uncertainty analysis additionally showed that inherent model variability is low.

Evofosfamide sensitizes esophageal carcinomas to radiation without increasing normal tissue toxicity.

BACKGROUND AND PURPOSE: Esophageal cancer incidence is increasing and is rarely curable. Hypoxic tumor areas cause resistance to conventional therapies, making them susceptible for treatment with hypoxia-activated prodrugs (HAPs). We investigated in vivo whether the HAP evofosfamide (TH-302) could increase the therapeutic ratio by sensitizing esophageal carcinomas to radiotherapy without increasing normal tissue toxicity. MATERIALS AND METHODS: To assess therapeutic efficacy, growth of xenografted esophageal squamous cell (OE21) or adeno (OE19) carcinomas was monitored after treatment with TH-302 (50 mg/kg, QD5) and irradiation (sham or 10 Gy). Short- and long-term toxicity was assessed in a gut mucosa and lung fibrosis irradiation model, sensitive to acute and late radiation injury respectively. Mice were injected with TH-302 (50 mg/kg, QD5) and the abdominal area (sham, 8 or 10 Gy) or the upper part of the right lung (sham, 20 Gy) was irradiated. Damage to normal tissues was assessed 84 hours later by histology and blood plasma citrulline levels (gut) and for up to 1 year by non-invasive micro CT imaging (lung). RESULTS: The combination treatment of TH-302 with radiotherapy resulted in significant tumor growth delay in OE19 (P = 0.02) and OE21 (P = 0.03) carcinomas, compared to radiotherapy only. Irradiation resulted in a dose-dependent decrease of crypt survival (P < 0.001), mucosal surface area (P < 0.01) and citrulline levels (P < 0.001) in both tumor and non-tumor bearing animals. On the long-term, irradiation increased CT density in the lung, indicating fibrosis, over time. TH-302 did not influence the radiation-induced short-term and long-term toxicity, confirmed by histological evaluation. CONCLUSION: The combination of TH-302 and radiotherapy might be a promising approach to improve the therapeutic index for esophageal cancer patients.

Dose painting by dynamic irradiation delivery on an image-guided small animal radiotherapy platform.

OBJECTIVE:: Using synchronized three-dimensional stage translation and multiangle radiation delivery to improve conformality and homogeneity of radiation delivery to complexly shaped target volumes for precision preclinical radiotherapy. METHODS:: A CT image of a mouse was used to design irradiation plans to target the spinal cord and an orthotopic lung tumour. A dose painting method is proposed that combines heterogeneous two-dimensional area irradiations from multiple beam directions. For each beam direction, a two-dimensional area was defined based on the projection of the target volume. Each area was divided into many single beam Monte Carlo simulations, based on radiochromic film characterization of a 2.4 mm beam of a commercial precision image-guided preclinical irradiation platform. Beam-on time optimization including all simulated beams from multiple beam directions was used to achieve clinically relevant irradiation objects. Dose painting irradiation plans were compared to irradiation plans using a fixed aperture and rotatable variable aperture collimator. RESULTS:: Irradiation plans for the proposed dose painting approach achieved good target coverage, similar dose to avoidance structures in comparison with irradiation using a rotatable variable aperture collimator, and considerably less dose to avoidance volumes in comparison with irradiation using a non-rotatable fixed aperture collimator. Required calculations and beam-on times were considerably longer for the dose painting method. CONCLUSION:: It was shown that the proposed dose painting strategy is a valuable extension to increase the versatility of current generation precision preclinical radiotherapy platforms. More conformal and homogeneous dose delivery may be achieved at the cost of increased radiation planning and delivery duration. ADVANCES IN KNOWLEDGE:: More advanced radiation planning for image-guided preclinical radiotherapy platforms can improve target dose conformality and homogeneity with the use of optimized dynamic irradiations with synchronized couch translation. The versatility of these platforms can be increased without hardware modifications.

Automatic multiatlas based organ at risk segmentation in mice.

OBJECTIVE:: During the treatment planning of a preclinical small animal irradiation, which has time limitations for reasons of animal wellbeing and workflow efficiency, the time consuming organ at risk (OAR) delineation is performed manually. This work aimed to develop, demonstrate, and quantitatively evaluate an automated contouring method for six OARs in a preclinical irritation treatment workflow. METHODS:: Microcone beam CT images of nine healthy mice were contoured with an in-house developed multiatlas-based image segmentation (MABIS) algorithm for six OARs: kidneys, eyes, heart, and brain. The automatic contouring was compared with the manual delineation using three quantitative metrics: the Dice Similarity Coefficient (DSC), 95th percentile Hausdorff Distance, and the centre of mass displacement. RESULTS:: A good agreement between manual and automatic contouring was found for OARs with sharp organ boundaries. For the brain and the heart, the median DSC was larger than 0.94, the median 95th Hausdorff Distance smaller than 0.44 mm, and the median centre of mass displacement smaller than 0.20 mm. Lower DSC values were obtained for the other OARs, but the median DSC was still larger than 0.74 for the left eye, 0.69 for the right eye, 0.89 for the left kidney and 0.80 for the right kidney. CONCLUSION:: The MABIS algorithm was able to delineate six OARs with a relatively high accuracy. Segmenting OARs with sharp organ boundaries performed better than low contrast OARs. ADVANCES IN KNOWLEDGE:: A MABIS algorithm is developed, evaluated, and demonstrated in a preclinical small animal irradiation research workflow.

An orthotopic non-small cell lung cancer model for image-guided small animal radiotherapy platforms.

METHODS:: An orthotopic non-small cell lung cancer model in NMRI-nude mice was established to investigate the complementary information acquired from 80 kVp microcone-beam CT (micro-CBCT) and bioluminescence imaging (BLI) using different angles and filter settings. Different micro-CBCT-based radiation-delivery plans were evaluated based on their dose-volume histogram metrics of tumor and organs at risk to select the optimal treatment plan. RESULTS:: H1299 cell suspensions injected directly into the lung render exponentially growing single tumor nodules whose CBCT-based volume quantification strongly correlated with BLI-integrated intensity. Parallel-opposed single angle beam plans through a single lung are preferred for smaller tumors, whereas for larger tumors, plans that spread the radiation dose across healthy tissues are favored. CONCLUSIONS:: Closely mimicking a clinical setting for lung cancer with highly advanced preclinical radiation treatment planning is possible in mice developing orthotopic lung tumors. ADVANCES IN KNOWLEDGE:: BLI and CBCT imaging of orthotopic lung tumors provide complementary information in a temporal manner. The optimal radiotherapy plan is tumor volume-dependent.

On the determination of planning target margins due to motion for mice lung tumours using a four-dimensional MOBY phantom.

OBJECTIVE:: This work aims to analyse the effect of respiratory motion on optimal irradiation margins for murine lung tumour models. METHODS:: Four-dimensional mathematical phantoms with different lung tumour locations affected by respiratory motion were created. Two extreme breathing curves were adopted and divided into time-points. Each time-point was loaded in a treatment planning system and Monte Carlo (MC) dose calculations were performed for a 360° arc plan. A time-resolved dose was derived, considering the gantry rotation and the breathing motion. Radiotherapy metrics were derived to assess the final treatment plans. An interpolation function was investigated to reduce calculation cost. RESULTS:: The effect of respiratory motion on the treatment plan quality is strongly dependent on the breathing pattern and the tumour position. Tumours located closer to the diaphragm required a compromise between tumour conformity and healthy tissue damage. A recipe, which considers collimator size, was proposed to derive tumour margins and spare the organs at risk (OARs) by respecting constraints on user-defined metrics. CONCLUSION:: It is recommended to add a target margin, especially on sites where movement is substantial. A simple recipe to derive tumour margins was developed. ADVANCES IN KNOWLEDGE:: This work is a first step towards a standard planning target volume concept in pre-clinical radiotherapy.

The impact of dual energy CT imaging on dose calculations for pre-clinical studies.

BACKGROUND: To investigate the feasibility of using dual-energy CT (DECT) for tissue segmentation and kilovolt (kV) dose calculations in pre-clinical studies and assess potential dose calculation accuracy gain. METHODS: Two phantoms and an ex-vivo mouse were scanned in a small animal irradiator with two distinct energies. Tissue segmentation was performed with the single-energy CT (SECT) and DECT methods. A number of different material maps was used. Dose calculations were performed to verify the impact of segmentations on the dose accuracy. RESULTS: DECT showed better overall results in comparison to SECT. Higher number of DECT segmentation media resulted in smaller dose differences in comparison to the reference. Increasing the number of materials in the SECT method yielded more instability. Both modalities showed a limit to which adding more materials with similar characteristics ceased providing better segmentation results, and resulted in more noise in the material maps and the dose distributions. The effect was aggravated with a decrease in beam energy. For the ex-vivo specimen, the choice of only one high dense bone for the SECT method resulted in large volumes of tissue receiving high doses. For the DECT method, the choice of more than one kind of bone resulted in lower dose values for the different tissues occupying the same volume. For the organs at risk surrounded by bone, the doses were lower when using the SECT method in comparison to DECT, due to the high absorption of the bone. SECT material segmentation may lead to an underestimation of the dose to OAR in the proximity of bone. CONCLUSIONS: The DECT method enabled the selection of a higher number of materials thereby increasing the accuracy in dose calculations. In phantom studies, SECT performed best with three materials and DECT with seven for the phantom case. For irradiations in preclinical studies with kV photon energies, the use of DECT segmentation combined with the choice of a low-density bone is recommended.

Nintedanib reduces radiation-induced microscopic lung fibrosis but this cannot be monitored by CT imaging: A preclinical study with a high precision image-guided irradiator.

BACKGROUND: Nintedanib has anti-fibrotic and anti-inflammatory activity and is approved for the treatment of idiopathic pulmonary fibrosis. The aim of this study was to noninvasively assess the efficacy of nintedanib in a mouse model of partial lung irradiation to prevent radiation-induced lung damage (RILD). METHODS: 266 C57BL/6 adult male mice were irradiated with a single radiation dose (0, 4, 8, 12, 16 or 20Gy) using parallel-opposed fields targeting the upper right lung using a precision image-guided small animal irradiator sparing heart and spine based on micro-CT images. One week post irradiation, mice were randomized across nintedanib daily oral gavage treatment (0, 30 or 60mg/kg). CT density analysis of the lungs was performed on monthly acquired micro-CT images. After 39weeks, lungs were processed to evaluate the fibrotic phenotype. RESULTS: Although the CT density increase correlated with the radiation dose, nintedanib did not influence this relationship. Immunohistochemical analysis confirmed the ability of nintedanib to reduce the microscopic fibrotic phenotype, in particular interstitial edema, interstitial and perivascular fibrosis and inflammation, and vasculitis. CONCLUSIONS: Nintedanib reduces radiation-induced lung fibrosis after partial lung irradiation without adverse effects, however, noninvasive CT imaging measuring electron density cannot be applied for monitoring its effects.

The influence of respiratory motion on dose delivery in a mouse lung tumour irradiation using the 4D MOBY phantom.

OBJECTIVE: During precision irradiation of a preclinical lung tumour model, the tumour is subject to breathing motion and it can partially move out of the irradiation field. This work aimed to perform a quantitative analysis of the impact of respiratory motion on a mouse lung tumour irradiation with small fields. METHODS: A four-dimensional digital mouse whole body phantom (MOBY) with a virtual 4-mm spherical lung tumour at different locations in both lungs is used to simulate a breathing anaesthetized mouse in different breathing phases representing a full breathing cycle. The breathing curve is determined by fluoroscopic imaging of an anaesthetized mouse. Each MOBY time frame is loaded in a dedicated treatment planning system (small animal radiotherapy-Plan) and is irradiated by a full arc with a 5-mm circular collimator. Mean and time-dependent organ doses are calculated for the tumour, heart and spinal cord. RESULTS: Depending on the location of the lung tumour, an overestimation of the mean tumour dose up to 11% is found. The mean heart dose could be both overestimated or underestimated because the heart moves in or out of the irradiation field depending on the beam target location. The respiratory motion does not affect the mean spinal cord dose. A dose gradient is visible in the time-dependent tumour dose distribution. CONCLUSION: In the future, new methods need to be developed to track the lung tumour motion before preclinical irradiation to adjust the irradiation plan. Margins, collimator diameter and target dose could be changed easily, but they all have their drawbacks. State-of-the-art clinical techniques such as respiratory gating or motion tracking may offer a solution for the cold spots in the time-dependent tumour dose. Advances in knowledge: A suitable method is found to quantify changes in organ dose due to respiratory motion in mouse lung tumour image-guided precision irradiation.

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 (Zeff) and relative electron densities (ρe) for phantom inserts with known elemental compositions and relative electron densities. RESULTS: The optimal energy combination was determined to be 50 and 90 kVp. For this combination, Zeff and ρe can be extracted with a mean error of 0.11 and 0.010, respectively, at a dose level of 60 cGy. 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 Zeff and ρe. 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 Zeff and ρe 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.

NOTCH blockade combined with radiation therapy and temozolomide prolongs survival of orthotopic glioblastoma.

Glioblastoma multiforme (GBM) is the most common malignant brain tumor in adults. The current standard of care includes surgery followed by radiotherapy (RT) and chemotherapy with temozolomide (TMZ). Treatment often fails due to the radiation resistance and intrinsic or acquired TMZ resistance of a small percentage of cells with stem cell-like behavior (CSC). The NOTCH signaling pathway is expressed and active in human glioblastoma and NOTCH inhibitors attenuate tumor growth in vivo in xenograft models. Here we show using an image guided micro-CT and precision radiotherapy platform that a combination of the clinically approved NOTCH/γ-secretase inhibitor (GSI) RO4929097 with standard of care (TMZ + RT) reduces tumor growth and prolongs survival compared to dual combinations. We show that GSI in combination with RT and TMZ attenuates proliferation, decreases 3D spheroid growth and results into a marked reduction in clonogenic survival in primary and established glioma cell lines. We found that the glioma stem cell marker CD133, SOX2 and Nestin were reduced following combination treatments and NOTCH inhibitors albeit in a different manner. These findings indicate that NOTCH inhibition combined with standard of care treatment has an anti-glioma stem cell effect which provides an improved survival benefit for GBM and encourages further translational and clinical studies.

A framework for inverse planning of beam-on times for 3D small animal radiotherapy using interactive multi-objective optimisation.

Advances in precision small animal radiotherapy hardware enable the delivery of increasingly complicated dose distributions on the millimeter scale. Manual creation and evaluation of treatment plans becomes difficult or even infeasible with an increasing number of degrees of freedom for dose delivery and available image data. The goal of this work is to develop an optimisation model that determines beam-on times for a given beam configuration, and to assess the feasibility and benefits of an automated treatment planning system for small animal radiotherapy. The developed model determines a Pareto optimal solution using operator-defined weights for a multiple-objective treatment planning problem. An interactive approach allows the planner to navigate towards, and to select the Pareto optimal treatment plan that yields the most preferred trade-off of the conflicting objectives. This model was evaluated using four small animal cases based on cone-beam computed tomography images. Resulting treatment plan quality was compared to the quality of manually optimised treatment plans using dose-volume histograms and metrics. Results show that the developed framework is well capable of optimising beam-on times for 3D dose distributions and offers several advantages over manual treatment plan optimisation. For all cases but the simple flank tumour case, a similar amount of time was needed for manual and automated beam-on time optimisation. In this time frame, manual optimisation generates a single treatment plan, while the inverse planning system yields a set of Pareto optimal solutions which provides quantitative insight on the sensitivity of conflicting objectives. Treatment planning automation decreases the dependence on operator experience and allows for the use of class solutions for similar treatment scenarios. This can shorten the time required for treatment planning and therefore increase animal throughput. In addition, this can improve treatment standardisation and comparability of research data within studies and among different institutes.

An image guided small animal radiation therapy platform (SmART) to monitor glioblastoma progression and therapy response.

BACKGROUND AND PURPOSE: Glioblastoma multiforme is the most common malignant brain tumor. Standard treatment including surgery, radiotherapy and chemotherapy with temozolomide is not curative. There is a great need for in vitro and in vivo models closely mimicking clinical practice to ensure better translation of novel preclinical findings. METHODS AND MATERIALS: A 3D spheroid model was established using the U87MG cell line. The efficacy of temozolomide, RT and combinations was assessed using growth delay assays. Orthotopic glioblastoma tumors were established, different radiation doses delivered based on micro-CT based treatment planning (SmART-plan) and dose volume histograms (DVH) were determined. Tumor growth was monitored using bioluminescent imaging. RESULTS: 3D spheroid cultures showed a dose-dependent growth delay upon single and combination treatments. Precise uniform radiation was achieved in all in vivo treatment groups at all doses tested, and DVHs showed accurate dose coverage in the planning target volume which resulted in tumor growth delay. CONCLUSION: We demonstrate that 3D spheroid technology can be reliably used for treatment efficacy evaluation and that mimicking a clinical setting is also possible in small animals. Both these in vitro and in vivo techniques can be combined for clinically relevant testing of novel drugs combined with radiation.

A longitudinal evaluation of partial lung irradiation in mice by using a dedicated image-guided small animal irradiator.

PURPOSE: In lung cancer radiation therapy, the dose constraints are determined mostly by healthy lung toxicity. Preclinical microirradiators are a new tool to evaluate treatment strategies closer to clinical irradiation devices. In this study, we quantified local changes in lung density symptomatic of radiation-induced lung fibrosis (RILF) after partial lung irradiation in mice by using a precision image-guided small animal irradiator integrated with micro-computed tomography (CT) imaging. METHODS AND MATERIALS: C57BL/6 adult male mice (n=76) were divided into 6 groups: a control group (0 Gy) and groups irradiated with a single fraction of 4, 8, 12, 16, or 20 Gy using 5-mm circular parallel-opposed fields targeting the upper right lung. A Monte Carlo model of the small animal irradiator was used for dose calculations. Following irradiation, all mice were imaged at regular intervals over 39 weeks (10 time points total). Nonrigid deformation was used to register the initial micro-CT scan to all subsequent scans. RESULTS: Significant differences could be observed between the 3 highest (>10 Gy) and 3 lowest irradiation (<10 Gy) dose levels. A mean difference of 120 ± 10 HU between the 0- and 20-Gy groups was observed at week 39. RILF was found to be spatially limited to the irradiated portion of the lung. CONCLUSIONS: The data suggest that the severity of RILF in partial lung irradiation compared to large field irradiation in mice for the same dose is reduced, and therefore higher doses can be tolerated.

A review of treatment planning for precision image-guided photon beam pre-clinical animal radiation studies.

Recently, precision irradiators integrated with a high-resolution CT imaging device became available for pre-clinical studies. These research platforms offer significant advantages over older generations of animal irradiators in terms of precision and accuracy of image-guided radiation targeting. These platforms are expected to play a significant role in defining experiments that will allow translation of research findings to the human clinical setting. In the field of radiotherapy, but also others such as neurology, the platforms create unique opportunities to explore e.g. the synergy between radiation and drugs or other agents. To fully exploit the advantages of this new technology, accurate methods are needed to plan the irradiation and to calculate the three-dimensional radiation dose distribution in the specimen. To this end, dedicated treatment planning systems are needed. In this review we will discuss specific issues for precision irradiation of small animals, we will describe the workflow of animal treatment planning, and we will examine several dose calculation algorithms (factorization, superposition-convolution, Monte Carlo simulation) used for animal irradiation with kilovolt photon beams. Issues such as dose reporting methods, photon scatter, tissue segmentation and motion will also be discussed briefly.

Development and validation of a treatment planning system for small animal radiotherapy: SmART-Plan.

BACKGROUND AND PURPOSE: Image-guided equipment for precision irradiation of small animals for pre-clinical radiotherapy research became recently available. To enable downscaled radiotherapy studies that can be translated into human radiotherapy knowledge, a treatment planning system for pre-clinical studies is required. MATERIAL AND METHODS: A dedicated treatment planning system (SmART-Plan) for small animal radiotherapy studies was developed. It is based on Monte Carlo simulation of particle transport in an animal. The voxel geometry is derived from the onboard cone beam CT imaging panel. SmART-Plan was validated using radiochromic film (RCF) dosimetry in various phantoms: uniform, multislab and a realistic plasticized mouse geometry. RESULTS: Good agreement was obtained between SmART-Plan dose calculations and RCF dose measurements in all phantoms. For various delivered plans agreement was obtained within 10% for the majority of the targeted dose region, with larger differences between 10% and 20% near the penumbra regions and for the smallest 1mm collimator. Absolute depth and lateral dose distributions showed better agreement for 5 and 15-mm collimators than for a 1-mm collimator, indicating that accurate dose prediction for the smallest field sizes is difficult. CONCLUSION: SmART-Plan offers a useful dose calculation tool for pre-clinical small animal irradiation studies.