In Vivo Microbeam Radiation Therapy at a Conventional Small Animal Irradiator.

Microbeam radiation therapy (MRT) is a still pre-clinical form of spatially fractionated radiotherapy, which uses an array of micrometer-wide, planar beams of X-ray radiation. The dose modulation in MRT has proven effective in the treatment of tumors while being well tolerated by normal tissue. Research on understanding the underlying biological mechanisms mostly requires large third-generation synchrotrons. In this study, we aimed to develop a preclinical treatment environment that would allow MRT independent of synchrotrons. We built a compact microbeam setup for pre-clinical experiments within a small animal irradiator and present in vivo MRT application, including treatment planning, dosimetry, and animal positioning. The brain of an immobilized mouse was treated with MRT, excised, and immunohistochemically stained against γH2AX for DNA double-strand breaks. We developed a comprehensive treatment planning system by adjusting an existing dose calculation algorithm to our setup and attaching it to the open-source software 3D-Slicer. Predicted doses in treatment planning agreed within 10% with film dosimetry readings. We demonstrated the feasibility of MRT exposures in vivo at a compact source and showed that the microbeam pattern is observable in histological sections of a mouse brain. The platform developed in this study will be used for pre-clinical research of MRT.

Dual energy CT for a small animal radiation research platform using an empirical dual energy calibration.

Objective.Dual energy computed tomography (DECT) has been shown to provide additional image information compared to conventional CT and has been used in clinical routine for several years. The objective of this work is to present a DECT implementation for a Small Animal Radiation Research Platform (SARRP) and to verify it with a quantitative analysis of a material phantom and a qualitative analysis with anex-vivomouse measurement.Approach.For dual energy imaging, two different spectra are required, but commercial small animal irradiators are usually not optimized for DECT. We present a method that enables dual energy imaging on a SARRP with sequential scanning and an Empirical Dual Energy Calibration (EDEC). EDEC does not require the exact knowledge of spectra and attenuation coefficients; instead, it is based on a calibration. Due to the SARRP geometry and reconstruction algorithm, the calibration is done using an artificial CT image based on measured values. The calibration yields coefficients to convert the measured images into material decomposed images.Main results.To analyze the method quantitatively, the electron density and the effective atomic number of a material phantom were calculated and compared with theoretical values. The electron density showed a maximum deviation from the theoretical values of less than 5% and the atomic number of slightly more than 6%. For use in mice, DECT is particularly useful in distinguishing iodine contrast agent from bone. A material decomposition of anex-vivomouse with iodine contrast agent was material decomposed to show that bone and iodine can be distinguished and iodine-corrected images can be calculated.Significance.DECT is capable of calculating electron density images and effective atomic number images, which are appropriate parameters for quantitative analysis. Furthermore, virtual monochromatic images can be obtained for a better differentiation of materials, especially bone and iodine contrast agent.

Treatment Planning Study for Microbeam Radiotherapy Using Clinical Patient Data.

Microbeam radiotherapy (MRT) is a novel, still preclinical dose delivery technique. MRT has shown reduced normal tissue effects at equal tumor control rates compared to conventional radiotherapy. Treatment planning studies are required to permit clinical application. The aim of this study was to establish a dose comparison between MRT and conventional radiotherapy and to identify suitable clinical scenarios for future applications of MRT. We simulated MRT treatment scenarios for clinical patient data using an inhouse developed planning algorithm based on a hybrid Monte Carlo dose calculation and implemented the concept of equivalent uniform dose (EUD) for MRT dose evaluation. The investigated clinical scenarios comprised fractionated radiotherapy of a glioblastoma resection cavity, a lung stereotactic body radiotherapy (SBRT), palliative bone metastasis irradiation, brain metastasis radiosurgery and hypofractionated breast cancer radiotherapy. Clinically acceptable treatment plans were achieved for most analyzed parameters. Lung SBRT seemed the most challenging treatment scenario. Major limitations comprised treatment plan optimization and dose calculation considering the tissue microstructure. This study presents an important step of the development towards clinical MRT. For clinical treatment scenarios using a sophisticated dose comparison concept based on EUD and EQD2, we demonstrated the capability of MRT to achieve clinically acceptable dose distributions.

Deep inspiration breath-hold for left-sided breast irradiation: Analysis of dose-mass histograms and the impact of lung expansion.

BACKGROUND: The aim of this study was to compare dose-volume histogram (DVH) with dose-mass histogram (DMH) parameters for treatment of left-sided breast cancer in deep inspiration breath-hold (DIBH) and free breathing (FB). Additionally, lung expansion and anatomical factors were analyzed and correlated to dose differences. METHODS: For 31 patients 3D conformal radiation therapy plans were retrospectively calculated on FB and DIBH CTs in the treatment planning system. The calculated doses, structures and CT data were transferred into MATLAB and DVHs and DMHs were calculated. Mean doses (Dmean), volumes and masses receiving certain doses (Vx, Mx) were determined for the left lung and the heart. Additionally, expansion of the left lung was evaluated using deformable image registration. Differences in DVH and DMH dose parameters between FB and DIBH were statistically analyzed and correlated to lung expansion and anatomical factors. RESULTS: DIBH reduced Dmean (DVH) and relative V20 (V20 [%]) of the left lung in all patients, on average by - 19 ± 9% (mean ± standard deviation) and - 24 ± 10%. Dmean (DMH) and M20 [%] were also significantly reduced (- 12 ± 11%, - 16 ± 13%), however 4 patients had higher DMH values in DIBH than in FB. Linear regression showed good correlations between DVH and DMH parameters, e.g. a dosimetric benefit smaller than 8.4% for Dmean (DVH) in DIBH indicated more irradiated lung mass in DIBH than in FB. The mean expansion of the left lung between FB and DIBH was 1.5 ± 2.4 mm (left), 16.0 ± 4.0 mm (anterior) and 12.2 ± 4.6 mm (caudal). No significant correlations were found between expansions and differences in Dmean for the left lung. The heart dose in DIBH was reduced in all patients by 53% (Dmean) and this dosimetric benefit correlated to lung expansion in anterior. CONCLUSIONS: Treatment of left-sided breast cancer in DIBH reduced dose to the heart and in most cases the lung dose, relative irradiated lung volume and lung mass. A mass related dosimetric benefit in DIBH can be achieved as long as the volume related benefit is about ≥8-9%. The lung expansion (breathing pattern) showed no impact on lung dose, but on heart dose. A stronger chest breathing (anterior expansion) for DIBH seems to be more beneficial than abdominal breathing.

Interobserver variability of patient positioning using four different CT datasets for image registration in lung stereotactic body radiotherapy.

PURPOSE: To assess the impact of different reference CT datasets on manual image registration with free-breathing three-dimensional (3D) cone beam CTs (FB-CBCT) for patient positioning by several observers. METHODS: For 48 patients with lung lesions, manual image registration with FB-CBCTs was performed by four observers. A slow planning CT (PCT), average intensity projection (AIP), maximum intensity projection (MIP), and midventilation CT (MidV) were used as reference images. Couch shift differences between the four reference CT datasets for each observer as well as shift differences between the observers for the same reference CT dataset were determined. Statistical analyses were performed and correlations between the registration differences and the 3D tumor motion and the CBCT score were calculated. RESULTS: The mean 3D shift difference between different reference CT datasets was the smallest for AIPvsMIP (range 1.1-2.2 mm) and the largest for MidVvsPCT (2.8-3.5 mm) with differences >10 mm. The 3D shifts showed partially significant correlations to 3D tumor motion and CBCT score. The interobserver comparison for the same reference CTs resulted in the smallest ∆3D mean differences and mean ∆3D standard deviation for ∆AIP (1.5 ± 0.7 mm, 0.7 ± 0.4 mm). The maximal 3D shift difference between observers was 10.4 mm (∆MidV). Both 3D tumor motion and mean CBCT score correlated with the shift differences (Rs = 0.336-0.740). CONCLUSION: The applied reference CT dataset impacts image registration and causes interobserver variabilities. The 3D tumor motion and CBCT quality affect shift differences. The smallest differences were found for AIP which might be the most appropriate CT dataset for image registration with FB-CBCT.

Systematic out-of-field secondary neutron spectrometry and dosimetry in pencil beam scanning proton therapy.

BACKGROUND AND PURPOSE: Systematic investigation of the energy and angular dependence of secondary neutron fluence energy distributions and ambient dose equivalents values (H*(10)) inside a pencil beam scanning proton therapy treatment room using a gantry. MATERIALS AND METHODS: Neutron fluence energy distributions were measured with an extended-range Bonner sphere spectrometer featuring ³He proportional counters, at four positions at 0°, 45°, 90°, and 135° with respect to beam direction and at a distance of 2 m from the isocenter. The energy distribution of secondary neutrons was investigated for initial proton beam energies of 75 MeV, 140 MeV, and 200 MeV, respectively, using a 2D scanned irradiation field of 11 × 11 cm² delivered to a 30 × 30 × 30 cm³ PMMA phantom. Additional measurements were performed at a proton energy of 118 MeV including a 5 cm range-shifter (PMMA), yielding a Bragg peak position similar to that of 75 MeV protons. RESULTS: Ambient dose equivalent values from 0.3 µSv/Gy (75 MeV; 90°) to 24 µSv/Gy (200 MeV; 0°) were measured inside the treatment room at a distance of 2 m from the isocenter. H*(10) values were lower (by factors of up to 7.2 (at 45°)) at 75 MeV compared to those at 118 MeV with the 5 cm range-shifter. At 0° and 45°, an evaporation peak was found in the measured neutron fluence energy distributions, at neutron energies around MeV, which contributes about 50% to total H*(10) values, for all investigated proton beam energies. CONCLUSIONS: This study showed a pronounced increase of secondary neutron H*(10) values inside the proton treatment room with increasing proton energy without beam modifiers. For example, in beam direction this increase was about a factor of 50 when protons of 75 MeV and 200 MeV were compared. The existence of a peak of secondary neutrons in the MeV region was demonstrated in beam direction (0°). This peak is due to evaporation neutrons produced in the existing surrounding materials such as those used for the gantry. Therefore, any simulation of the secondary neutrons within a proton treatment room must take these materials into account. In addition, the results obtained here show that the use of a range-shifter increases the production of secondary neutrons inside the treatment room. Using a range-shifter, the higher neutron doses observed mainly result from the higher incident proton energy (118 MeV instead of 75 MeV when no range-shifter was used), due to higher neutron production cross-sections.

Registration uncertainties between 3D cone beam computed tomography and different reference CT datasets in lung stereotactic body radiation therapy.

BACKGROUND: The aim of this study was to analyze differences in couch shifts (setup errors) resulting from image registration of different CT datasets with free breathing cone beam CTs (FB-CBCT). As well automatic as manual image registrations were performed and registration results were correlated to tumor characteristics. METHODS: FB-CBCT image registration was performed for 49 patients with lung lesions using slow planning CT (PCT), average intensity projection (AIP), maximum intensity projection (MIP) and mid-ventilation CTs (MidV) as reference images. Both, automatic and manual image registrations were applied. Shift differences were evaluated between the registered CT datasets for automatic and manual registration, respectively. Furthermore, differences between automatic and manual registration were analyzed for the same CT datasets. The registration results were statistically analyzed and correlated to tumor characteristics (3D tumor motion, tumor volume, superior-inferior (SI) distance, tumor environment). RESULTS: Median 3D shift differences over all patients were between 0.5 mm (AIPvsMIP) and 1.9 mm (MIPvsPCT and MidVvsPCT) for the automatic registration and between 1.8 mm (AIPvsPCT) and 2.8 mm (MIPvsPCT and MidVvsPCT) for the manual registration. For some patients, large shift differences (>5.0 mm) were found (maximum 10.5 mm, automatic registration). Comparing automatic vs manual registrations for the same reference CTs, ∆AIP achieved the smallest (1.1 mm) and ∆MIP the largest (1.9 mm) median 3D shift differences. The standard deviation (variability) for the 3D shift differences was also the smallest for ∆AIP (1.1 mm). Significant correlations (p < 0.01) between 3D shift difference and 3D tumor motion (AIPvsMIP, MIPvsMidV) and SI distance (AIPvsMIP) (automatic) and also for 3D tumor motion (∆PCT, ∆MidV; automatic vs manual) were found. CONCLUSIONS: Using different CT datasets for image registration with FB-CBCTs can result in different 3D couch shifts. Manual registrations achieved partly different 3D shifts than automatic registrations. AIP CTs yielded the smallest shift differences and might be the most appropriate CT dataset for registration with 3D FB-CBCTs.

Dosimetric impact of different CT datasets for stereotactic treatment planning using 3D conformal radiotherapy or volumetric modulated arc therapy.

BACKGROUND: The purpose of this study was to assess the impact on dose to the planning target volume (PTV) and organs at risk (OAR) by using four differently generated CT datasets for dose calculation in stereotactic body radiotherapy (SBRT) of lung and liver tumors. Additionally, dose differences between 3D conformal radiotherapy and volumetric modulated arc therapy (VMAT) plans calculated on these CT datasets were determined. METHODS: Twenty SBRT patients, ten lung cases and ten liver cases, were retrospectively selected for this study. Treatment plans were optimized on average intensity projection (AIP) CTs using 3D conformal radiotherapy (3D-CRT) and volumetric modulated arc therapy (VMAT). Afterwards, the plans were copied to the planning CTs (PCT), maximum intensity projection (MIP) and mid-ventilation (MidV) CT datasets and dose was recalculated keeping all beam parameters and monitor units unchanged. Ipsilateral lung and liver volumes and dosimetric parameters for PTV (Dmean, D2, D98, D95), ipsilateral lung and liver (Dmean, V30, V20, V10) were determined and statistically analysed using Wilcoxon test. RESULTS: Significant but small mean differences were found for PTV dose between the CTs (lung SBRT: ≤2.5 %; liver SBRT: ≤1.6 %). MIPs achieved the smallest lung and the largest liver volumes. OAR mean doses in MIP plans were distinctly smaller than in the other CT datasets. Furthermore, overlapping of tumors with the diaphragm results in underestimated ipsilateral lung dose in MIP plans. Best agreement was found between AIP and MidV (lung SBRT). Overall, differences in liver SBRT were smaller than in lung SBRT and VMAT plans achieved slightly smaller differences than 3D-CRT plans. CONCLUSIONS: Only small differences were found for PTV parameters between the four CT datasets. Larger differences occurred for the doses to organs at risk (ipsilateral lung, liver) especially for MIP plans. No relevant differences were observed between 3D-CRT or VMAT plans. MIP CTs are not appropriate for OAR dose assessment. PCT, AIP and MidV resulted in similar doses. If a 4DCT is acquired PCT can be omitted using AIP or MidV for treatment planning.

Impact of interfractional changes in head and neck cancer patients on the delivered dose in intensity modulated radiotherapy with protons and photons.

PURPOSE: To investigate the influence of interfractional changes on the delivered dose of intensity modulated proton (IMPT) and photon plans (IMXT). METHODS AND MATERIALS: Five postoperative head and neck cancer patients, previously treated with tomotherapy at our institute, were analyzed. The planning study is based on megavoltage (MV) control images. For each patient one IMPT plan and one IMXT plan were generated on the first MV-CT and recalculated on weekly control MV-CTs in the actual treatment position. Dose criteria for evaluation were coverage and conformity of the planning target volume (PTV), as well as mean dose to parotids and maximum dose to spinal cord. RESULTS: Considerable dosimetric changes were observed for IMPT and IMXT plans. Proton plans showed a more pronounced increase of maximum dose and decrease of minimum dose with local underdosage occurring even in the center of the PTV (worst IMPT vs. IMXT coverage: 66.7% vs. 85.0%). The doses to organs at risk (OARs) increased during the treatment period. However, the OAR doses of IMPT stayed below corresponding IMXT values at any time. For both modalities treatment plans did not necessarily worsen monotonically throughout the treatment. CONCLUSIONS: Although absolute differences between planned and reconstructed doses were larger in IMPT plans, doses to OARs were higher in IMXT plans. Tumor coverage was more stable in IMXT plans; IMPT dose distributions indicated a high risk for local underdosage during the treatment course.

Comparative analysis of an image-guided versus a non-image-guided setup approach in terms of delivered dose to the parotid glands in head-and-neck cancer IMRT.

PURPOSE: To assess the impact of interfractional variations of shape and setup uncertainties on the dose to the parotid glands (PGs) in head-and-neck cancer intensity-modulated radiotherapy and image-guided radiotherapy (IGRT). METHODS AND MATERIALS: Two scenarios were analyzed retrospectively for 10 head-and-neck cancer patients, treated with helical TomoTherapy (TomoTherapy Inc., Madison, WI): the IGRT scenario and the non-IGRT scenario. The initial dose-volume histograms derived from the planning computed tomography (PCT) scan and 120 recalculated dose-volume histograms of the PGs of each scenario and of corresponding fractions were compared. Setup errors, cumulative median doses (CMDs) for 6 fractions, overall volumes of the PGs, and volumes that received less than 1 Gy or more than 1.6 Gy per fraction were analyzed. RESULTS: The mean decrease in the PG volume was 0.13 cm(3)/d. There was a significantly higher CMD than initially predicted (mean increase for 6 fractions, 1.13 Gy for IGRT and 0.96 Gy for non-IGRT). The volume that received less than 1 Gy per fraction decreased (mean difference to PCT, 1.36 cm(3) for IGRT [p = 0.003] and 1.35 cm(3) for non-IGRT [p = 0.003]) and the volume that received more than 1.6 Gy per fraction increased with increasing fraction number (mean difference to PCT, 1.14 cm(3) for IGRT [p = 0.01] and 1.16 cm(3) for non-IGRT [p = 0.006]). There was no statistically significant difference between the two scenarios (CMD, p = 0.095; volume that received <1 Gy per fraction, p = 0.896; and volume that received >1.6 Gy per fraction, p = 0.855). CONCLUSIONS: In the analyzed group the actual delivered dose to the PGs does not differ significantly between an IGRT and a non-IGRT approach. However, IGRT in head-and-neck cancer intensity-modulated radiotherapy is strongly recommended to improve patient setup.