The role of biomechanical anatomical modeling via computed tomography for identification of restrictive allograft syndrome.

Chronic lung allograft dysfunction (CLAD) reduces long-term graft survival. It is important to distinguish CLAD subtypes: bronchiolitis obliterans syndrome (BOS) and restrictive allograft syndrome (RAS) as RAS has a worse prognosis and accurate subtyping could facilitate targeted treatments. However, the current diagnosis of CLAD subtypes is based on pulmonary function test (PFT) results that reflect global estimates of lung function; anatomical modeling based on computed tomography (CT) has the potential to provide detailed analysis of global and regional lung function. The purpose of this study is to evaluate the utility of CT-based anatomical modeling for the identification of RAS. This retrospective study included 51 patients (CLAD: 17 BOS and 17 RAS, control: 17 No-CLAD). CT data were assessed using a biomechanical model-based platform (MORFEUS) to characterize changes in lung deformation between baseline and disease onset. Lung deformation demonstrated high sensitivity and specificity (>80%) in differentiating RAS from BOS (P<.0001) and No-CLAD (P<.0001). There were matching radiological reading and inward deformation abnormalities in 79% of lung sections in patients with RAS. Anatomical modeling is complementary to conventional assessment in the diagnosis of RAS and potentially provides quantitative data that can help in the characterization and detailed assessment of heterogeneous lung parenchymal disease.

A novel technique to enable experimental validation of deformable dose accumulation.

PURPOSE: To propose a novel technique to experimentally validate deformable dose algorithms by measuring 3D dose distributions under the condition of deformation using deformable gel dosimeters produced by a novel gel fabrication method. METHOD: Five gel dosimeters, two rigid control gels and three deformable gels, were manufactured and treated with the same conformal plan that prescribed 400 cGy to the isocenter. The control gels were treated statically; the deformable gels were treated while being compressed by an actuation device to simulate breathing motion (amplitude of compression = 1, 1.5, and 2 cm, respectively; frequency = 16 rpm). Comparison between the dose measured by the control gels and the corresponding static dose distribution calculated in the treatment planning system (TPS) has determined the intrinsic dose measurement uncertainty of the gel dosimeters. Doses accumulated using MORFEUS, a biomechanical model-based deformable registration and dose accumulation algorithm, were compared with the doses measured by the deformable gel dosimeters to verify the accuracy of MORFEUS using dose differences at each voxel as well as the gamma index test. Flexible plastic wraps were used to contain and protect the deformable gels from oxygen infiltration, which inhibits the gels' dose sensitizing ability. Since the wraps were imperfect oxygen barrier, dose comparison between MORFEUS and the deformable gels was performed only in the central region with a received dose of 200 cGy or above to exclude the peripheral region where oxygen penetration had likely affected dose measurements. RESULTS: Dose measured with the control gels showed that the intrinsic dose measurement uncertainty of the gel dosimeters was 11.8 cGy or 4.7% compared to the TPS. The absolute mean voxel-by-voxel dose difference between the accumulated dose and the dose measured with the deformable gels was 4.7 cGy (SD = 36.0 cGy) or 1.5% (SD = 13.4%) for the three deformable gels. The absolute mean vector distance between the 250, 300, 350, and 400 cGy isodose surfaces on the accumulated and measured distributions was 1.2 mm (SD < 1.5 mm). The gamma index test that used the dose measurement precision of the control gels as the dose difference criterion and 2 mm as the distance criterion was performed, and the average pass rate of the accumulated dose distributions for all three deformable gels was 92.7%. When the distance criterion was relaxed to 3 mm, the average pass rate increased to 96.9%. CONCLUSION: This study has proposed a novel technique to manufacture deformable volumetric gel dosimeters. By comparing the doses accumulated in MORFEUS and the doses measured with the dosimeters under the condition of deformation, the study has also demonstrated the potential of using deformable gel dosimetry to experimentally validate algorithms that include deformations into dose computation. Since dose less than 200 cGy was not evaluated in this study, future investigations will focus more on low dose regions by either using bigger gel dosimeters or prescribing a lower dose to provide a more complete experimental validation of MORFEUS across a wider dose range.

Deformable image registration of heterogeneous human lung incorporating the bronchial tree.

PURPOSE: To investigate the effect of the bronchial tree on the accuracy of biomechanical-based deformable image registration of human lungs. METHODS: Three dimensional finite element models have been developed using four dimensional computed tomography image data of ten lung cancer patients. Each model is built of a body, left and right lungs, tumor, and bronchial trees. Triangular shell elements are used for the bronchial trees while tetrahedral elements are used for other components. Hyperelastic material properties based on experimental investigation on human lungs are used for the lung parenchyma. Different material properties are assigned for the bronchial tree using five values for the modulus of elasticity of 0.01, 0.12, 0.5, 10, and 18 MPa. Lungs are modeled to slide inside chest cavities by applying frictionless contact surfaces between each lung and corresponding chest cavity. The accuracy of the models is examined using an average of 40 bronchial bifurcation points identified on inhale and exhale images. Relative accuracy is evaluated by comparing the displacement of all nodes within the lungs as well as the dosimetric difference at the exhale position predicted by the model. RESULTS: There is no significant effect of bronchial tree on the model accuracy based on the bifurcation points analysis. However, on the local level, using an average of 38 000 nodes, there is a maximum difference of 8.5 mm in the deformation of the bronchial trees, as the modulus of elasticity of the bronchial trees increases from 0.01 to 18 MPa; however, more than 96% of nodes are within a 2.5 mm difference in each direction. The average dose difference at the predicted exhale position is less than 35 cGy between the models. CONCLUSIONS: The bronchial tree has little effect on the global deformation and the accuracy of deformable image registration of lungs. Hence, the homogenous model is a reasonable assumption. Since there are some local deformation differences between nodes as the material properties of the bronchial tree change that may affect the accuracy of dosimetric results, heterogeneity may be required for a smaller scale modeling of lungs.

Reconstruction of 3D lung models from 2D planning data sets for Hodgkin's lymphoma patients using combined deformable image registration and navigator channels.

PURPOSE: Late complications (cardiac toxicities, secondary lung, and breast cancer) remain a significant concern in the radiation treatment of Hodgkin's lymphoma (HL). To address this issue, predictive dose-risk models could potentially be used to estimate radiotherapy-related late toxicities. This study investigates the use of deformable image registration (DIR) and navigator channels (NCs) to reconstruct 3D lung models from 2D radiographic planning images, in order to retrospectively calculate the treatment dose exposure to HL patients treated with 2D planning, which are now experiencing late effects. METHODS: Three-dimensional planning CT images of 52 current HL patients were acquired. 12 image sets were used to construct a male and a female population lung model. 23 "Reference" images were used to generate lung deformation adaptation templates, constructed by deforming the population model into each patient-specific lung geometry using a biomechanical-based DIR algorithm, MORFEUS. 17 "Test" patients were used to test the accuracy of the reconstruction technique by adapting existing templates using 2D digitally reconstructed radiographs. The adaptation process included three steps. First, a Reference patient was matched to a Test patient by thorax measurements. Second, four NCs (small regions of interest) were placed on the lung boundary to calculate 1D differences in lung edges. Third, the Reference lung model was adapted to the Test patient's lung using the 1D edge differences. The Reference-adapted Test model was then compared to the 3D lung contours of the actual Test patient by computing their percentage volume overlap (POL) and Dice coefficient. RESULTS: The average percentage overlapping volumes and Dice coefficient expressed as a percentage between the adapted and actual Test models were found to be 89.2 +/- 3.9% (Right lung = 88.8%; Left lung = 89.6%) and 89.3 +/- 2.7% (Right = 88.5%; Left = 90.2%), respectively. Paired T-tests demonstrated that the volumetric reconstruction method made a statistically significant improvement to the population lung model shape (p < 0.05). The error in the results were also comparable to the volume overlap difference observed between inhale and exhale lung volumes during free-breathing respiratory motion (POL: p = 0.43; Dice: p = 0.20), which implies that the accuracies of the reconstruction method are within breathing constraints and would not be the confining factor in estimating normal tissue dose exposure. CONCLUSIONS: The result findings show that the DIR-NC technique can achieve a high degree of reconstruction accuracy, and could be useful in approximating 3D dosimetric representations of historical 2D treatment. In turn, this could provide a better understanding of the biophysical relationship between dose-volume exposure and late term radiotherapy effects.

Evaluating the extent of cell death in 3D high frequency ultrasound by registration with whole-mount tumor histopathology.

PURPOSE: High frequency ultrasound imaging, 10-30 MHz, has the capability to assess tumor response to radiotherapy in mouse tumors as early as 24 h after treatment administration. The advantage of this technique is that the image contrast is generated by changes in the physical properties of dying cells. Therefore, a subject can be imaged before and multiple times during the treatment without the requirement of injecting specialized contrast agents. This study is motivated by a need to provide metrics of comparison between the volume and localization of cell death, assessed from histology, with the volume and localization of cell death surrogate, assessed as regions with increased echogeneity from ultrasound images. METHODS: The mice were exposed to radiation doses of 2, 4, and 8 Gy. Ultrasound images ivere collected from each tumor before and 24 h after exposure to radiation using a broadband 25 MHz center frequency transducer. After radiotherapy, tumors exhibited hyperechoic regions in ultrasound images that corresponded to areas of cell death in histology. The ultrasound and histological images were rigidly registered. The tumors and regions of cell death were manually outlined on histological images. Similarly, the tumors and hyperechoic regions were outlined on the ultrasound images. Each set of contours was converted to a volumetric mesh in order to compare the volumes and the localization of cell death in histological and ultrasound images. RESULTS: A shrinkage factor of 17 +/- 2% was calculated from the difference in the tumor volumes evaluated from histological and ultrasound images. This was used to correct the tumor and cell death volumes assessed from histology. After this correction, the average absolute difference between the volume of cell death assessed from ultrasound and histological images was 11 +/- 14% and the volume overlap was 70 +/- 12%. CONCLUSIONS: The method provided metrics of comparison between the volume of cell death assessed from histology and that assessed from ultrasound images. It was applied here to evaluate the capability of ultrasound imaging to assess early tumor response to radiotherapy in mouse tumors. Similarly, it can be applied in the future to evaluate the capability of ultrasound imaging to assess early tumor response to other modalities of cancer treatment. The study contributes to an understanding of the capabilities and limitation of ultrasound imaging at noninvasively detecting cell death. This provides a foundation for future developments regarding the use of ultrasound in preclinical and clinical applications to adapt treatments based on tumor response to cancer therapy.

Accuracy and sensitivity of finite element model-based deformable registration of the prostate.

PURPOSE: Evaluate the accuracy and the sensitivity to contour variation and model size of a finite element model-based deformable registration algorithm for the prostate. METHODS AND MATERIALS: Two magnetic resonance images (MRIs) were obtained for 21 prostate patients with three implanted markers. A single observer contoured the prostate and markers and performed blinded recontouring of the first MRI. A biomechanical-model based deformable registration algorithm, MORFEUS, was applied to each dataset pair, deforming the second image (B) to the first image (A). The residual error was calculated by comparing the center of mass (COM) of the markers with the predicted COM. Sensitivity to contour variation was calculated by deforming B to the repeat contour of A (A2). The sensitivity to the model size was calculated by reducing the number of nodes (B', A', A2') and repeating the analysis. RESULTS: The average residual error of the registration for B to A and B to A2 was 0.22 cm (SD: 0.08 cm) and 0.24 cm (SD: 0.09 cm), respectively. The average residual error of the registration of B' to A' and B' to A2' was 0.22 cm (SD: 0.10 cm) and 0.25 cm (SD: 0.10 cm), respectively. The average time to run MORFEUS on the standard and reduced model was 3606 s (SD: 7788 s) and 56 s (SD: 16 s), respectively. CONCLUSIONS: The accuracy of the algorithm, equal to the image voxel size, is not affected by intraobserver contour variability or model size. Reducing the model size significantly increases algorithm efficiency.

Improving image-guided target localization through deformable registration.

PURPOSE: To quantify the improvements in online target localization using kV cone beam CT (CBCT) with deformable registration. METHODS AND MATERIAL: Twelve patients treated under a 6 fraction liver cancer radiation therapy protocol were imaged in breath hold using kV CBCT at each treatment fraction. The images were imported into the treatment planning software and rigidly registered by fitting the liver, identified on the daily kV CBCT image, into the liver contours, previously drawn on the planning CT. The liver was then manually contoured on each CBCT image. Deformable registration was automatically performed, aligning the CT liver to the liver on each CBCT image using MORFEUS, a biomechanical model based deformable registration algorithm. The tumor, defined on planning CT, was mapped onto the CBCT, through MORFEUS. The center of mass (COM) displacement of the tumor was computed. RESULTS: The mean (SD) displacement magnitude (absolute value) of the COM following deformable registration was 0.08 (0.07), 0.10 (0.11), and 0.10 (0.17) cm in the left-right (LR), anterior-posterior (AP), and superior-inferior (SI) directions, respectively. The maximum displacement of the COM was 0.34, 0.65, and 0.97 cm in the LR, AP, and SI directions, respectively. Fifteen percent of the treatment fractions had a COM displacement of greater than 0.3 cm and 33% of patients had at least 1 fraction with a displacement of greater than 0.3 cm. The deformable registration, excluding the manual contouring of the liver, was performed in less than 1 minute, on average. DISCUSSION: Rigid registration of the liver volume between planning CT and verification kV CBCT localizes the tumor to within 0.3 cm for the majority (66%) of patients; however, larger offsets in tumor position can be observed due to liver deformation.

Development of multiorgan finite element-based prostate deformation model enabling registration of endorectal coil magnetic resonance imaging for radiotherapy planning.

PURPOSE: Endorectal coil (ERC) magnetic resonance imaging (MRI) provides superior visualization of the prostate compared with computed tomography at the expense of deformation. This study aimed to develop a multiorgan finite element deformable method, Morfeus, to accurately co-register these images for radiotherapy planning. METHODS: Patients with prostate cancer underwent fiducial marker implantation and computed tomography simulation for radiotherapy planning. A series of axial MRI scans were acquired with and without an ERC. The prostate, bladder, rectum, and pubic bones were manually segmented and assigned linear elastic material properties. Morfeus mapped the surface of the bladder and rectum between two imaged states, calculating the deformation of the prostate through biomechanical properties. The accuracy of deformation was measured as fiducial marker error and residual surface deformation between the inferred and actual prostate. The deformation map was inverted to deform from 100 cm(3) to no coil. RESULTS: The data from 19 patients were analyzed. Significant prostate deformation occurred with the ERC (mean intrapatient range, 0.88 +/- 0.25 cm). The mean vector error in fiducial marker position (n = 57) was 0.22 +/- 0.09 cm, and the mean vector residual surface deformation (n = 19) was 0.15 +/- 0.06 cm for deformation from no coil to 100-cm(3) ERC, with an image vector resolution of 0.22 cm. Accurately deformed MRI scans improved soft-tissue resolution of the anatomy for radiotherapy planning. CONCLUSIONS: This method of multiorgan deformable registration enabled accurate co-registration of ERC-MRI scans with computed tomography treatment planning images. Superior structural detail was visible on ERC-MRI, which has potential for improving target delineation.

Anatomic boundaries of the clinical target volume (prostate bed) after radical prostatectomy.

PURPOSE: We sought to derive and validate an interdisciplinary consensus definition for the anatomic boundaries of the postoperative clinical target volume (CTV, prostate bed). METHODS AND MATERIALS: Thirty one patients who had planned for radiotherapy after radical prostatectomy were enrolled and underwent computed tomography and magnetic resonance imaging (MRI) simulation prior to radiotherapy. Through an iterative process of consultation and discussion, an interdisciplinary consensus definition was derived based on a review of published data, patterns of local failure, surgical practice, and radiologic anatomy. In validation, we analyzed the distribution of surgical clips in reference to the consensus CTV and measured spatial uncertainties in delineating the CTV and vesicourethral anastomosis. Clinical radiotherapy plans were retrospectively evaluated against the consensus CTV (prostate bed). RESULTS: Anatomic boundaries of the consensus CTV (prostate bed) are described. Surgical clips (n = 339) were well distributed throughout the CTV. The vesicourethral anastomosis was accurately localized using central sagittal computed tomography reconstruction, with a mean +/- standard deviation uncertainty of 1.8 +/- 2.5 mm. Delineation uncertainties were small for both MRI and computed tomography (mean reproducibility, 0-3.8 mm; standard deviation, 1.0-2.3); they were most pronounced in the anteroposterior and superoinferior dimensions and at the superior/posterior-most aspect of the CTV. Retrospectively, the mean +/- standard deviation CTV (prostate bed) percentage of volume receiving 100% of prescribed dose was only 77% +/- 26%. CONCLUSIONS: We propose anatomic boundaries for the CTV (prostate bed) and present evidence supporting its validity. In the absence of gross recurrence, the role of MRI in delineating the CTV remains to be confirmed. The CTV is larger than historically practiced at our institution and should be encompassed by a microscopic tumoricidal dose.

Validation of biomechanical deformable image registration in the abdomen, thorax, and pelvis in a commercial radiotherapy treatment planning system.

PURPOSE: The accuracy of deformable image registration tools can vary widely between imaging modalities and specific implementations of the same algorithms. A biomechanical model-based algorithm initially developed in-house at an academic institution was translated into a commercial radiotherapy treatment planning system and validated for multiple imaging modalities and anatomic sites. METHODS: Biomechanical deformable registration (Morfeus) is a geometry-driven algorithm based on the finite element method. Boundary conditions are derived from the model-based segmentation of controlling structures in each image which establishes a point-to-point surface correspondence. For each controlling structure, material properties and fixed or sliding interfaces are assigned. The displacements of internal volumes for controlling structures and other structures implicitly deformed are solved with finite element analysis. Registration was performed for 74 patients with images (mean vector resolution) of thoracic and abdominal 4DCT (2.8 mm) and MR (5.3 mm), liver CT-MR (4.5 mm), and prostate MR (2.6 mm). Accuracy was quantified between deformed and actual target images using distance-to-agreement (DTA) for structure surfaces and the target registration error (TRE) for internal point landmarks. RESULTS: The results of the commercial implementation were as follows. The mean DTA was ≤ 1.0 mm for controlling structures and 1.0-3.5 mm for implicitly deformed structures on average. TRE ranged from 2.0 mm on prostate MR to 5.1 mm on lung MR on average, within 0.1 mm or lower than the image voxel sizes. Accuracy was not overly sensitive to changes in the material properties or variability in structure segmentations, as changing these inputs affected DTA and TRE by ≤ 0.8 mm. Maximum DTA > 5 mm occurred for 88% of the structures evaluated although these were within the inherent segmentation uncertainty for 82% of structures. Differences in accuracy between the commercial and in-house research implementations were ≤ 0.5 mm for mean DTA and ≤ 0.7 mm for mean TRE. CONCLUSIONS: Accuracy of biomechanical deformable registration evaluated on a large cohort of images in the thorax, abdomen and prostate was similar to the image voxel resolution on average across multiple modalities. Validation of this treatment planning system implementation supports biomechanical deformable registration as a versatile clinical tool to enable accurate target delineation at planning and treatment adaptation.

Feasibility of 4D perfusion CT imaging for the assessment of liver treatment response following SBRT and sorafenib.

OBJECTIVES: To evaluate the feasibility of 4-dimensional perfusion computed tomography (CT) as an imaging biomarker for patients with hepatocellular carcinoma and metastatic liver disease. METHODS AND MATERIALS: Patients underwent volumetric dynamic contrast-enhanced CT on a 320-slice scanner before and during stereotactic body radiation therapy and sorafenib, and at 1 and 3 months after treatment. Quiet free breathing was used in the CT acquisition and multiple techniques (rigid or deformable registration as well as outlier removal) were applied to account for residual liver motion. Kinetic modeling was performed on a voxel-by-voxel basis in the gross tumor volume and normal liver resulting in 3-dimensional parameter maps of blood perfusion, capillary permeability, blood volume, and mean transit time. Perfusion characteristics in the tumor and adjacent liver were correlated with radiation dose distributions to evaluate dose-response. Paired t tests assessed change in spatial and histogram parameters from baseline to different time points during and after treatment. Technique reproducibility as well as the impact of arterial and portal vein input functions was also investigated using intra- and inter-subject variance and Bland-Altman analysis. RESULTS: Quantitative perfusion parameters were reproducible (±5.7%; range, 2%-10%) depending on tumor/normal liver type and kinetic parameter. Statistically significant reductions in tumor perfusion were measurable over the course of treatment and as early as 1 week after sorafenib administration (P < .05). Marked liver parenchyma perfusion reduction was seen with a strong dose-response effect (R2 = 0.95) that increased significantly over the course treatment. CONCLUSIONS: The proposed methodology demonstrated feasibility of evaluating spatiotemporal changes in liver tumor perfusion and normal liver function following antiangiogenic therapy and radiation treatment warranting further evaluation of biomarker prognostication.

Impact of image registration surrogates on the planning target volume geometry for bladder radiation therapy.

PURPOSE: The use of Lipiodol and cone beam computed tomography (CT) has facilitated the generation of patient-specific planning target volumes (PTV) to reduce irradiation of normal tissue. However, injecting Lipiodol to demarcate the target volume is an invasive procedure. Center of bladder (COB) and bladder wall surface (BWS) encompassed by the clinical target volume (CTV) are proposed to be the alternative noninvasive surrogates. This study examines the impact of using these 3 surrogates for image registration on the resultant geometry of patient-specific PTVs. METHODS AND MATERIALS: Twenty bladder cancer patients who had Lipiodol injection before planning CT were included. Lipiodol, CTV, and bladder were delineated on the planning CT. In addition, CTVs were delineated on 5 cone beam CT scans from each patient. Cone beam CT scans were registered to planning CT using Lipiodol, COB, and BWS to generate Lipiodol-PTV, COB-PTV, and BWS-PTV. Using Lipiodol as the reference, the difference in the 2-dimensional/3-dimensional displacement values and the geometry of the resultant PTVs were quantified. RESULTS: A total of 1200 displacement values and 60 volumes were included for analysis. The overall median and standard deviation (SD) of the 3-dimensional displacement (mm) measured by Lipiodol, BWS, and COB are 25 (SD, 15), 24 (SD, 14), and 21 (SD, 15), respectively. Lipiodol-PTV has the smallest mean volume, followed by BWS-PTV and COB-PTV. BWS-PTV was more geometrically similar to Lipiodol-PTV when compared with COB-PTV. Six of 20 COB-PTVs who had CTV located at either the dome or the base of the bladder were larger than the corresponding Lipiodol-PTV by more than 20%. CONCLUSION: Lipiodol is the optimal image registration surrogate for partial bladder radiation therapy. However, for patients who are contraindicated for Lipiodol injection, BWS is the preferred noninvasive surrogate because the derived PTV has a smaller geometric variation from the Lipiodol-PTV when compared with COB, especially when the CTV was located at the dome or the base of the bladder.

Planned versus 'delivered' bladder dose reconstructed using solid and hollow organ models during prostate cancer IMRT.

BACKGROUND AND PURPOSE: All studies to date have evaluated the dosimetric effect of bladder deformation using an organ model that includes the dose to the urine. This research reconstructed bladder dose using both hollow and solid organ models, to determine if dose/volume differences exist. MATERIALS AND METHODS: 35 prostate IMRT patients were selected, who had received 78Gy in 39 fractions and full bladder instructions. Biomechanical modelling and finite element analysis were used to reconstruct bladder dose (solid and hollow organ model) using every third CBCT throughout the treatment course. RESULTS: Reconstructed dose (ReconDose) was 11.3Gy greater than planned dose (planDose) with a hollow bladder model (p<0.001) and 12.3Gy greater with a solid bladder model (p<0.0001). Median reconstructed volumes within the 30Gy, 65Gy and 78Gy isodoses were 3-4 times larger with the solid organ model (p<0.0001). The difference between planning bladder volume and median treatment volume was associated with the difference between the planDose and reconDose below 78Gy (R(2)>0.61). CONCLUSIONS: Substantial differences exist between planned and reconstructed bladder dose, associated with the differences in bladder filling between planning and treatment. Dose reconstructed using a solid bladder model over-reports the volume of bladder within key isodose levels and overestimates the differences between planned and reconstructed dose. Dose reconstruction with a hollow organ model is recommended if the goal is to associate that dose with toxicity.

Radiation dose response simulation for biomechanical-based deformable image registration of head and neck cancer treatment.

Biomechanical-based deformable image registration is conducted on the head and neck region. Patient specific 3D finite element models consisting of parotid glands (PG), submandibular glands (SG), tumor, vertebrae (VB), mandible, and external body are used to register pre-treatment MRI to post-treatment MR images to model the dose response using image data of five patients. The images are registered using combinations of vertebrae and mandible alignments, and surface projection of the external body as boundary conditions. In addition, the dose response is simulated by applying a new loading technique in the form of a dose-induced shrinkage using the dose-volume relationship. The dose-induced load is applied as dose-induced shrinkage of the tumor and four salivary glands. The Dice Similarity Coefficient (DSC) is calculated for the four salivary glands, and tumor to calculate the volume overlap of the structures after deformable registration. A substantial improvement in the registration is found by including the dose-induced shrinkage. The greatest registration improvement is found in the four glands where the average DSC increases from 0.53, 0.55, 0.32, and 0.37 to 0.68, 0.68, 0.51, and 0.49 in the left PG, right PG, left SG, and right SG, respectively by using bony alignment of vertebrae and mandible (M), body (B) surface projection and dose (D) (VB+M+B+D).

Utility and validation of biomechanical deformable image registration in low-contrast images.

PURPOSE: The application of a biomechanical deformable image registration algorithm has been demonstrated to overcome the potential limitations in the use of intensity-based algorithms on low-contrast images that lack prominent features. Because validation of deformable registration is particularly challenging on such images, the dose distribution predicted via a biomechanical algorithm was evaluated using the measured dose from a deformable dosimeter. METHODS AND MATERIALS: A biomechanical model-based image registration algorithm registered computed tomographic (CT) images of an elastic radiochromic dosimeter between its undeformed and deformed positions. The algorithm aligns the external boundaries of the dosimeter, created from CT contours, and the internal displacements are solved by modeling the physical material properties of the dosimeter. The dosimeter was planned and irradiated in its deformed position, and subsequently, the delivered dose was measured with optical CT in the undeformed position. The predicted dose distribution, created by applying the deformable registration displacement map to the planned distribution, was then compared with the measured optical CT distribution. RESULTS: Compared with the optical CT distribution, biomechanical image registration predicted the position and size of the deformed dose fields with mean errors of ≤1 mm (maximum, 3 mm). The accuracy did not differ between cross sections with a greater or lesser deformation magnitude despite the homogenous CT intensities throughout the dosimeter. The overall 3-dimensional voxel passing rate of the predicted distribution was γ3%/3mm = 91% compared with optical CT. CONCLUSIONS: Biomechanical registration accurately predicted the deformed dose distribution measured in a deformable dosimeter, whereas previously, evaluations of a commercial intensity-based algorithm demonstrated substantial errors. The addition of biomechanical algorithms to the collection of adaptive radiation therapy tools would be valuable for dose accumulation, particularly in feature-poor images such as cone beam CT and organs such as the liver.

Simplified strategies to determine the mean respiratory position for liver radiation therapy planning.

PURPOSE: Establishing the time-weighted mean respiratory position in the liver is challenging due to poor tumor contrast on 4-dimensional (4D) imaging. The purpose of this study is to validate simplified strategies in determining the mean position of liver tumors for radiation therapy planning, and quantify the potential for planning target volume (PTV) reduction. METHODS AND MATERIALS: Full, 10-phase 4D computed tomography (CT) data sets from 10 liver radiation therapy patients were analyzed to compare 2 techniques. First, a mid-ventilation CT was chosen from the initial reconstruction of the 4DCT. This was based on the minimum displacement of the diaphragm at each phase relative to its mean respiratory position, calculated using rigid registration over all 4DCT phases. Second, the exhale 4DCT was deformed to the inhale 4DCT using biomechanical-based deformable registration. The diaphragm's mean cranio-caudal position in the respiratory cycle (normalized as a percentage relative to exhale) was applied to the exhale-to-inhale deformation map assuming a linear trajectory to reconstruct a mid-position CT. These strategies were compared with the time-weighted mean respiratory position, calculated with deformable registration over all 10 4DCT phases. PTVs incorporating respiratory motion were then compared for 2 planning strategies: exhale 4DCT using the internal target volume (ITV), or mid-position CT using dose-probability margins. RESULTS: Compared with the mean respiratory tumor position, the mid-ventilation CT and mid-position CT had mean (maximum) tumor vector errors of 1.0 ± 0.5 (2.1) mm and 0.6 ± 0.3 (1.4) mm, respectively, within the image resolution. Compared with ITV-based PTV, dose-probability PTV reduced the irradiated volume by 34% ± 7% on average, up to 43%. CONCLUSIONS: Simplified strategies to select a mid-ventilation CT or reconstruct a mid-position CT for the liver were validated with respect to the mean respiratory position. These data sets require significantly smaller PTVs, potentially allowing for dose-escalated liver stereotactic body radiation therapy to improve local control.

Dose escalated liver stereotactic body radiation therapy at the mean respiratory position.

PURPOSE: The dosimetric impact of dose probability based planning target volume (PTV) margins for liver cancer patients receiving stereotactic body radiation therapy (SBRT) was compared with standard PTV based on the internal target volume (ITV). Plan robustness was evaluated by accumulating the treatment dose to ensure delivery of the intended plan. METHODS AND MATERIALS: Twenty patients planned on exhale CT for 27 to 50 Gy in 6 fractions using an ITV-based PTV and treated free-breathing were retrospectively evaluated. Isotoxic, dose escalated plans were created on midposition computed tomography (CT), representing the mean breathing position, using a dose probability PTV. The delivered doses were accumulated using biomechanical deformable registration of the daily cone beam CT based on liver targeting at the exhale or mean breathing position, for the exhale and midposition CT plans, respectively. RESULTS: The dose probability PTVs were on average 38% smaller than the ITV-based PTV, enabling an average ± standard deviation increase in the planned dose to 95% of the PTV of 4.0 ± 2.8 Gy (9 ± 5%) on the midposition CT (P<.01). For both plans, the delivered minimum gross tumor volume (GTV) doses were greater than the planned nominal prescribed dose in all 20 patients and greater than the planned dose to 95% of the PTV in 18 (90%) patients. Nine patients (45%) had 1 or more GTVs with a delivered minimum dose more than 5 Gy higher with the midposition CT plan using dose probability PTV, compared with the delivered dose with the exhale CT plan using ITV-based PTV. CONCLUSIONS: For isotoxic liver SBRT planned and delivered at the mean respiratory, reduced dose probability PTV enables a mean escalation of 4 Gy (9%) in 6 fractions over ITV-based PTV. This may potentially improve local control without increasing the risk of tumor underdosing.

Assessment of nonrespiratory stomach motion in healthy volunteers in fasting and postprandial states.

PURPOSE: To characterize nonrespiratory stomach motion in the fasting state and postprandial. METHODS AND MATERIALS: Ten healthy volunteers underwent 2-dimensional Fiesta cine magnetic resonance imaging studies in 30-second voluntary breath hold, in axial, coronal, and 2 oblique planes while fasting, and 5, 15, 30, 45, and 60 minutes postmeal. Each stomach contour was delineated and sampled with 200 points. Matching points were found for all contours in the same 30-second acquisition. Using deformable parametric analysis (Matlab, version 7.1), mean magnitude, and standard deviation of displacement of each point were determined for each patient. Maximal, minimal, and median population values in 6 cardinal, and in any direction, were calculated. RESULTS: The median of mean displacements for the baseline position of each point was small and rarely exceeded 1.1 mm; greatest value was 1.6 mm superior-inferior. Median displacement (pooled across time) in the right-left, superior-inferior, and anterior-posterior directions was 0.3 (range, -0.7 to 1.3), 0.8 (-0.4 to 2.4), and 0.3 (-1.1 to 1.6) mm, respectively. Fasting and postprandial standard deviation did not differ. CONCLUSIONS: Nonrespiratory stomach displacement is small and stomach position is stable after a small, standard meal. Radiation therapy may be delivered at any time within the first hour after eating without significant compromise of planned planning target volumes.

Hybrid adaptive radiotherapy with on-line MRI in cervix cancer IMRT.

PURPOSE: Substantial organ motion and tumor shrinkage occur during radiotherapy for cervix cancer. IMRT planning studies have shown that the quality of radiation delivery is influenced by these anatomical changes, therefore the adaptation of treatment plans may be warranted. Image guidance with off-line replanning, i.e. hybrid-adaptation, is recognized as one of the most practical adaptation strategies. In this study, we investigated the effects of soft tissue image guidance using on-line MR while varying the frequency of off-line replanning on the adaptation of cervix IMRT. MATERIALS AND METHOD: 33 cervical cancer patients underwent planning and weekly pelvic MRI scans during radiotherapy. 5 patients of 33 were identified in a previous retrospective adaptive planning study, in which the coverage of gross tumor volume/clinical target volume (GTV/CTV) was not acceptable given single off-line IMRT replan using a 3mm PTV margin with bone matching. These 5 patients and a randomly selected 10 patients from the remaining 28 patients, a total of 15 patients of 33, were considered in this study. Two matching methods for image guidance (bone to bone and soft tissue to dose matrix) and three frequencies of off-line replanning (none, single, and weekly) were simulated and compared with respect to target coverage (cervix, GTV, lower uterus, parametrium, upper vagina, tumor related CTV and elective lymph node CTV) and OAR sparing (bladder, bowel, rectum, and sigmoid). Cost (total process time) and benefit (target coverage) were analyzed for comparison. RESULTS: Hybrid adaptation (image guidance with off-line replanning) significantly enhanced target coverage for both 5 difficult and 10 standard cases. Concerning image guidance, bone matching was short of delivering enough doses for 5 difficult cases even with a weekly off-line replan. Soft tissue image guidance proved successful for all cases except one when single or more frequent replans were utilized in the difficult cases. Cost and benefit analysis preferred (soft tissue) image guidance over (frequent) off-line replanning. CONCLUSIONS: On-line MRI based image guidance (with combination of dose distribution) is a crucial element for a successful hybrid adaptive radiotherapy. Frequent off-line replanning adjuvantly enhances adaptation quality.

Dosimetrically triggered adaptive intensity modulated radiation therapy for cervical cancer.

PURPOSE: The widespread use of intensity modulated radiation therapy (IMRT) for cervical cancer has been limited by internal target and normal tissue motion. Such motion increases the risk of underdosing the target, especially as planning margins are reduced in an effort to reduce toxicity. This study explored 2 adaptive strategies to mitigate this risk and proposes a new, automated method that minimizes replanning workload. METHODS AND MATERIALS: Thirty patients with cervical cancer participated in a prospective clinical study and underwent pretreatment and weekly magnetic resonance (MR) scans over a 5-week course of daily external beam radiation therapy. Target volumes and organs at risk (OARs) were contoured on each of the scans. Deformable image registration was used to model the accumulated dose (the real dose delivered to the target and OARs) for 2 adaptive replanning scenarios that assumed a very small PTV margin of only 3 mm to account for setup and internal interfractional motion: (1) a preprogrammed, anatomy-driven midtreatment replan (A-IMRT); and (2) a dosimetry-triggered replan driven by target dose accumulation over time (D-IMRT). RESULTS: Across all 30 patients, clinically relevant target dose thresholds failed for 8 patients (27%) if 3-mm margins were used without replanning. A-IMRT failed in only 3 patients and also yielded an additional small reduction in OAR doses at the cost of 30 replans. D-IMRT assured adequate target coverage in all patients, with only 23 replans in 16 patients. CONCLUSIONS: A novel, dosimetry-triggered adaptive IMRT strategy for patients with cervical cancer can minimize the risk of target underdosing in the setting of very small margins and substantial interfractional motion while minimizing programmatic workload and cost.