Purpose: To create a dose-response model that predicts lung ventilation change following radiation therapy, and examine the effects of out-of-phase ventilation. Methods: The dose-response model was built using 27 human subjects who underwent radiation therapy (RT) from an IRB-approved trial. For each four-dimensional computed tomography, two ventilation maps were created by calculating the N-phase local expansion ratio (LER N ) using most or all breathing phases and the 2-phase LER (LER 2 ) using only the end inspiration and end expiration breathing phases. A polynomial regression model was created using the LER N ventilation maps pre-RT and post-RT and dose distributions for each subject, and crossvalidated with a leave-one-out method. Further validation of the model was performed using 15 additional human subjects using common statistical operating characteristics and gamma pass rates. Results: For voxels receiving 20 Gy or greater, there was a significant increase from 52% to 59% (P = 0.03) in the gamma pass rates of the LER N model predicted post-RT Jacobian maps to the actual post-RT Jacobian maps, relative to the LER 2 model. Additionally, accuracy significantly increased (P = 0.03) from 68% to 75% using the LER N model, relative to the LER 2 model. Conclusions: The LER N model was significantly more accurate than the LER 2 model at predicting post-RT ventilation maps. More accurate post-RT ventilation maps will aid in producing a higher quality functional avoidance treatment plan, allowing for potentially better normal tissue sparing.

To analyze radiation induced changes in Hounsfield units and determine their correlation with changes in perfusion and ventilation. Additionally, to compare the post-RT changes in human subjects to those measured in a swine model used to quantify perfusion changes and validate their use as a preclinical model. A cohort of 5 Wisconsin Miniature Swine (WMS) were studied. Additionally, 19 human subjects were recruited as part of an IRB approved clinical trial studying functional avoidance radiation therapy for lung cancer and were treated with SBRT. Imaging (a contrast enhanced dynamic perfusion CT in the swine and 4DCT in the humans) was performed prior to and post-RT. Jacobian elasticity maps were calculated on all 4DCT images. Contours were created from the isodose lines to discretize analysis into 10 Gy dose bins. B-spline deformable image registration allowed for voxel-by-voxel comparative analysis in these contours between timepoints. The WMS underwent a research course of 60 Gy in 5 fractions delivered locally to a target in the lung using an MRI-LINAC system. In the WMS subjects, the dose-bin contours were copied onto the contralateral lung, which received < 5 Gy for comparison. Changes in HU and changes in Jacobian were analyzed in these contours. Statistically significant (p < 0.05) changes in the mean HU value post-RT compared to pre-RT were observed in both the human and WMS groups at all timepoints analyzed. The HU increased linearly with dose for both groups. Strong linear correlation was observed between the changes seen in the swine and humans (Pearson coefficient > 0.97, p < 0.05) at all timepoints. Changes seen in the swine closely modeled the changes seen in the humans at 12 months post RT (slope = 0.95). Jacobian analysis showed between 30 and 60% of voxels were damaged post-RT. Perfusion analysis in the swine showed a statistically significant (p < 0.05) reduction in contrast inside the vasculature 3 months post-RT compared to pre-RT. The increases in contrast outside the vasculature was strongly correlated (Pearson Correlation 0.88) with the reduction in HU inside the vasculature but were not correlated with the changes in Jacobians. Radiation induces changes in pulmonary anatomy at 3 months post-RT, with a strong linear correlation with dose. The change in HU seen in the non-vessel lung parenchyma suggests this metric is a potential biomarker for change in perfusion. Finally, this work suggests that the WMS swine model is a promising pre-clinical model for analyzing radiation-induced changes in humans and poses several benefits over conventional swine models.

Recent functional lung imaging studies have presented evidence of an “indirect effect” on perfusion damage, where regions that are unirradiated or lowly irradiated but that are supplied by highly irradiated regions observe perfusion damage post-radiation therapy (RT). The purpose of this work was to investigate this effect using a contrast-enhanced dynamic CT protocol to measure perfusion change in five novel swine subjects. A cohort of five Wisconsin Miniature Swine (WMS) were given a research course of 60 Gy in five fractions delivered locally to a vessel in the lung using an Accuray Radixact tomotherapy system with Synchrony motion tracking to increase delivery accuracy. Imaging was performed prior to delivering RT and 3 months post-RT to yield a 28–36 frame image series showing contrast flowing in and out of the vasculature. Using MIM software, contours were placed in six vessels on each animal to yield a contrast flow curve for each vessel. The contours were placed as follows: one at the point of max dose, one low-irradiated (5–20 Gy) branching from the max dose vessel, one low-irradiated (5–20 Gy) not branching from the max dose vessel, one unirradiated (<5 Gy) branching from the max dose vessel, one unirradiated (<5 Gy) not branching from the max dose vessel, and one in the contralateral lung. Seven measurements (baseline-to-baseline time and difference, slope up and down, max rise and value, and area under the curve) were acquired for each vessel’s contrast flow curve in each subject. Paired Student t-tests showed statistically significant (p<0.05) reductions in the area under the curve in the max dose, and both fed contours indicating an overall reduction in contrast in these regions. Additionally, there were statistically significant reductions observed when comparing pre- and post-RT in slope up and down in the max dose, low-dose fed, and no-dose fed contours but not the low-dose not-fed, no-dose not-fed, or contralateral contours. These findings suggest an indirect damage effect where irradiation of the vasculature causes a reduction in perfusion in irradiated regions as well as regions fed by the irradiated vasculature.

Purpose. To investigate indirect radiation-induced changes in airways as precursors to atelectasis post radiation therapy (RT). Methods. Three Wisconsin Miniature Swine (WMS TM ) underwent a research course of 60 Gy in 5 fractions delivered to a targeted airway/vessel in the inferior left lung. The right lung received a max point dose <5 Gy. Airway segmentation was performed on the pre- and three months post-RT maximum inhale phase of the four-dimensional (4D) computed tomography (CT) scans. Changes in luminal area (Ai) and square root of wall area ( WA ) for each airway were investigated. Changes in ventilation were assessed using the Jacobian ratio and were measured in three different regions: the inferior left lung <5 Gy (ILL), the superior left lung <5 Gy (SLL), and the contralateral right lung <5 Gy (RL). Results. Airways (n = 25) in the right lung for all swine showed no significant changes (p = 0.48) in Ai post-RT compared to pre-RT. Airways (n = 28) in the left lung of all swine were found to have a significant decrease (p < 0.001) in Ai post-RT compared to pre-RT, correlated (Pearson R = −0.97) with airway dose. Additionally, WA decreased significantly (p < 0.001) with airway dose. Lastly, the Jacobian ratio of the ILL (0.883) was lower than that of the SLL (0.932) and the RL (0.955). Conclusions. This work shows that for the swine analyzed, there were significant correlations between Ai and WA change with radiation dose. Additionally, there was a decrease in lung function in the regions of the lung supplied by the irradiated airways compared to the regions supplied by unirradiated airways. These results support the hypothesis that airway dose should be considered during treatment planning in order to potentially preserve functional lung and reduce lung toxicities.

Vessel segmentation in the lung is an ongoing challenge. While many methods have been able to successfully identify vessels in normal, healthy, lungs, these methods struggle in the presence of abnormalities. Following radiotherapy, these methods tend to identify regions of radiographic change due to post-radiation therapytoxicities as vasculature falsely. By combining texture analysis and existing vasculature and masking techniques, we have developed a novel vasculature segmentation workflow that improves specificity in irradiated lung while preserving the sensitivity of detection in the rest of the lung. Furthermore, radiation dose has been shown to cause vascular injury as well as reduce pulmonary function post-RT. This work shows the improvements our novel vascular segmentation method provides relative to existing methods. Additionally, we use this workflow to show a dose dependent radiation-induced change in vasculature which is correlated with previously measured perfusion changes (R2 = 0.72) in both directly irradiated and indirectly damaged regions of perfusion. These results present an opportunity to extend non-contrast CT-derived models of functional change following radiation therapy.