Clinical implementation of automated treatment planning for whole-brain radiotherapy.

The purpose of the study was to develop and clinically deploy an automated, deep learning-based approach to treatment planning for whole-brain radiotherapy (WBRT). We collected CT images and radiotherapy treatment plans to automate a beam aperture definition from 520 patients who received WBRT. These patients were split into training (n = 312), cross-validation (n = 104), and test (n = 104) sets which were used to train and evaluate a deep learning model. The DeepLabV3+ architecture was trained to automatically define the beam apertures on lateral-opposed fields using digitally reconstructed radiographs (DRRs). For the beam aperture evaluation, 1st quantitative analysis was completed using a test set before clinical deployment and 2nd quantitative analysis was conducted 90 days after clinical deployment. The mean surface distance and the Hausdorff distances were compared in the anterior-inferior edge between the clinically used and the predicted fields. Clinically used plans and deep-learning generated plans were evaluated by various dose-volume histogram metrics of brain, cribriform plate, and lens. The 1st quantitative analysis showed that the average mean surface distance and Hausdorff distance were 7.1 mm (±3.8 mm) and 11.2 mm (±5.2 mm), respectively, in the anterior-inferior edge of the field. The retrospective dosimetric comparison showed that brain dose coverage (D99%, D95%, D1%) of the automatically generated plans was 29.7, 30.3, and 32.5 Gy, respectively, and the average dose of both lenses was up to 19.0% lower when compared to the clinically used plans. Following the clinical deployment, the 2nd quantitative analysis showed that the average mean surface distance and Hausdorff distance between the predicted and clinically used fields were 2.6 mm (±3.2 mm) and 4.5 mm (±5.6 mm), respectively. In conclusion, the automated patient-specific treatment planning solution for WBRT was implemented in our clinic. The predicted fields appeared consistent with clinically used fields and the predicted plans were dosimetrically comparable.

Initial clinical experience with ArcCHECK for IMRT/VMAT QA.

Many devices designed for the purpose of performing patient-specific IMRT/VMAT QA are commercially available. In this work we report our experience and initial clinical results with the ArcCHECK. The ArcCHECK consists of a cylindrical array of diode detectors measuring entry and exit doses. The measured result is a cumulative dose displayed as a 2D matrix. The detector array requires both an absolute dose calibration, and a calibration of the detector response, relative to each other. In addition to the calibrations suggested by the manufacturer, various tests were performed in order to assess its stability and performance prior to clinical introduction. Tests of uniformity, linearity, and repetition rate dependence of the detector response were conducted and described in this work. Following initial test-ing, the ArcCHECK device was introduced in the clinic for routine patient-specific IMRT QA. The clinical results from one year of use were collected and analyzed. The gamma pass rates at the 3%/3 mm criterion were reported for 3,116 cases that included both IMRT and VMAT treatment plans delivered on 18 linear accelera-tors. The gamma pass rates were categorized based on the treatment site, treatment technique, type of MLCs, operator, ArcCHECK device, and LINAC model. We recorded the percent of failures at the clinically acceptable threshold of 90%. In addition, we calculated the threshold that encompasses two standard deviations (2 SD) (95%) of QAs (T95) for each category investigated. The commissioning measurements demonstrated that the device performed as expected. The uniformity of the detector response to a constant field arc delivery showed a 1% standard deviation from the mean. The variation in dose with changing repetition rate was within 1 cGy of the mean, while the measured dose showed a linear relation with delivered MUs. Our initial patient QA results showed that, at the clinically selected passing criterion, 4.5% of cases failed. On average T95 was 91%, rang-ing from 73% for gynecological sites to 96.5% for central nervous system sites. There are statistically significant differences in passing rates between IMRT and VMAT, high-definition (HD) and non-HD MLCs, and different LINAC models (p-values << 0.001). An additional investigation into the failing QAs and a com-parison with ion-chamber measurements reveals that the differences observed in the passing rates between the different studied factors can be largely explained by the field size dependence of the device. Based on our initial experience with the ArcCHECK, our passing rates are, on average, consistent with values reported in the AAPM TG-119. However, the significant variations between QAs that were observed based on the size of the treatment fields may need to be corrected to improve the specificity and sensitivity of the device.

Is there an impact of heart exposure on the incidence of radiation pneumonitis? Analysis of data from a large clinical cohort.

BACKGROUND: The goal of the present study was to determine, in a large clinical cohort, whether incidental radiation exposure to the heart during definitive radiotherapy of inoperable non-small cell lung cancer (NSCLC) detectably increased the risk of radiation pneumonitis (RP) beyond that resulting from radiation exposure to lung. MATERIAL AND METHODS: Data were analyzed from all patients who received definitive three-dimensional (3D) concurrent radiotherapy or intensity-modulated radiotherapy for the treatment of NSCLC over a 10-year period at our institution, except those who had previous lung cancer or for whom radiation treatment plans were unavailable for calculation of heart and lung dose-volume histograms (DVHs). Parameters computed from heart and lung DVHs included mean lung dose (MLD), effective lung dose computed using volume parameter n = 0.5 (Deff), mean heart dose (MHD), percentage of heart receiving > 65 Gy (V65), and minimum dose to the hottest 10% of heart (D10). Univariate and multivariate normal-tissue complication probability (NTCP) models were used to analyze incidence of Grade ≥ 2 or Grade ≥ 3 RP as a function of these and other parameters. RESULTS: The study cohort included 629 patients, with crude rates of Grade ≥ 2 RP and Grade ≥ 3 RP of N = 263 (42%) and N = 124 (20%), respectively. Univariate NTCP models based on dosimetric lung parameters (MLD and Deff) fit the data better than models based on univariate heart parameters (heart D10, heart V65 or MHD). In multivariate modeling, incorporation of heart parameters did not significantly improve the fit of RP risk models based on lung parameters alone (p > 0.38 in each case). CONCLUSIONS: In this large clinical cohort, there was no evidence that incidental heart exposure during radiotherapy of NSCLC had a detectable impact on the occurrence of moderate or severe RP.

A technique to use CT images for in vivo detection and quantification of the spatial distribution of radiation-induced esophagitis.

The purpose of the study was to examine whether CT imaging can be used to quantify radiation-induced injury to the esophagus. Weekly CT images for 14 patients receiving proton therapy for thoracic tumors were retrospectively reviewed. The images were registered with the original treatment planning CT image using deformable registration techniques, and the esophageal contours from the treatment plan were automatically mapped to the weekly images. The relative change in the size of the esophagus was calculated for each CT slice as the ratio of the cross-sectional area of the esophagus (minus air) in the weekly CT image to the same area in the planning CT image. The maximum relative change in cross sectional area for each CT image was calculated and examined for correlation with the clinical toxicity score for all the patients. The average maximum relative expansion of the esophagus at the end of treatment was 1.41 ± 0.26, 1.68 ± 0.36, and 2.10 ± 0.18 for patients with grade 0, 2, and 3 esophagitis, respectively. An unpaired t-test, with the level of significance corrected with a Bonferroni correction, showed that the difference between grade 3 and 0 was significant, but the differences between grade 0 and 2, and 2 and 3 were not. The timing of changes in esophageal expansion closely matched that of clinically noted changes in patient symptoms. Expansion of the esophagus on CT images has potential as an objective measure of toxicity. The ability to quantify objectively the spatial distribution of radiation-induced injury will be a useful tool in understanding the impact of partial esophageal sparing on the probability of esophagitis.

A real-time contouring feedback tool for consensus-based contour training.

Purpose: Variability in contouring structures of interest for radiotherapy continues to be challenging. Although training can reduce such variability, having radiation oncologists provide feedback can be impractical. We developed a contour training tool to provide real-time feedback to trainees, thereby reducing variability in contouring. Methods: We developed a novel metric termed localized signed square distance (LSSD) to provide feedback to the trainee on how their contour compares with a reference contour, which is generated real-time by combining trainee contour and multiple expert radiation oncologist contours. Nine trainees performed contour training by using six randomly assigned training cases that included one test case of the heart and left ventricle (LV). The test case was repeated 30 days later to assess retention. The distribution of LSSD maps of the initial contour for the training cases was combined and compared with the distribution of LSSD maps of the final contours for all training cases. The difference in standard deviations from the initial to final LSSD maps, ΔLSSD, was computed both on a per-case basis and for the entire group. Results: For every training case, statistically significant ΔLSSD were observed for both the heart and LV. When all initial and final LSSD maps were aggregated for the training cases, before training, the mean LSSD ([range], standard deviation) was -0.8 mm ([-37.9, 34.9], 4.2) and 0.3 mm ([-25.1, 32.7], 4.8) for heart and LV, respectively. These were reduced to -0.1 mm ([-16.2, 7.3], 0.8) and 0.1 mm ([-6.6, 8.3], 0.7) for the final LSSD maps during the contour training sessions. For the retention case, the initial and final LSSD maps of the retention case were aggregated and were -1.5 mm ([-22.9, 19.9], 3.4) and -0.2 mm ([-4.5, 1.5], 0.7) for the heart and 1.8 mm ([-16.7, 34.5], 5.1) and 0.2 mm ([-3.9, 1.6],0.7) for the LV. Conclusions: A tool that uses real-time contouring feedback was developed and successfully used for contour training of nine trainees. In all cases, the utility was able to guide the trainee and ultimately reduce the variability of the trainee's contouring.

Use of weekly 4DCT-based ventilation maps to quantify changes in lung function for patients undergoing radiation therapy.

PURPOSE: A method has been proposed to calculate ventilation maps from four-dimensional computed tomography (4DCT) images. Weekly 4DCT data were acquired throughout the course of radiation therapy for patients with lung cancer. The purpose of our work was to use ventilation maps calculated from weekly 4DCT data to study how ventilation changed throughout radiation therapy. METHODS: Quantitative maps representing ventilation were generated for six patients. Deformable registration was used to link corresponding lung volume elements between the inhale and exhale phases of the 4DCT dataset. Following spatial registration, corresponding Hounsfield units were input into a density-change-based model for quantifying the local ventilation. The ventilation data for all weeks were registered to the pretreatment ventilation image set. We quantitatively analyzed the data by defining regions of interest (ROIs) according to dose (V(20)) and lung lobe and by tracking the weekly ventilation of each ROI throughout treatment. The slope of the linear fit to the weekly ventilation data was used to evaluate the change in ventilation throughout treatment. A positive slope indicated an increase in ventilation, a negative slope indicated a decrease in ventilation, and a slope of 0 indicated no change. The dose ROI ventilation and slope data were used to study how ventilation changed throughout treatment as a function of dose. The lung lobe ROI ventilation data were used to study the impact of the presence of tumor on pretreatment ventilation. In addition, the lobe ROI data were used to study the impact of tumor reduction on ventilation change throughout treatment. RESULTS: Using the dose ROI data, we found that three patients had an increase in weekly ventilation as a function of dose (slopes of 1.1, 1.4, and 1.5) and three patients had no change or a slight decrease in ventilation as a function of dose (slopes of 0.3, -0.6, -0.5). Visually, pretreatment ventilation appeared to be lower in the lobes that contained tumor. Pretreatment ventilation was 39% for lobes that contained tumor and 54% for lobes that did not contain tumor. The difference in ventilation between the two groups was statistically significant (p = 0.017). When the weekly lobe ventilation data were qualitatively observed, two distinct patterns emerged. When the tumor volume in a lobe was reduced, ventilation increased in the lobe. When the tumor volume was not reduced, the ventilation distribution did not change. The average slope of the group of lobes that contained tumors that shrank was 1.18, while the average slope of the group that did not contain tumors (or contained tumors that did not shrink) was -0.32. The slopes for the two groups were significantly different (p = 0.014). CONCLUSIONS: We did not find a consistent pattern of ventilation change as a function of radiation dose. Pretreatment ventilation was significantly lower for lobes that contained tumor, due to occlusion of the central airway. The weekly lobe ventilation data indicated that when tumor volume shrinks, ventilation increases, and when the thoracic anatomy is not visibly changed, ventilation is likely to remain unchanged.

The use and QA of biologically related models for treatment planning: short report of the TG-166 of the therapy physics committee of the AAPM.

Treatment planning tools that use biologically related models for plan optimization and/or evaluation are being introduced for clinical use. A variety of dose-response models and quantities along with a series of organ-specific model parameters are included in these tools. However, due to various limitations, such as the limitations of models and available model parameters, the incomplete understanding of dose responses, and the inadequate clinical data, the use of biologically based treatment planning system (BBTPS) represents a paradigm shift and can be potentially dangerous. There will be a steep learning curve for most planners. The purpose of this task group is to address some of these relevant issues before the use of BBTPS becomes widely spread. In this report, the authors (1) discuss strategies, limitations, conditions, and cautions for using biologically based models and parameters in clinical treatment planning; (2) demonstrate the practical use of the three most commonly used commercially available BBTPS and potential dosimetric differences between biologically model based and dose-volume based treatment plan optimization and evaluation; (3) identify the desirable features and future directions in developing BBTPS; and (4) provide general guidelines and methodology for the acceptance testing, commissioning, and routine quality assurance (QA) of BBTPS.

Acute and Late Pulmonary Effects After Radiation Therapy in Childhood Cancer Survivors: A PENTEC Comprehensive Review.

OBJECTIVES: The Pediatric Normal Tissue Effects in the Clinic (PENTEC) pulmonary task force reviewed dosimetric and clinical factors associated with radiation therapy (RT)-associated pulmonary toxicity in children. METHODS: Comprehensive search of PubMed (1965-2020) was conducted to assess available evidence and predictive models of RT-induced lung injury in pediatric cancer patients (<21 years old). Lung dose for radiation pneumonitis (RP) was obtained from dose-volume histogram (DVH) data. RP grade was obtained from standard criteria. Clinical pulmonary outcomes were evaluated using pulmonary function tests (PFTs), clinical assessment, and questionnaires. RESULTS: More than 2,400 abstracts were identified; 460 articles had detailed treatment and toxicity data; and 11 articles with both detailed DVH and toxicity data were formally reviewed. Pooled cohorts treated during 1999 to 2016 included 277 and 507 patients age 0.04 to 22.7 years who were evaluable for acute and late RP analysis, respectively. After partial lung RT, there were 0.4% acute and 2.8% late grade 2, 0.4% acute and 0.8% late grade 3, and no grade 4 to 5 RP. RP risk after partial thoracic RT with mean lung dose (MLD) <14 Gy and total lung V20Gy <30% is low. Clinical and self-reported pulmonary outcomes data included 8,628 patients treated during 1970 to 2013, age 0 to 21.9 years. At a median 2.9- to 21.9-year follow-up, patients were often asymptomatic; abnormal PFTs were common and severity correlated with lung dose. At ≥10-year follow-up, multi-institutional studies suggested associations between total or ipsilateral lung doses >10 Gy and pulmonary complications and deaths. After whole lung irradiation (WLI), pulmonary toxicity is higher; no dose response relationship was identified. Bleomycin and other chemotherapeutics at current dose regimens do not contribute substantially to adverse pulmonary outcomes after partial lung irradiation but increase risk with WLI. CONCLUSIONS: After partial lung RT, acute pulmonary toxicity is uncommon; grade 2 to 3 RP incidences are <1%. Late toxicities, including subclinical/asymptomatic impaired pulmonary function, are more common (<4%). Incidence and severity appear to increase over time. Upon review of available literature, there appears to be low risk of pulmonary complications in children with MLD < 14 Gy and V20Gy <30% using standard fractionated RT to partial lung volumes. A lack of robust data limit guidance on lung dose/volume constraints, highlighting the need for additional work to define factors associated with RT-induced lung injury.

Our Experience Leading a Large Medical Physics Practice During the COVID-19 Pandemic.

PURPOSE: To provide a series of suggestions for other Medical Physics practices to follow in order to provide effective radiation therapy treatments during the COVID-19 pandemic. METHODS AND MATERIALS: We reviewed our entire Radiation Oncology infrastructure to identify a series of workflows and policy changes that we implemented during the pandemic that yielded more effective practices during this time. RESULTS: We identified a structured list of several suggestions that can help other Medical Physics practices overcome the challenges involved in delivering high quality radiotherapy services during this pandemic. CONCLUSIONS: Our facility encompasses 4 smaller Houston Area Locations (HALs), a main campus with 8 distinct services based on treatment site (ie. Thoracic, Head and Neck, Breast, Gastrointestinal, Gynecology, Genitourinary, Hematologic Malignancies, Melanoma and Sarcoma and Central Nervous System/Pediatrics), a Proton Center facility, an MR-Linac, a Gamma Knife clinic and an array of brachytherapy services. Due to the scope of our services, we have gained experience in dealing with the rapidly changing pandemic effects on our clinical practice. Our paper provides a resource to other Medical Physics practices in search of workflows that have been resilient during these challenging times.

A quality assurance procedure to evaluate cone-beam CT image center congruence with the radiation isocenter of a linear accelerator.

A quality assurance (QA) procedure was developed to evaluate the congruence between the cone-beam computed tomography (CBCT) image center and the radiation isocenter on a Varian Trilogy linac. In contrast to the published QA procedures, this method did not require a ball bearing (BB) phantom to be placed exactly at the radiation isocenter through precalibrated room lasers or light field crosshairs. The only requirement was that the BB phantom be in a stationary position near the radiation isocenter during the image acquisition process. The radiation isocenter was determined with respect to the center of the BB using a Winston-Lutz test. The CBCT image center was found to have excellent short-term positional repro-ducibility (i.e., less than 0.1 mm of wobble in each of the x (lateral), y (vertical), and z (longitudinal) directions) in 10 consecutive acquisitions. Measured over a seven-month period, the CBCT image center deviated from the radiation isocenter by 0.40 ± 0.12 mm (x), 0.43 ± 0.04 mm (y), and 0.34 ± 0.14 mm (z). The z displacement of the 3D CBCT image center was highly correlated (ρ = 0.997) with that of the 2D kV portal image center. The correlation coefficients in the x and y directions were poor (ρ = 0.66 and -0.35, respectively). Systematic discrepancies were found between the CBCT image center and the 2D MV, kV portal image centers. For the linear accelerator studied, we detected a 0.8 mm discrepancy between the CBCT image center and the MV EPID image center in the anterior-posterior direction.This discrepancy was demonstrated in a clinical case study where the patient was positioned with CBCT followed by MV portal verification. The results from the new QA procedure are useful for guiding high-precision patient positioning in stereotactic body radiation therapy.

Report from the International Atomic Energy Agency (IAEA) consultants' meeting on elective nodal irradiation in lung cancer: small-cell lung cancer (SCLC).

Thoracic radiotherapy (RT) is an integral part of the management of small-cell lung cancer (SCLC) because its administration provides a survival benefit in patients with limited-stage disease. However, there are many areas of controversy with respect to the delivery of curative RT, and these include definition of the target to be irradiated. A current area of concern is defining what the RT portal must encompass with respect to the mediastinal lymph nodes; that is, whether one should electively treat all mediastinal nodes, or selectively include those with some clinical risk for harboring disease, or perhaps omit elective nodal irradiation altogether. The purpose of the present report is therefore to address the concepts underlying elective or selective nodal irradiation as it applies to SCLC, looking at clinical, imaging, and RT reports to help define the parameters appropriate to treating individual patients.

Report from the International Atomic Energy Agency (IAEA) consultants' meeting on elective nodal irradiation in lung cancer: non-small-Cell lung cancer (NSCLC).

Lymphatic spread is an important pathway of progression in non-small-cell lung cancer (NSCLC), along with local spread and distant metastasis. The probability of lymph node (LN) involvement is dependent on the site of the primary tumor, stage, and histology. Elective nodal irradiation (ENI) is the irradiation of clinical and radiological uninvolved LN to account for microscopic tumor invasion in these LNs because we have not been able to determine the extent of LN spread accurately. The clinical value of ENI is uncertain. The impact of ENI is dependent on many (staging-, treatment-, and patient-related) factors. The purpose of this report is to analyze the current status of ENI and to provide comprehensive in-depth analysis and guidance on how to generally approach this issue in NSCLC.

Analysis of radiation pneumonitis risk using a generalized Lyman model.

PURPOSE: To introduce a version of the Lyman normal-tissue complication probability (NTCP) model adapted to incorporate censored time-to-toxicity data and clinical risk factors and to apply the generalized model to analysis of radiation pneumonitis (RP) risk. METHODS AND MATERIALS: Medical records and radiation treatment plans were reviewed retrospectively for 576 patients with non-small cell lung cancer treated with radiotherapy. The time to severe (Grade >/=3) RP was computed, with event times censored at last follow-up for patients not experiencing this endpoint. The censored time-to-toxicity data were analyzed using the standard and generalized Lyman models with patient smoking status taken into account. RESULTS: The generalized Lyman model with patient smoking status taken into account produced NTCP estimates up to 27 percentage points different from the model based on dose-volume factors alone. The generalized model also predicted that 8% of the expected cases of severe RP were unobserved because of censoring. The estimated volume parameter for lung was not significantly different from n = 1, corresponding to mean lung dose. CONCLUSIONS: NTCP models historically have been based solely on dose-volume effects and binary (yes/no) toxicity data. Our results demonstrate that inclusion of nondosimetric risk factors and censored time-to-event data can markedly affect outcome predictions made using NTCP models.

The utility of quantitative CT radiomics features for improved prediction of radiation pneumonitis.

PURPOSE: The purpose of this study was to explore gains in predictive model performance for radiation pneumonitis (RP) using pretreatment CT radiomics features extracted from the normal lung volume. METHODS: A total of 192 patients treated for nonsmall cell lung cancer with definitive radiotherapy were considered in the current study. In addition to clinical and dosimetric data, CT radiomics features were extracted from the total lung volume defined using the treatment planning scan. A total of 6851 features (15 clinical, 298 total lung and heart dosimetric, and 6538 image features) were gathered and considered candidate predictors for modeling of RP grade ≥3. Models were built with the least absolute shrinkage and selection operator (LASSO) logistic regression and applied to the set of candidate predictors with 50 iterations of tenfold nested cross-validation. RESULTS: In the current cohort, 30 of 192 patients (15.6%) presented with RP grade ≥3. Average cross-validated AUC (CV-AUC) using only the clinical and dosimetric parameters was 0.51. CV-AUC was 0.68 when total lung CT radiomics features were added. Analysis with the entire set of available predictors revealed seven different image features selected in at least 40% of the model fits. CONCLUSIONS: We have successfully incorporated CT radiomics features into a framework for building predictive RP models via LASSO logistic regression. Addition of normal lung image features produced superior model performance relative to traditional dosimetric and clinical predictors of RP, suggesting that pretreatment CT radiomics features should be considered in the context of RP prediction.

A Gaussian mixture model for definition of lung tumor volumes in positron emission tomography.

The increased interest in 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET) in radiation treatment planning in the past five years necessitated the independent and accurate segmentation of gross tumor volume (GTV) from FDG-PET scans. In some studies the radiation oncologist contours the GTV based on a computed tomography scan, while incorporating pertinent data from the PET images. Alternatively, a simple threshold, typically 40% of the maximum intensity, has been employed to differentiate tumor from normal tissue, while other researchers have developed algorithms to aid the PET based GTV definition. None of these methods, however, results in reliable PET tumor segmentation that can be used for more sophisticated treatment plans. For this reason, we developed a Gaussian mixture model (GMM) based segmentation technique on selected PET tumor regions from non-small cell lung cancer patients. The purpose of this study was to investigate the feasibility of using a GMM-based tumor volume definition in a robust, reliable and reproducible way. A GMM relies on the idea that any distribution, in our case a distribution of image intensities, can be expressed as a mixture of Gaussian densities representing different classes. According to our implementation, each class belongs to one of three regions in the image; the background (B), the uncertain (U) and the target (T), and from these regions we can obtain the tumor volume. User interaction in the implementation is required, but is limited to the initialization of the model parameters and the selection of an "analysis region" to which the modeling is restricted. The segmentation was developed on three and tested on another four clinical cases to ensure robustness against differences observed in the clinic. It also compared favorably with thresholding at 40% of the maximum intensity and a threshold determination function based on tumor to background image intensities proposed in a recent paper. The parts of the method that are user dependent were evaluated and resulted in initial estimates of the method's precision, which is in the order of +/-10% of the average tumor volume estimate. With this work we have established the applicability of the GMM-based segmentation on clinical studies and we have made an initial assessment of the method's precision with respect to tumor volume segmentation.

Differences in Normal Tissue Response in the Esophagus Between Proton and Photon Radiation Therapy for Non-Small Cell Lung Cancer Using In Vivo Imaging Biomarkers.

PURPOSE: To determine whether there exists any significant difference in normal tissue toxicity between intensity modulated radiation therapy (IMRT) or proton therapy for the treatment of non-small cell lung cancer. METHODS AND MATERIALS: A total of 134 study patients (n=49 treated with proton therapy, n=85 with IMRT) treated in a randomized trial had a previously validated esophageal toxicity imaging biomarker, esophageal expansion, quantified during radiation therapy, as well as esophagitis grade (Common Terminology Criteria for Adverse Events version 3.0), on a weekly basis during treatment. Differences between the 2 modalities were statically analyzed using the imaging biomarker metric value (Kruskal-Wallis analysis of variance), as well as the incidence and severity of esophagitis grade (χ2 and Fisher exact tests, respectively). The dose-response of the imaging biomarker was also compared between modalities using esophageal equivalent uniform dose, as well as delivered dose to an isotropic esophageal subvolume. RESULTS: No statistically significant difference in the distribution of esophagitis grade, the incidence of grade ≥3 esophagitis (15 and 11 patients treated with IMRT and proton therapy, respectively), or the esophageal expansion imaging biomarker between cohorts (P>.05) was found. The distribution of imaging biomarker metric values had similar distributions between treatment arms, despite a slightly higher dose volume in the proton arm (P>.05). Imaging biomarker dose-response was similar between modalities for dose quantified as esophageal equivalent uniform dose and delivered esophageal subvolume dose. Regardless of treatment modality, there was high variability in imaging biomarker response, as well as esophagitis grade, for similar esophageal doses between patients. CONCLUSIONS: There was no significant difference in esophageal toxicity from either proton- or photon-based radiation therapy as quantified by esophagitis grade or the esophageal expansion imaging biomarker.

Lung Size and the Risk of Radiation Pneumonitis.

PURPOSE: The purpose of this study was to identify patient populations treated for non-small cell lung cancer (NSCLC) who may be more at risk of radiation pneumonitis. METHODS AND MATERIALS: A total of 579 patients receiving fractionated 3D conformal or intensity modulated radiation therapy (IMRT) for NSCLC were included in the study. Statistical analysis was performed to search for cohorts of patients with higher incidences of radiation pneumonitis. In addition to conventional risk factors, total and spared lung volumes were analyzed. The Lyman-Kutcher-Burman (LKB) and cure models were then used to fit the incidence of radiation pneumonitis as a function of lung dose and other factors. RESULTS: Total lung volumes with a sparing of less than 1854 cc at 40 Gy were associated with a significantly higher incidence of radiation pneumonitis at 6 months (38% vs 12% for patients with larger volumes, P<.001). This patient cohort was overwhelmingly female and represented 22% of the total female population of patients and nearly 30% of the cases of radiation pneumonitis. An LKB fit to normal tissue complication probability (NTCP) including volume as a dose modifying factor resulted in a dose that results in a 50% probability of complication for the smaller spared volume cohort that was 9 Gy lower than the fit to all mean lung dose data and improved the ability to predict radiation pneumonitis (P<.001). Using an effective dose parameter of n=0.42 instead of mean lung dose further improved the LKB fit. Fits to the data using the cure model produced similar results. CONCLUSIONS: Spared lung volume should be considered when treating NSCLC patients. Separate dose constraints based on smaller spared lung volume should be considered. Smaller spared lung volume patients should be followed closely for signs of radiation pneumonitis.

(18)F-Fluorodeoxyglucose Positron Emission Tomography Can Quantify and Predict Esophageal Injury During Radiation Therapy.

PURPOSE: We sought to investigate the ability of mid-treatment (18)F-fluorodeoxyglucose positron emission tomography (PET) studies to objectively and spatially quantify esophageal injury in vivo from radiation therapy for non-small cell lung cancer. METHODS AND MATERIALS: This retrospective study was approved by the local institutional review board, with written informed consent obtained before enrollment. We normalized (18)F-fluorodeoxyglucose PET uptake to each patient's low-irradiated region (<5 Gy) of the esophagus, as a radiation response measure. Spatially localized metrics of normalized uptake (normalized standard uptake value [nSUV]) were derived for 79 patients undergoing concurrent chemoradiation therapy for non-small cell lung cancer. We used nSUV metrics to classify esophagitis grade at the time of the PET study, as well as maximum severity by treatment completion, according to National Cancer Institute Common Terminology Criteria for Adverse Events, using multivariate least absolute shrinkage and selection operator (LASSO) logistic regression and repeated 3-fold cross validation (training, validation, and test folds). This 3-fold cross-validation LASSO model procedure was used to predict toxicity progression from 43 asymptomatic patients during the PET study. Dose-volume metrics were also tested in both the multivariate classification and the symptom progression prediction analyses. Classification performance was quantified with the area under the curve (AUC) from receiver operating characteristic analysis on the test set from the 3-fold analyses. RESULTS: Statistical analysis showed increasing nSUV is related to esophagitis severity. Axial-averaged maximum nSUV for 1 esophageal slice and esophageal length with at least 40% of axial-averaged nSUV both had AUCs of 0.85 for classifying grade 2 or higher esophagitis at the time of the PET study and AUCs of 0.91 and 0.92, respectively, for maximum grade 2 or higher by treatment completion. Symptom progression was predicted with an AUC of 0.75. Dose metrics performed poorly at classifying esophagitis (AUC of 0.52, grade 2 or higher mid treatment) or predicting symptom progression (AUC of 0.67). CONCLUSIONS: Normalized uptake can objectively, locally, and noninvasively quantify esophagitis during radiation therapy and predict eventual symptoms from asymptomatic patients. Normalized uptake may provide patient-specific dose-response information not discernible from dose.

Objectively Quantifying Radiation Esophagitis With Novel Computed Tomography-Based Metrics.

PURPOSE: To study radiation-induced esophageal expansion as an objective measure of radiation esophagitis in patients with non-small cell lung cancer (NSCLC) treated with intensity modulated radiation therapy. METHODS AND MATERIALS: Eighty-five patients had weekly intra-treatment CT imaging and esophagitis scoring according to Common Terminlogy Criteria for Adverse Events 4.0, (24 Grade 0, 45 Grade 2, and 16 Grade 3). Nineteen esophageal expansion metrics based on mean, maximum, spatial length, and volume of expansion were calculated as voxel-based relative volume change, using the Jacobian determinant from deformable image registration between the planning and weekly CTs. An anatomic variability correction method was validated and applied to these metrics to reduce uncertainty. An analysis of expansion metrics and radiation esophagitis grade was conducted using normal tissue complication probability from univariate logistic regression and Spearman rank for grade 2 and grade 3 esophagitis endpoints, as well as the timing of expansion and esophagitis grade. Metrics' performance in classifying esophagitis was tested with receiver operating characteristic analysis. RESULTS: Expansion increased with esophagitis grade. Thirteen of 19 expansion metrics had receiver operating characteristic area under the curve values >0.80 for both grade 2 and grade 3 esophagitis endpoints, with the highest performance from maximum axial expansion (MaxExp1) and esophageal length with axial expansion ≥30% (LenExp30%) with area under the curve values of 0.93 and 0.91 for grade 2, 0.90 and 0.90 for grade 3 esophagitis, respectively. CONCLUSIONS: Esophageal expansion may be a suitable objective measure of esophagitis, particularly maximum axial esophageal expansion and esophageal length with axial expansion ≥30%, with 2.1 Jacobian value and 98.6 mm as the metric value for 50% probability of grade 3 esophagitis. The uncertainty in esophageal Jacobian calculations can be reduced with anatomic correction methods.