Feasibility of patient-specific quality assurance (PSQA) for real-time robotic stereotactic body radiotherapy (SBRT) based on tumor motion traces.

PURPOSE: To design a patient specific quality assurance (PSQA) process for the CyberKnife Synchrony system and quantify its dosimetric accuracy using a motion platform driven by patient tumor traces with rotation. METHODS: The CyberKnife Synchrony system was evaluated using a motion platform (MODUSQA) and a SRS MapCHECK phantom. The platform was programed to move in the superior-inferior (SI) direction based on tumor traces. The detector array housed by the StereoPhan was placed on the platform. Extra rotational angles in pitch (head down, 4.0° ± 0.15° or 1.2° ± 0.1°) were added to the moving phantom to examine robot capability of angle correction during delivery. A total of 15 Synchrony patients were performed SBRT PSQA on the moving phantom. All the results were benchmarked by the PSQA results based on static phantom. RESULTS: For smaller pitch angles, the mean gamma passing rates were 99.75% ± 0.87%, 98.63% ± 2.05%, and 93.11% ± 5.52%, for 3%/1 mm, 2%/1 mm, and 1%/1 mm, respectively. Large discrepancy in the passing rates was observed for different pitch angles due to limited angle correction by the robot. For larger pitch angles, the corresponding mean passing rates were dropped to 93.00% ± 10.91%, 88.05% ± 14.93%, and 80.38% ± 17.40%. When comparing with the static phantom, no significant statistic difference was observed for smaller pitch angles (p = 0.1 for 3%/1 mm), whereas a larger statistic difference was observed for larger pitch angles (p < 0.02 for all criteria). All the gamma passing rates were improved, if applying shift and rotation correction. CONCLUSIONS: The significance of this work is that it is the first study to benchmark PSQA for the CyberKnife Synchrony system using realistically moving phantoms with rotation. With reasonable delivery time, we found it may be feasible to perform PSQA for Synchrony patients with a realistic breathing pattern.

Cardiac metabolic changes on 18 F-positron emission tomography after thoracic radiotherapy predict for overall survival in esophageal cancer patients.

PURPOSE: Heart doses have been shown to be predictive of cardiac toxicity and overall survival (OS) for esophageal cancer patients. There is potential for functional imaging to provide valuable cardiac information. The purpose of this study was to evaluate the cardiac metabolic dose-response using 18 F-deoxyglucose (FDG)-PET and to assess whether standard uptake value (SUV) changes in the heart were predictive of OS. METHODS: Fifty-one patients with esophageal cancer treated with radiation who underwent pre- and post-treatment FDG-PET scans were retrospectively evaluated. Pre- and post-treatment PET-scans were rigidly registered to the planning CT for each patient. Pre-treatment to post-treatment absolute mean SUV (SUVmean) changes in the heart were calculated to assess dose-response. A dose-response curve was generated by binning each voxel in the heart into 10 Gy dose-bins and analyzing the SUVmean changes in each dose-bin. Multivariate cox proportional hazard models were used to assess whether pre-to-post treatment cardiac SUVmean changes predicted for OS. RESULTS: The cardiac dose-response curve demonstrated a trend of increasing cardiac SUV changes as a function of dose with an average increase of 0.044 SUV for every 10 Gy dose bin. In multivariate analysis, disease stage and SUVmean change in the heart were predictive (p < 0.05) for OS. CONCLUSIONS: Changes in pre- to post-treatment cardiac SUV were predictive of OS with patients having a higher pre- to post-treatment cardiac SUV change surviving longer.

Functional avoidance-based intensity modulated proton therapy with 4DCT derived ventilation imaging for lung cancer.

The primary objective is to evaluate the potential dosimetric gains of performing functional avoidance-based proton treatment planning using 4DCT derived ventilation imaging. 4DCT data of 31 patients from a prospective functional avoidance clinical trial were evaluated with intensity modulated proton therapy (IMPT) plans and compared with clinical volumetric modulated arc therapy (VMAT) plans. Dosimetric parameters were compared between standard and functional plans with IMPT and VMAT with one-way analysis of variance and post hoc paired student t-test. Normal Tissue Complication Probability (NTCP) models were employed to estimate the risk of two toxicity endpoints for healthy lung tissues. Dose degradation due to proton motion interplay effect was evaluated. Functional IMPT plans led to significant dose reduction to functional lung structures when compared with functional VMAT without significant dose increase to Organ at Risk (OAR) structures. When interplay effect is considered, no significant dose degradation was observed for the OARs or the clinical target volume (CTV) volumes for functional IMPT. Using fV20 as the dose metric and Grade 2+ pneumonitis as toxicity endpoint, there is a mean 5.7% reduction in Grade 2+ RP with the functional IMPT and as high as 26% in reduction for individual patient when compared to the standard IMPT planning. Functional IMPT was able to spare healthy lung tissue to avoid excess dose to normal structures while maintaining satisfying target coverage. NTCP calculation also shows that the risk of pulmonary complications can be further reduced with functional based IMPT.

Implementation and operation of incident learning across a newly-created health system.

PURPOSE: The purpose of this work is to describe our experience launching an expanded incident learning system for patient safety and quality that takes into account aspects beyond therapeutic dose delivery, specifically imaging/simulation incidents, medical care incidents, and operational issues. METHODS: Our ILS was designed for a newly created health system comprised of a midsized academic hospital and two smaller community hospitals. The main design goal was to create a highly sensitive system to capture as much information throughout the department as possible. Reports were classified according to incidents and near misses involving therapeutic radiation, imaging/simulation, and patient care (not involving radiation), unsafe conditions, operational issues, and accolades/suggestions. Reports were analyzed according to impact on various steps in the process of care. Actions made in response to reports were assessed and characterized by intervention reliability. RESULTS: A total of 1125 reports were submitted in the first 23 months. For all three departments, therapeutic radiation incidents and near misses consisted of less than one-third of all reports submitted. For the midsized academic department, operational issues and unsafe conditions comprised the largest percentage of reports (70%). Although the majority of reports impacted steps related to the technical aspects of treatment (simulation, planning, and treatment delivery), 20% impacted other steps such as scheduling or clinic visits. More than 160 actions were performed in response to reports. Of these actions, 63 were quality improvement interventions to improve practices, while 97 were learning actions for raising awareness. CONCLUSIONS: We have developed an ILS that identifies issues related to the entire process of care delivery in radiation oncology, as evidenced by frequent and varied reported events. By identifying a broad spectrum of issues in a department, opportunities for improvement can be identified.

Using 4DCT-ventilation to characterize lung function changes for pediatric patients getting thoracic radiotherapy.

PURPOSE: A form of lung functional imaging has been developed that uses 4DCT data to calculate ventilation (4DCT-ventilation). Because 4DCTs are acquired as standard-of-care to manage breathing motion during radiotherapy, 4DCT-ventilation provides functional information at no extra dosimetric or monetary cost. 4DCT-ventilation has yet to be described in children. 4DCT-ventilation can be used as a tool to help assess post-treatment lung function and predict for future clinical thoracic toxicities for pediatric patients receiving radiotherapy to the chest. The purpose of this work was to perform a preliminary evaluation of 4DCT-ventilation-based lung function changes for pediatric patients receiving radiotherapy to the lungs. METHODS: The study used four patients with pre and postradiotherapy 4DCTs. The 4DCTs, deformable image registration, and a density-change-based algorithm were used to compute pre and post-treatment 4DCT-ventilation images. The post-treatment 4DCT-ventilation images were compared to the pretreatment 4DCT-ventilation images for a global lung response and for an intrapatient dose-response (providing an assessment for dose-dependent regional dose-response). RESULTS: For three of the four patients, a global ventilation decline of 7-37% was observed, while one patient did not demonstrate a global functional decline. Dose-response analysis did not reveal an intrapatient dose-response from 0 to 20 Gy for three patients while one patient demonstrated increased 4DCT-ventilation decline as a function of increasing lung doses up to 50 Gy. CONCLUSIONS: Compared to adults, pediatric patients have unique lung function, dosimetric, and toxicity profiles. The presented work is the first to evaluate spatial lung function changes in pediatric patients using 4DCT-ventilation and showed lung function changes for three of the four patients. The early changes demonstrated with lung function imaging warrant further longitudinal work to determine whether the imaging-based early changes can be predicted for long-term clinical toxicity.

Hypofractionated re-irradiation to the brainstem in children with recurrent brain tumors.

To characterize radiation necrosis following hypofractionated brainstem re-irradiation in pediatric patients, we reviewed 23 cases with 28 tumors invading or abutting brainstem and treated with hypofractionated re-irradiation from 2004 to 2014. Re-irradiation delivered total doses of 16-30 Gy in two to five fractions. The most commons regimens used were 24 Gy in three fractions and 25 Gy in five fractions. At median follow-up of 12.8 months, median overall survival was 14.7 months and eight in-field recurrences were detected (median time 10.5 months). Five patients experienced symptomatic brainstem necrosis, and all having received 24 Gy in three fractions. Hypofractionated brainstem re-irradiation may be safer in five fractions.

A complete 4DCT-ventilation functional avoidance virtual trial: Developing strategies for prospective clinical trials.

INTRODUCTION: 4DCT-ventilation is an exciting new imaging modality that uses 4DCT data to calculate lung-function maps. Because 4DCTs are acquired as standard of care for lung cancer patients undergoing radiotherapy, 4DCT-ventiltation provides functional information at no extra dosimetric or monetary cost to the patient. The development of clinical trials is underway to use 4DCT-ventilation imaging to spare functional lung in patients undergoing radiotherapy. The purpose of this work was to perform a virtual trial using retrospective data to develop the practical aspects of a 4DCT-ventilation functional avoidance clinical trial. METHODS: The study included 96 stage III lung cancer patients. A 4DCT-ventilation map was calculated using the patient's 4DCT-imaging, deformable registration, and a density-change-based algorithm. Clinical trial inclusion assessment used quantitative and qualitative metrics based on the patient's spatial ventilation profile. Clinical and functional plans were generated for 25 patients. The functional plan aimed to reduce dose to functional lung while meeting standard target and critical structure constraints. Standard and dose-function metrics were compared between the clinical and functional plans. RESULTS: Our data showed that 69% and 59% of stage III patients have regional variability in function based on qualitative and quantitative metrics, respectively. Functional planning demonstrated an average reduction of 2.8 Gy (maximum 8.2 Gy) in the mean dose to functional lung. CONCLUSIONS: Our work demonstrated that 60-70% of stage III patients would be eligible for functional planning and that a typical functional lung mean dose reduction of 2.8 Gy can be expected relative to standard clinical plans. These findings provide salient data for the development of functional clinical trials.

Should we customize PTV expansions for BMI? Daily cone beam computerized tomography to assess organ motion in postoperative endometrial and cervical cancer patients.

AIM: A single-institution review assessing patient characteristics contributing to daily organ motion in postoperative endometrial and cervical cancer patients treated with intensity-modulated radiotherapy (IMRT). BACKGROUND: The Radiation Therapy Oncology Group has established consensus guidelines for postoperative pelvic IMRT, recommending a 7 mm margin on all three axes of the target volume. MATERIALS AND METHODS: Daily shifts on 457 radiation setups for 18 patients were recorded in the x axis (lateral), y axis (superior-inferior) and z axis (anterior-posterior); daily positions of the planning tumor volume were referenced with the initial planning scan to quantify variations. RESULTS: Of the 457 sessions, 85 (18.6%) had plan shifts of at least 7 mm in one of the three dimensions. For obese patients (body mass index [BMI] ≥ 30), 75/306 (24.5%) sessions had plan shifts ≥7 mm. Odds of having a shift ≥7 mm in any direction was greater for obese patients under both univariate (OR 4.227, 95% CI 1.235-14.466, p = 0.021) and multivariate (OR 5.000, 95% CI 1.341-18.646, p = 0.016) analyses (MVA). Under MVA, having a BMI ≥ 30 was associated with increased odds of shifts in the anterior-posterior (1.173 mm, 95% CI 0.281-2.065, p = 0.001) and lateral (2.074 mm, 95% CI 1.284-2.864, p < 0.000) directions but not in the superior-inferior axis (0.298 mm, 95% CI -0.880 to 1.475, p = 0.619) exceeding 7 mm. CONCLUSIONS: Based on these findings, the standard planned tumor volume expansion of 7 mm is less likely to account for daily treatment changes in obese patients.

Radiation Oncology Ransomware Attack Response Risk Analysis Using Failure Modes and Effects Analysis.

PURPOSE: There have been numerous significant ransomware attacks impacting Radiation Oncology in the past 5 years. Research into ransomware attack response in Radiation Oncology has consisted of case reports and descriptive articles and has lacked quantitative studies. The purpose of this work was to identify the significant safety risks to patients being treated with radiation therapy during a ransomware attack scenario, using Failure Modes and Effects Analysis. METHODS AND MATERIALS: A multi-institutional and multidisciplinary team conducted a Failure Modes and Effects Analysis by developing process maps and using Risk Priority Number (RPN) scores to quantify the increased likelihood of incidents in a ransomware attack scenario. The situation that was simulated was a ransomware attack that had removed the capability to access the Record and Verify (R&V) system. Five situations were considered: 1) a standard treatment of a patient with and without an R&V, 2) a standard treatment of a patient for the first fraction right after the R&V capabilities are disabled, and 3) 3 situations in which a plan modification was required. RPN scores were compared with and without R&V functionality. RESULTS: The data indicate that RPN scores increased by 71% (range, 38%-96%) when R&V functionality is disabled compared with a nonransomware attack state where R&V functionality is available. The failure modes with the highest RPN in the simulated ransomware attack state included incorrectly identifying patients on treatment, incorrectly identifying where a patient is in their course of treatment, treating the incorrect patient, and incorrectly tracking delivered fractions. CONCLUSIONS: The presented study quantifies the increased risk of incidents when treating in a ransomware attack state, identifies key failure modes that should be prioritized when preparing for a ransomware attack, and provides data that can be used to guide future ransomware resiliency research.

I-125 eye-plaque seed economics: To re-use or to not re-use? A single institutional cost savings analysis of re-using I-125 radioactive seeds for eye-Plaque brachytherapy.

INTRODUCTION: Iodine-125 (I-125) seeds, commonly used in low-dose rate brachytherapy for ocular malignancies, are often discarded after a single use. This study examines the potential cost savings at an institution with high ocular melanoma referrals, by re-using I-125 seeds for eye-plaque brachytherapy. METHODS: In this single-institutional retrospective analysis, data was collected from I-125 seed orders from 8/2019 through 10/2022. Information including number of seeds ordered per lot, number of plaques built per lot, and number of seeds used per lot were collected. Cost per lot of seed was assumed to be the current cost from the most recent lot of 35 seeds. RESULTS: During the study, 72 I-125 seed lots were ordered bi-weekly, with a median of 35 seeds per lot (Range: 15-35). Each seed was used on average 2.26 times prior to being discarded. The average duration of each seed lot used was 62.2 days (Range: 21-126). Each seed lot contributed to the construction of an average of 8.4 eye plaques (Range: 2-20). With seed recycling, 2,475 seeds were used to construct 608 eye-plaques. Without re-using practice this would require 5,694 seeds. This resulted in a percentage cost savings of 56.5%, with a total seed cost reduction of $344,884, or $559 per eye-plaque on average. CONCLUSION: This is the first study to evaluate cost savings relative to re-using I-125 seeds for eye plaques. The data demonstrates how an institution can decrease costs associated with I-125 radiation seeds used for eye-plaque brachytherapy by re-using them.

Systematic Evaluation of the Impact of Lung Segmentation Methods on 4-Dimensional Computed Tomography Ventilation Imaging Using a Large Patient Database.

PURPOSE: A novel form of lung functional imaging applied for functional avoidance radiation therapy has been developed that uses 4-dimensional computed tomography (4DCT) data and image processing techniques to calculate lung ventilation (4DCT-ventilation). Lung segmentation is a common step to define a region of interest for 4DCT-ventilation generation. The purpose of this study was to quantitatively evaluate the sensitivity of 4DCT-ventilation imaging using different lung segmentation methods. METHODS AND MATERIALS: The 4DCT data of 350 patients from 2 institutions were used. Lung contours were generated using 3 methods: (1) reference segmentations that removed airways and pulmonary vasculature manually (Lung-Manual), (2) standard lung contours used for planning (Lung-RadOnc), and (3) artificial intelligence (AI)-based contours that removed the airways and pulmonary vasculature (Lung-AI). The AI model was based on a residual 3-dimensional U-Net and was trained using the Lung-Manual contours of 279 patients. We compared the Lung-RadOnc or Lung-AI with Lung-Manual contours for the entire 4DCT-ventilation functional avoidance process including lung segmentation (surface Dice similarity coefficient [Surface DSC]), 4DCT-ventilation generation (correlation), and subanalysis of 10 patients on a dosimetric endpoint (percentage of high functional volume of lung receiving ≥20 Gy [fV20{%}]). RESULTS: Surface DSC comparing Lung-Manual/Lung-RadOnc and Lung-Manual/Lung-AI contours was 0.40 ± 0.06 and 0.86 ± 0.04, respectively. The correlation between 4DCT-ventilation images generated with Lung-Manual/Lung-RadOnc and Lung-Manual/Lung-AI were 0.48 ± 0.14 and 0.85 ± 0.14, respectively. The difference in fV20[%] between 4DCT-ventilation generated with Lung-Manual/Lung-RadOnc and Lung-Manual/Lung-AI was 2.5% ± 4.1% and 0.3% ± 0.5%, respectively. CONCLUSIONS: Our work showed that using standard planning lung contours can result in significantly variable 4DCT-ventilation images. The study demonstrated that AI-based segmentations generate lung contours and 4DCT-ventilation images that are similar to those generated using manual methods. The significance of the study is that it characterizes the lung segmentation sensitivity of the 4DCT-ventilation process and develops methods that can facilitate the integration of this novel imaging in busy clinics.

Evaluation of a novel patient-specific quality assurance phantom for robotic single-isocentre, multiple-target stereotactic radiosurgery, and stereotactic radiotherapy.

OBJECTIVES: To evaluate patient-specific quality assurance (PSQA) of 3 targets in a single delivery using a novel film-based phantom. METHODS: The phantom was designed to rotate freely as a sphere and could measure 3 targets with film in a single delivery. After identifying the coordinates of 3 targets in the skull, the rotation angles about the equator and meridian were computed for optimal phantom setup, ensuring the film plane intersected the 3 targets. The plans were delivered on the CyberKnife system using fiducial tracking. The irradiated films were scanned and processed. All films were analysed using 3 gamma criteria. RESULTS: Fifteen CyberKnife test plans with 3 different modalities were delivered on the phantom. Both automatic and marker-based registration methods were applied when registering the irradiated film and dose plane. Gamma analysis was performed using a 3%/1 mm, 2%/1 mm, and 1%/1 mm criteria with a 10% threshold. For the automatic registration method, the passing rates were 98.2% ± 1.9%, 94.2% ± 3.7%, and 80.9% ± 6.3%, respectively. For the marker-based registration approach, the passing rates were 96.4% ± 2.7%, 91.7% ± 4.3%, and 78.4% ± 6.2%, respectively. CONCLUSIONS: A novel spherical phantom was evaluated for the CyberKnife system and achieved acceptable PSQA passing rates using TG218 recommendations. The phantom can measure true-composite dose and offers high-resolution results for PSQA, making it a valuable device for robotic radiosurgery. ADVANCES IN KNOWLEDGE: This is the first study on PSQA of 3 targets concurrently on the CyberKnife system.

Incorporation of Functional Lung Imaging Into Radiation Therapy Planning in Patients With Lung Cancer: A Systematic Review and Meta-Analysis.

Our purpose was to provide an understanding of current functional lung imaging (FLI) techniques and their potential to improve dosimetry and outcomes for patients with lung cancer receiving radiation therapy (RT). Excerpta Medica dataBASE (EMBASE), PubMed, and Cochrane Library were searched from 1990 until April 2023. Articles were included if they reported on FLI in one of: techniques, incorporation into RT planning for lung cancer, or quantification of RT-related outcomes for patients with lung cancer. Studies involving all RT modalities, including stereotactic body RT and particle therapy, were included. Meta-analyses were conducted to investigate differences in dose-function parameters between anatomic and functional RT planning techniques, as well as to investigate correlations of dose-function parameters with grade 2+ radiation pneumonitis (RP). One hundred seventy-eight studies were included in the narrative synthesis. We report on FLI modalities, dose-response quantification, functional lung (FL) definitions, FL avoidance techniques, and correlations between FL irradiation and toxicity. Meta-analysis results show that FL avoidance planning gives statistically significant absolute reductions of 3.22% to the fraction of well-ventilated lung receiving 20 Gy or more, 3.52% to the fraction of well-perfused lung receiving 20 Gy or more, 1.3 Gy to the mean dose to the well-ventilated lung, and 2.41 Gy to the mean dose to the well-perfused lung. Increases in the threshold value for defining FL are associated with decreases in functional parameters. For intensity modulated RT and volumetric modulated arc therapy, avoidance planning results in a 13% rate of grade 2+ RP, which is reduced compared with results from conventional planning cohorts. A trend of increased predictive ability for grade 2+ RP was seen in models using FL information but was not statistically significant. FLI shows promise as a method to spare FL during thoracic RT, but interventional trials related to FL avoidance planning are sparse. Such trials are critical to understanding the effect of FL avoidance planning on toxicity reduction and patient outcomes.

Novel Functional Radiomics for Prediction of Cardiac Positron Emission Tomography Avidity in Lung Cancer Radiotherapy.

PURPOSE: Traditional methods of evaluating cardiotoxicity focus on radiation doses to the heart. Functional imaging has the potential to provide improved prediction for cardiotoxicity for patients with lung cancer. Fluorine-18 (18F) fluorodeoxyglucose (FDG)-positron emission tomography (PET)/computed tomography (CT) imaging is routinely obtained in a standard cancer staging workup. This work aimed to develop a radiomics model predicting clinical cardiac assessment using 18F-FDG PET/CT scans before thoracic radiation therapy. METHODS: Pretreatment 18F-FDG PET/CT scans from three study populations (N = 100, N = 39, N = 70) were used, comprising two single-institutional protocols and one publicly available data set. A clinician (V.J.) classified the PET/CT scans per clinical cardiac guidelines as no uptake, diffuse uptake, or focal uptake. The heart was delineated, and 210 novel functional radiomics features were selected to classify cardiac FDG uptake patterns. Training data were divided into training (80%)/validation (20%) sets. Feature reduction was performed using the Wilcoxon test, hierarchical clustering, and recursive feature elimination. Ten-fold cross-validation was carried out for training, and the accuracy of the models to predict clinical cardiac assessment was reported. RESULTS: From 202 of 209 scans, cardiac FDG uptake was scored as no uptake (39.6%), diffuse uptake (25.3%), and focal uptake (35.1%), respectively. Sixty-two independent radiomics features were reduced to nine clinically pertinent features. The best model showed 93% predictive accuracy in the training data set and 80% and 92% predictive accuracy in two external validation data sets. CONCLUSION: This work used an extensive patient data set to develop a functional cardiac radiomic model from standard-of-care 18F-FDG PET/CT scans, showing good predictive accuracy. The radiomics model has the potential to provide an automated method to predict existing cardiac conditions and provide an early functional biomarker to identify patients at risk of developing cardiac complications after radiotherapy.

Clinical and Dosimetric Impact of 2D kV Motion Monitoring and Intervention in Liver Stereotactic Body Radiation Therapy.

Purpose: Positional errors resulting from motion are a principal challenge across all disease sites in radiation therapy. This is particularly pertinent when treating lesions in the liver with stereotactic body radiation therapy (SBRT). To achieve dose escalation and margin reduction for liver SBRT, kV real-time imaging interventions may serve as a potential solution. In this study, we report results of a retrospective cohort of liver patients treated using real-time 2D kV-image guidance SBRT with emphasis on the impact of (1) clinical workflow, (2) treatment accuracy, and (3) tumor dose. Methods and Materials: Data from 33 patients treated with 41 courses of liver SBRT were analyzed. During treatment, planar kV images orthogonal to the treatment beam were acquired to determine treatment interventions, namely treatment pauses (ie, adequacy of gating thresholds) or treatment shifts. Patients were shifted if internal markers were >3 mm, corresponding to the PTV margin used, from the expected reference condition. The frequency, duration, and nature of treatment interventions (ie, pause vs shift) were recorded, and the dosimetric impact associated with treatment shifts was estimated using a machine learning dosimetric model. Results: Of all fractions delivered, 39% required intervention, which took on average 1.9 ± 1.6 minutes and occurred more frequently in treatments lasting longer than 7 minutes. The median realignment shift was 5.7 mm in size, and the effect of these shifts on minimum tumor dose in simulated clinical scenarios ranged from 0% to 50% of prescription dose per fraction. Conclusion: Real-time kV-based imaging interventions for liver SBRT minimally affect clinical workflow and dosimetrically benefit patients. This potential solution for addressing positional errors from motion addresses concerns about target accuracy and may enable safe dose escalation and margin reduction in the context of liver SBRT.

Prospective Trial of Functional Lung Avoidance Radiation Therapy for Lung Cancer: Quality of Life Report.

PURPOSE: A novel form of lung function imaging has been developed that uses 4-dimensional computed tomography (4DCT) data to generate lung ventilation images (4DCT-ventilation). Functional avoidance uses 4DCT-ventilation to reduce doses to functional lung with the aim of reducing pulmonary side effects. A phase 2, multicenter 4DCT-ventilation functional avoidance clinical trial was completed. The purpose of this work was to quantify changes in patient-reported outcomes (PROs) for patients treated with functional avoidance and determine which metrics are predictive of PRO changes. MATERIALS AND METHODS: Patients with locally advanced lung cancer receiving curative-intent radiation therapy were accrued. Each patient had a 4DCT-ventilation image generated using 4DCT data and image processing. PRO instruments included the Functional Assessment of Cancer Therapy-Lung (FACT-L) questionnaire administered pretreatment; at the end of treatment; and at 3, 6, and 12 months posttreatment. Using the FACT-Trial Outcome Index and the FACT-Lung Cancer Subscale results, the percentage of clinically meaningful declines (CMDs) were determined. A linear mixed-effects model was used to determine which patient, clinical, dose, and dose-function metrics were predictive of PRO decline. RESULTS: Of the 59 patients who completed baseline PRO surveys. 83% had non-small cell lung cancer, with 75% having stage 3 disease. The median dose was 60 Gy in 30 fractions. CMD FACT-Trial Outcome Index decline was 46.3%, 38.5%, and 26.8%, at 3, 6, and 12 months, respectively. CMD FACT-Lung Cancer Subscale decline was 33.3%, 33.3%, and 29.3%, at 3, 6, and 12 months, respectively. Although an increase in most dose and dose-function parameters was associated with a modest decline in PROs, none of the results were significant (all P > .053). CONCLUSIONS: The current work presents an innovative combination of use of functional avoidance and PRO assessment and is the first report of PROs for patients treated with prospective 4DCT-ventilation functional avoidance. Approximately 30% of patients had clinically significant decline in PROs at 12 months posttreatment. The study provides additional data on outcomes with 4DCT-ventilation functional avoidance.

Is individual perfusion dose-response different than ventilation dose-response for lung cancer patients treated with radiotherapy?

OBJECTIVE: Current ventilation and perfusion dose-response studies focus on single-modalities (ventilation or perfusion) and perform pulmonary-toxicity assessment related to radiotherapy on a population-based basis. This study aims at quantitative and clinical evaluation of intrapatient differences between ventilation and perfusion dose-responses among lung cancer patients treated with radiotherapy. METHODS: 20 patients enrolled on a prospective functional avoidance protocol underwent single photon emission computed tomography-CT ventilation and perfusion scans pre- and post-radiotherapy. Relative changes in pre- to post-treatment ventilation and perfusion in lung regions receiving ≥20 Gy were calculated. In addition, the slopes of the linear fit to the relative ventilation and perfusion changes in regions receiving 0-60 Gy were calculated. A radiologist read and assigned a functional defect score to pre- and post-treatment ventilation/perfusion scans. RESULTS: 25% of patients had a difference >35% between ventilation and perfusion pre- to post-treatment changes and 20-30% of patients had opposite directions for ventilation and perfusion pre- to post-treatment changes. Using a semi-quantitative scale, radiologist assessment showed that 20% of patients had different pre- to post-treatment ventilation changes when compared to pre- to post-treatment perfusion changes. CONCLUSION: Our data showed that ventilation dose-response can differ from perfusion dose-response for 20-30% of patients. Therefore, when performing thoracic dose-response in cancer patients, it is insufficient to look at ventilation or perfusion alone; but rather both modes of functional imaging may be needed when predicting for clinical outcomes. ADVANCES IN KNOWLEDGE: The significance of this study can be highlighted by the differences between the intrapatient dose-response assessments of this analysis compared to existing population-based dose-response analyses. Elucidating intrapatient ventilation and perfusion dose-response differences may be valuable in predicting pulmonary toxicity in lung cancer patients post-radiotherapy.

Evaluation of variables predicting PFT changes for lung cancer patients treated on a prospective 4DCT-ventilation functional avoidance clinical trial.

PURPOSE: Functional avoidance radiotherapy uses functional imaging to reduce pulmonary toxicity by designing radiotherapy plans that reduce doses to functional regions of the lung. A phase-II, multi-center, prospective study of 4DCT-ventilation functional avoidance was completed. Pre and post-treatment pulmonary function tests (PFTs) were acquired and assessed pulmonary function change. This study aims to evaluate which clinical, dose and dose-function factors predict PFT changes for patients treated with 4DCT-ventilation functional avoidance radiotherapy. MATERIALS AND METHODS: 56 patients with locally advanced lung cancer receiving radiotherapy were accrued. PFTs were obtained at baseline and three months following radiotherapy and included forced expiratory volume in 1-second (FEV1), forced vital capacity (FVC), and FEV1/FVC. The ability of patient, clinical, dose (lung and heart), and dose-function metrics (metrics that combine dose and 4DCT-ventilation-based function) to predict PFT changes were evaluated using univariate and multivariate linear regression. RESULTS: Univariate analysis showed that only dose-function metrics and the presence of chronic obstructive pulmonary disease (COPD) were significant (p<0.05) in predicting FEV1 decline. Multivariate analysis identified a combination of clinical (immunotherapy status, presence of thoracic comorbidities, smoking status, and age), along with lung dose, heart dose, and dose-function metrics in predicting FEV1 and FEV1/FVC changes. CONCLUSION: The current work evaluated factors predicting PFT changes for patients treated in a prospective functional avoidance radiotherapy study. The data revealed that lung dose- function metrics could predict PFT changes, validating the significance of reducing the dose to the functional lung to mitigate the decline in pulmonary function and providing guidance for future clinical trials.

Characterizing Pulmonary Function Test Changes for Patients With Lung Cancer Treated on a 2-Institution, 4-Dimensional Computed Tomography-Ventilation Functional Avoidance Prospective Clinical Trial.

Purpose: Four-dimensional computed tomography (4DCT)-ventilation-based functional avoidance uses 4DCT images to generate plans that avoid functional regions of the lung with the goal of reducing pulmonary toxic effects. A phase 2, multicenter, prospective study was completed to evaluate 4DCT-ventilation functional avoidance radiation therapy. The purpose of this study was to report the results for pretreatment to posttreatment pulmonary function test (PFT) changes for patients treated with functional avoidance radiation therapy. Methods and Materials: Patients with locally advanced lung cancer receiving chemoradiation were accrued. Functional avoidance plans based on 4DCT-ventilation images were generated. PFTs were obtained at baseline and 3 months after chemoradiation. Differences for PFT metrics are reported, including diffusing capacity for carbon monoxide (DLCO), forced expiratory volume in 1 second (FEV1), and forced vital capacity (FVC). PFT metrics were compared for patients who did and did not experience grade 2 or higher pneumonitis. Results: Fifty-six patients enrolled on the study had baseline and posttreatment PFTs evaluable for analysis. The mean change in DLCO, FEV1, and FVC was -11.6% ± 14.2%, -5.6% ± 16.9%, and -9.0% ± 20.1%, respectively. The mean change in DLCO was -15.4% ± 14.4% for patients with grade 2 or higher radiation pneumonitis and -10.8% ± 14.1% for patients with grade <2 radiation pneumonitis (P = .37). The mean change in FEV1 was -14.3% ± 22.1% for patients with grade 2 or higher radiation pneumonitis and -3.9% ± 15.4% for patients with grade <2 radiation pneumonitis (P = .09). Conclusions: The current work is the first to quantitatively characterize PFT changes for patients with lung cancer treated on a prospective functional avoidance radiation therapy study. In comparison with patients treated with standard thoracic radiation planning, the data qualitatively show that functional avoidance resulted in less of a decline in DLCO and FEV1. The presented data can help elucidate the potential pulmonary function improvement with functional avoidance radiation therapy.

Phase 1 Dose Escalation Study of SBRT Using 3 Fractions for Locally Advanced Pancreatic Cancer.

PURPOSE: The optimal dose and fractionation of stereotactic body radiation therapy (SBRT) for locally advanced pancreatic cancer (LAPC) have not been defined. Single-fraction SBRT was associated with more gastrointestinal toxicity, so 5-fraction regimens have become more commonly employed. We aimed to determine the safety and maximally tolerated dose of 3-fraction SBRT for LAPC. METHODS AND MATERIALS: Two parallel phase 1 dose escalation trials were conducted from 2016 to 2019 at Memorial Sloan Kettering Cancer Center and University of Colorado. Patients with histologically confirmed LAPC without distant progression after at least 2 months of induction chemotherapy were eligible. Patients received 3-fraction linear accelerator-based SBRT at 3 dose levels, 27, 30, and 33 Gy, following a modified 3+3 design. Dose-limiting toxicity, defined as grade ≥3 gastrointestinal toxicity within 90 days, was scored by National Cancer Institute Common Terminology Criteria for Adverse Events, version 4. The secondary endpoints included cumulative incidence of local failure (LF) and distant metastasis (DM), as well as progression-free and overall survival PFS and OS, respectively, toxicity, and quality of life (QoL) using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (QLQ-C30) and the pancreatic cancer-specific QLQ-PAN26 questionnaire. RESULTS: Twenty-four consecutive patients were enrolled (27 Gy: 9, 30 Gy: 8, 33 Gy: 7). The median (range) age was 67 (52-79) years, and 12 (50%) had a head/uncinate tumor location, with a median tumor size of 3.8 (1.1-11) cm and CA19-9 of 60 (1-4880) U/mL. All received chemotherapy for a median of 4 (1.4-10) months. There were no grade ≥3 toxicities. Two-year rates (95% confidence interval) of LF, DM, PFS, and OS were 31.7% (8.6%-54.8%), 70.2% (49.7%-90.8%), 20.8% (4.6%-37.1%), and 29.2% (11.0%-47.4%), respectively. Three- and 6-month QoL assessment showed no detriment. CONCLUSIONS: For select patients with LAPC, dose escalation to 33 Gy in 3 fractions resulted in no dose-limiting toxicities, no detriments to QoL, and disease outcomes comparable with conventional RT. Further exploration of SBRT schemes to maximize tumor control while enabling efficient integration with systemic therapy is warranted.