GAiN: An integrative tool utilizing generative adversarial neural networks for augmented gene expression analysis.

Big genomic data and artificial intelligence (AI) are ushering in an era of precision medicine, providing opportunities to study previously under-represented subtypes and rare diseases rather than categorize them as variances. However, clinical researchers face challenges in accessing such novel technologies as well as reliable methods to study small datasets or subcohorts with unique phenotypes. To address this need, we developed an integrative approach, GAiN, to capture patterns of gene expression from small datasets on the basis of an ensemble of generative adversarial networks (GANs) while leveraging big population data. Where conventional biostatistical methods fail, GAiN reliably discovers differentially expressed genes (DEGs) and enriched pathways between two cohorts with limited numbers of samples (n = 10) when benchmarked against a gold standard. GAiN is freely available at GitHub. Thus, GAiN may serve as a crucial tool for gene expression analysis in scenarios with limited samples, as in the context of rare diseases, under-represented populations, or limited investigator resources.

Technical note: Minimizing CIED artifacts on a 0.35 T MRI-Linac using deep learning.

BACKGROUND: Artifacts from implantable cardioverter defibrillators (ICDs) are a challenge to magnetic resonance imaging (MRI)-guided radiotherapy (MRgRT). PURPOSE: This study tested an unsupervised generative adversarial network to mitigate ICD artifacts in balanced steady-state free precession (bSSFP) cine MRIs and improve image quality and tracking performance for MRgRT. METHODS: Fourteen healthy volunteers (Group A) were scanned on a 0.35 T MRI-Linac with and without an MR conditional ICD taped to their left pectoral to simulate an implanted ICD. bSSFP MRI data from 12 of the volunteers were used to train a CycleGAN model to reduce ICD artifacts. The data from the remaining two volunteers were used for testing. In addition, the dataset was reorganized three times using a Leave-One-Out scheme. Tracking metrics [Dice similarity coefficient (DSC), target registration error (TRE), and 95 percentile Hausdorff distance (95% HD)] were evaluated for whole-heart contours. Image quality metrics [normalized root mean square error (nRMSE), peak signal-to-noise ratio (PSNR), and multiscale structural similarity (MS-SSIM) scores] were evaluated. The technique was also tested qualitatively on three additional ICD datasets (Group B) including a patient with an implanted ICD. RESULTS: For the whole-heart contour with CycleGAN reconstruction: 1) Mean DSC rose from 0.910 to 0.935; 2) Mean TRE dropped from 4.488 to 2.877 mm; and 3) Mean 95% HD dropped from 10.236 to 7.700 mm. For the whole-body slice with CycleGAN reconstruction: 1) Mean nRMSE dropped from 0.644 to 0.420; 2) Mean MS-SSIM rose from 0.779 to 0.819; and 3) Mean PSNR rose from 18.744 to 22.368. The three Group B datasets evaluated qualitatively displayed a reduction in ICD artifacts in the heart. CONCLUSION: CycleGAN-generated reconstructions significantly improved both tracking and image quality metrics when used to mitigate artifacts from ICDs.

Feasibility of surface-guidance combined with CBCT for intra-fractional breath-hold motion management during Ethos RT.

PURPOSE: High-quality CBCT and AI-enhanced adaptive planning techniques allow CBCT-guided stereotactic adaptive radiotherapy (CT-STAR) to account for inter-fractional anatomic changes. Studies of intra-fractional respiratory motion management with a surface imaging solution for CT-STAR have not been fully conducted. We investigated intra-fractional motion management in breath-hold Ethos-based CT-STAR and CT-SBRT (stereotactic body non-adaptive radiotherapy) using optical surface imaging combined with onboard CBCTs. METHODS: Ten cancer patients with mobile lower lung or upper abdominal malignancies participated in an IRB-approved clinical trial (Phase I) of optical surface image-guided Ethos CT-STAR/SBRT. In the clinical trial, a pre-configured gating window (± 2 mm in AP direction) on optical surface imaging was used for manually triggering intra-fractional CBCT acquisition and treatment beam irradiation during breath-hold (seven patients for the end of exhalation and three patients for the end of inhalation). Two inter-fractional CBCTs at the ends of exhalation and inhalation in each fraction were acquired to verify the primary direction and range of the tumor/imaging-surrogate (donut-shaped fiducial) motion. Intra-fractional CBCTs were used to quantify the residual motion of the tumor/imaging-surrogate within the pre-configured breath-hold window in the AP direction. Fifty fractions of Ethos RT were delivered under surface image-guidance: Thirty-two fractions with CT-STAR (adaptive RT) and 18 fractions with CT-SBRT (non-adaptive RT). The residual motion of the tumor was quantified by determining variations in the tumor centroid position. The dosimetric impact on target coverage was calculated based on the residual motion. RESULTS: We used 46 fractions for the analysis of intra-fractional residual motion and 43 fractions for the inter-fractional motion analysis due to study constraints. Using the image registration method, 43 pairs of inter-fractional CBCTs and 100 intra-fractional CBCTs attached to dose maps were analyzed. In the motion range study (image registration) from the inter-fractional CBCTs, the primary motion (mean ± std) was 16.6 ± 9.2 mm in the SI direction (magnitude: 26.4 ± 11.3 mm) for the tumors and 15.5 ± 7.3 mm in the AP direction (magnitude: 20.4 ± 7.0 mm) for the imaging-surrogate, respectively. The residual motion of the tumor (image registration) from intra-fractional breath-hold CBCTs was 2.2 ± 2.0 mm for SI, 1.4 ± 1.4 mm for RL, and 1.3 ± 1.3 mm for AP directions (magnitude: 3.5 ± 2.1 mm). The ratio of the actual dose coverage to 99%, 90%, and 50% of the target volume decreased by 0.95 ± 0.11, 0.96 ± 0.10, 0.99 ± 0.05, respectively. The mean percentage of the target volume covered by the prescribed dose decreased by 2.8 ± 4.4%. CONCLUSION: We demonstrated the intra-fractional motion-managed treatment strategy in breath-hold Ethos CT-STAR/SBRT using optical surface imaging and CBCT. While the controlled residual tumor motion measured at 3.5 mm exceeded the predetermined setup value of 2 mm, it is important to note that this motion still fell within the clinically acceptable range defined by the PTV margin of 5 mm. Nonetheless, additional caution is needed with intra-fractional motion management in breath-hold Ethos CT-STAR/SBRT using optical surface imaging and CBCT.

Inter-fractional portability of deep learning models for lung target tracking on cine imaging acquired in MRI-guided radiotherapy.

MRI-guided radiotherapy systems enable beam gating by tracking the target on planar, two-dimensional cine images acquired during treatment. This study aims to evaluate how deep-learning (DL) models for target tracking that are trained on data from one fraction can be translated to subsequent fractions. Cine images were acquired for six patients treated on an MRI-guided radiotherapy platform (MRIdian, Viewray Inc.) with an onboard 0.35 T MRI scanner. Three DL models (U-net, attention U-net and nested U-net) for target tracking were trained using two training strategies: (1) uniform training using data obtained only from the first fraction with testing performed on data from subsequent fractions and (2) adaptive training in which training was updated each fraction by adding 20 samples from the current fraction with testing performed on the remaining images from that fraction. Tracking performance was compared between algorithms, models and training strategies by evaluating the Dice similarity coefficient (DSC) and 95% Hausdorff Distance (HD95) between automatically generated and manually specified contours. The mean DSC for all six patients in comparing manual contours and contours generated by the onboard algorithm (OBT) were 0.68 ± 0.16. Compared to OBT, the DSC values improved 17.0 - 19.3% for the three DL models with uniform training, and 24.7 - 25.7% for the models based on adaptive training. The HD95 values improved 50.6 - 54.5% for the models based on adaptive training. DL-based techniques achieved better tracking performance than the onboard, registration-based tracking approach. DL-based tracking performance improved when implementing an adaptive strategy that augments training data fraction-by-fraction.

Bintrafusp Alfa With CCRT Followed by Bintrafusp Alfa Versus Placebo With CCRT Followed by Durvalumab in Patients With Unresectable Stage III NSCLC: A Phase 2 Randomized Study.

INTRODUCTION: Preclinical evaluation of bintrafusp alfa (BA) combined with radiotherapy revealed greater antitumor effects than BA or radiotherapy alone. In a phase 1 study, BA exhibited encouraging clinical activity in patients with stage IIIB or IV NSCLC who had received previous treatment. METHODS: This multicenter, double-blind, controlled phase 2 study (NCT03840902) evaluated the safety and efficacy of BA with concurrent chemoradiotherapy (cCRT) followed by BA (BA group) versus placebo with cCRT followed by durvalumab (durvalumab group) in patients with unresectable stage III NSCLC. The primary end point was progression-free survival according to Response Evaluation Criteria in Solid Tumors version 1.1 as assessed by the investigator. On the basis of the recommendation of an independent data monitoring committee, the study was discontinued before the maturity of overall survival data (secondary end point). RESULTS: A total of 153 patients were randomized to either BA (n = 75) or durvalumab groups (n = 78). The median progression-free survival was 12.8 months versus 14.6 months (stratified hazard ratio = 1.48 [95% confidence interval: 0.69-3.17]), in the BA and durvalumab groups, respectively. Trends for overall response rate (29.3% versus 32.1%) and disease control rate (66.7% versus 70.5%) were similar between the two groups. Any-grade treatment-emergent adverse events occurred in 94.6% versus 96.1% of patients in the BA versus durvalumab groups, respectively. Bleeding events in the BA group were mostly grade 1 (21.6%) or 2 (9.5%). CONCLUSIONS: BA with cCRT followed by BA exhibited no efficacy benefit over placebo with cCRT followed by durvalumab in patients with stage III unresectable NSCLC.

Development of a comprehensive cardiac atlas on a 1.5 Tesla Magnetic Resonance Linear Accelerator.

Background and purpose: The 1.5 Tesla (T) Magnetic Resonance Linear Accelerator (MRL) provides an innovative modality for improved cardiac imaging when planning radiation treatment. No MRL based cardiac atlases currently exist, thus, we sought to comprehensively characterize cardiac substructures, including the conduction system, from cardiac images acquired using a 1.5 T MRL and provide contouring guidelines. Materials and methods: Five volunteers were enrolled in a prospective protocol (NCT03500081) and were imaged on the 1.5 T MRL with Half Fourier Single-Shot Turbo Spin-Echo (HASTE) and 3D Balanced Steady-State Free Precession (bSSFP) sequences in axial, short axis, and vertical long axis. Cardiac anatomy was contoured by (AS) and confirmed by a board certified cardiologist (JR) with expertise in cardiac MR imaging. Results: A total of five volunteers had images acquired with the HASTE sequence, with 21 contours created on each image. One of these volunteers had additional images obtained with 3D bSSFP sequences in the axial plane and additional images obtained with HASTE sequences in the key cardiac planes. Contouring guidelines were created and outlined. 15-16 contours were made for the short axis and vertical long axis. The cardiac conduction system was demonstrated with eleven representative contours. There was reasonable variation of contour volume across volunteers, with structures more clearly delineated on the 3D bSSFP sequence. Conclusions: We present a comprehensive cardiac atlas using novel images acquired prospectively on a 1.5 T MRL. This cardiac atlas provides a novel resource for radiation oncologists in delineating cardiac structures for treatment with radiotherapy, with special focus on the cardiac conduction system.

NRG/RTOG 0837: Randomized, phase II, double-blind, placebo-controlled trial of chemoradiation with or without cediranib in newly diagnosed glioblastoma.

Background: A randomized, phase II, placebo-controlled, and blinded clinical trial (NCT01062425) was conducted to determine the efficacy of cediranib, an oral pan-vascular endothelial growth factor receptor tyrosine kinase inhibitor, versus placebo in combination with radiation and temozolomide in newly diagnosed glioblastoma. Methods: Patients with newly diagnosed glioblastoma were randomly assigned 2:1 to receive (1) cediranib (20 mg) in combination with radiation and temozolomide; (2) placebo in combination with radiation and temozolomide. The primary endpoint was 6-month progression-free survival (PFS) based on blinded, independent radiographic assessment of postcontrast T1-weighted and noncontrast T2-weighted MRI brain scans and was tested using a 1-sided Z test for 2 proportions. Adverse events (AEs) were evaluated per CTCAE version 4. Results: One hundred and fifty-eight patients were randomized, out of which 9 were ineligible and 12 were not evaluable for the primary endpoint, leaving 137 eligible and evaluable. 6-month PFS was 46.6% in the cediranib arm versus 24.5% in the placebo arm (P = .005). There was no significant difference in overall survival between the 2 arms. There was more grade ≥ 3 AEs in the cediranib arm than in the placebo arm (P = .02). Conclusions: This study met its primary endpoint of prolongation of 6-month PFS with cediranib in combination with radiation and temozolomide versus placebo in combination with radiation and temozolomide. There was no difference in overall survival between the 2 arms.

Cardiac radiation improves ventricular function in mice and humans with cardiomyopathy.

BACKGROUND: Rapidly dividing cells are more sensitive to radiation therapy (RT) than quiescent cells. In the failing myocardium, macrophages and fibroblasts mediate collateral tissue injury, leading to progressive myocardial remodeling, fibrosis, and pump failure. Because these cells divide more rapidly than cardiomyocytes, we hypothesized that macrophages and fibroblasts would be more susceptible to lower doses of radiation and that cardiac radiation could therefore attenuate myocardial remodeling. METHODS: In three independent murine heart failure models, including models of metabolic stress, ischemia, and pressure overload, mice underwent 5 Gy cardiac radiation or sham treatment followed by echocardiography. Immunofluorescence, flow cytometry, and non-invasive PET imaging were employed to evaluate cardiac macrophages and fibroblasts. Serial cardiac magnetic resonance imaging (cMRI) from patients with cardiomyopathy treated with 25 Gy cardiac RT for ventricular tachycardia (VT) was evaluated to determine changes in cardiac function. FINDINGS: In murine heart failure models, cardiac radiation significantly increased LV ejection fraction and reduced end-diastolic volume vs. sham. Radiation resulted in reduced mRNA abundance of B-type natriuretic peptide and fibrotic genes, and histological assessment of the LV showed reduced fibrosis. PET and flow cytometry demonstrated reductions in pro-inflammatory macrophages, and immunofluorescence demonstrated reduced proliferation of macrophages and fibroblasts with RT. In patients who were treated with RT for VT, cMRI demonstrated decreases in LV end-diastolic volume and improvements in LV ejection fraction early after treatment. CONCLUSIONS: These results suggest that 5 Gy cardiac radiation attenuates cardiac remodeling in mice and humans with heart failure. FUNDING: NIH, ASTRO, AHA, Longer Life Foundation.

Pre-radiotherapy ctDNA liquid biopsy for risk stratification of oligometastatic non-small cell lung cancer.

The optimal treatment paradigm for patients with oligometastatic non-small cell lung cancer (NSCLC) remains unclear. Some patients with oligometastatic disease experience prolonged remission after locally consolidative radiation therapy (RT), while others harbor micrometastatic disease (below limits of detection by imaging) and benefit from systemic therapy. To risk-stratify and identify the patients most likely to benefit from locally consolidative RT, we performed a multi-institutional cohort study of 1487 patients with oligometastatic NSCLC undergoing liquid biopsy analysis of circulating tumor DNA (ctDNA). In total, 1880 liquid biopsies were performed and approximately 20% of patients (n = 309) had ctDNA measured prior to RT and after their diagnosis of oligometastatic disease. Patients with undetectable ctDNA (pathogenic or likely pathogenic variants in plasma using the Tempus xF assay) before RT had significantly improved progression-free survival (PFS) (P = 0.004) and overall survival (OS) (P = 0.030). ctDNA maximum variant allele frequency (VAF) pre-RT and ctDNA mutational burden pre-RT were both significantly inversely correlated with PFS (maximum VAF P = 0.008, mutational burden P = 0.003) and OS (maximum VAF P = 0.007, mutational burden P = 0.045). These findings were corroborated by multivariate Cox proportional hazards models that included eight additional clinical and genomic parameters. Overall, these data suggest that in patients with oligometastatic NSCLC, pre-RT ctDNA can potentially identify the patients most likely to benefit from locally consolidative RT and experience prolonged PFS and OS. Similarly, ctDNA may be useful to identify undiagnosed micrometastatic disease where it may be appropriate to prioritize systemic therapies.

Interobserver variability in target definition for stereotactic arrhythmia radioablation.

Background: Stereotactic arrhythmia radioablation (STAR) is a potential new therapy for patients with refractory ventricular tachycardia (VT). The arrhythmogenic substrate (target) is synthesized from clinical and electro-anatomical information. This study was designed to evaluate the baseline interobserver variability in target delineation for STAR. Methods: Delineation software designed for research purposes was used. The study was split into three phases. Firstly, electrophysiologists delineated a well-defined structure in three patients (spinal canal). Secondly, observers delineated the VT-target in three patients based on case descriptions. To evaluate baseline performance, a basic workflow approach was used, no advanced techniques were allowed. Thirdly, observers delineated three predefined segments from the 17-segment model. Interobserver variability was evaluated by assessing volumes, variation in distance to the median volume expressed by the root-mean-square of the standard deviation (RMS-SD) over the target volume, and the Dice-coefficient. Results: Ten electrophysiologists completed the study. For the first phase interobserver variability was low as indicated by low variation in distance to the median volume (RMS-SD range: 0.02-0.02 cm) and high Dice-coefficients (mean: 0.97 ± 0.01). In the second phase distance to the median volume was large (RMS-SD range: 0.52-1.02 cm) and the Dice-coefficients low (mean: 0.40 ± 0.15). In the third phase, similar results were observed (RMS-SD range: 0.51-1.55 cm, Dice-coefficient mean: 0.31 ± 0.21). Conclusions: Interobserver variability is high for manual delineation of the VT-target and ventricular segments. This evaluation of the baseline observer variation shows that there is a need for methods and tools to improve variability and allows for future comparison of interventions aiming to reduce observer variation, for STAR but possibly also for catheter ablation.

The Inherited KRAS-variant as a Biomarker of Cetuximab Response in NSCLC.

PURPOSE: RTOG 0617 was a phase III randomized trial for patients with unresectable stage IIIA/IIIB non-small cell lung cancer comparing standard-dose (60 Gy) versus high-dose (74 Gy) radiotherapy and chemotherapy, plus or minus cetuximab. Although the study was negative, based on prior evidence that patients with the KRAS-variant, an inherited germline mutation, benefit from cetuximab, we evaluated KRAS-variant patients in RTOG 0617. EXPERIMENTAL DESIGN: From RTOG 0617, 328 of 496 (66%) of patients were included in this analysis. For time-to-event outcomes, stratified log-rank tests and multivariable Cox regression models were used. For binary outcomes, Cochran-Mantel-Haenzel tests and multivariable logistic regression models were used. All statistical tests were two sided, and a P value <0.05 was considered significant. RESULTS: A total of 17.1% (56/328) of patients had the KRAS-variant, and overall survival rates were similar between KRAS-variant and non-variant patients. However, there was a time-dependent effect of cetuximab seen only in KRAS-variant patients-while the hazard of death was higher in cetuximab-treated patients within year 1 [HR = 3.37, 95% confidence interval (CI): 1.13-10.10, P = 0.030], death was lower from year 1 to 4 (HR = 0.33, 95% CI: 0.11-0.97, P = 0.043). In contrast, in non-variant patients, the addition of cetuximab significantly increased local failure (HR = 1.59, 95% CI: 1.11-2.28, P = 0.012). CONCLUSIONS/DISCUSSION: Although an overall survival advantage was not achieved in KRAS-variant patients, there is potential impact of cetuximab for this genetic subset of patients. In contrast, cetuximab seems to harm non-variant patients. These findings further support the importance of genetic patient selection in trials studying the addition of systemic agents to radiotherapy. SIGNIFICANCE: The KRAS-variant is the first functional, inherited miRNA-disrupting variant identified in cancer. Our findings support that cetuximab has a potentially beneficial impact on KRAS-variant patients treated with radiation. The work confirms prior evidence that KRAS-variant patients are a subgroup who are especially sensitive to radiation. These findings further support the potential of this class of variants to enable true treatment personalization, considering the equally important endpoints of response and toxicity.

Initial clinical experience building a dual CT- and MR-guided adaptive radiotherapy program.

Introduction: Our institution was the first in the world to clinically implement MR-guided adaptive radiotherapy (MRgART) in 2014. In 2021, we installed a CT-guided adaptive radiotherapy (CTgART) unit, becoming one of the first clinics in the world to build a dual-modality ART clinic. Herein we review factors that lead to the development of a high-volume dual-modality ART program and treatment census over an initial, one-year period. Materials and Methods: The clinical adaptive service at our institution is enabled with both MRgART (MRIdian, ViewRay, Inc, Mountain View, CA) and CTgART (ETHOS, Varian Medical Systems, Palo Alto, CA) platforms. We analyzed patient and treatment information including disease sites treated, radiation dose and fractionation, and treatment times for patients on these two platforms. Additionally, we reviewed our institutional workflow for creating, verifying, and implementing a new adaptive workflow on either platform. Results: From October 2021 to September 2022, 256 patients were treated with adaptive intent at our institution, 186 with MRgART and 70 with CTgART. The majority (106/186) of patients treated with MRgART had pancreatic cancer, and the most common sites treated with CTgART were pelvis (23/70) and abdomen (20/70). 93.0% of treatments on the MRgART platform were stereotactic body radiotherapy (SBRT), whereas only 72.9% of treatments on the CTgART platform were SBRT. Abdominal gated cases were allotted a longer time on the CTgART platform compared to the MRgART platform, whereas pelvic cases were allotted a shorter time on the CTgART platform when compared to the MRgART platform. Our adaptive implementation technique has led to six open clinical trials using MRgART and seven using CTgART. Conclusions: We demonstrate the successful development of a dual platform ART program in our clinic. Ongoing efforts are needed to continue the development and integration of ART across platforms and disease sites to maximize access and evidence for this technique worldwide.

Bintrafusp Alfa Versus Pembrolizumab in Patients With Treatment-Naive, Programmed Death-Ligand 1-High Advanced NSCLC: A Randomized, Open-Label, Phase 3 Trial.

INTRODUCTION: Bintrafusp alfa, a first-in-class bifunctional fusion protein composed of the extracellular domain of TGF-ßRII (a TGF-ß "trap") fused to a human immunoglobulin G1 monoclonal antibody blocking programmed death-ligand 1 (PD-L1), has exhibited clinical activity in a phase 1 expansion cohort of patients with PD-L1-high advanced NSCLC. METHODS: This adaptive phase 3 trial (NCT03631706) compared the efficacy and safety of bintrafusp alfa versus pembrolizumab as first-line treatment in patients with PD-L1-high advanced NSCLC. Primary end points were progression-free survival according to Response Evaluation Criteria in Solid Tumors version 1.1 per independent review committee and overall survival. RESULTS: Patients (N = 304) were randomized one-to-one to receive either bintrafusp alfa or pembrolizumab (n = 152 each). The median follow-up was 14.3 months (95% confidence interval [CI]: 13.1-16.0 mo) for bintrafusp alfa and 14.5 months (95% CI: 13.1-15.9 mo) for pembrolizumab. Progression-free survival by independent review committee was not significantly different between bintrafusp alfa and pembrolizumab arms (median = 7.0 mo [95% CI: 4.2 mo-not reached (NR)] versus 11.1 mo [95% CI: 8.1 mo-NR]; hazard ratio = 1.232 [95% CI: 0.885-1.714]). The median overall survival was 21.1 months (95% CI: 21.1 mo-NR) for bintrafusp alfa and 22.1 months (95% CI: 20.4 mo-NR) for pembrolizumab (hazard ratio = 1.201 [95% CI: 0.796-1.811]). Treatment-related adverse events were higher with bintrafusp alfa versus pembrolizumab; grade 3-4 treatment-related adverse events occurred in 42.4% versus 13.2% of patients, respectively. The study was discontinued at an interim analysis as it was unlikely to meet the primary end point. CONCLUSIONS: First-line treatment with bintrafusp alfa did not exhibit superior efficacy compared with pembrolizumab in patients with PD-L1-high, advanced NSCLC.

Sustained Preservation of Cognition and Prevention of Patient-Reported Symptoms With Hippocampal Avoidance During Whole-Brain Radiation Therapy for Brain Metastases: Final Results of NRG Oncology CC001.

PURPOSE: Initial report of NRG Oncology CC001, a phase 3 trial of whole-brain radiation therapy plus memantine (WBRT + memantine) with or without hippocampal avoidance (HA), demonstrated neuroprotective effects of HA with a median follow-up of fewer than 8 months. Herein, we report the final results with complete cognition, patient-reported outcomes, and longer-term follow-up exceeding 1 year. METHODS AND MATERIALS: Adult patients with brain metastases were randomized to HA-WBRT + memantine or WBRT + memantine. The primary endpoint was time to cognitive function failure, defined as decline using the reliable change index on the Hopkins Verbal Learning Test-Revised (HVLT-R), Controlled Oral Word Association, or the Trail Making Tests (TMT) A and B. Patient-reported symptom burden was assessed using the MD Anderson Symptom Inventory with Brain Tumor Module and EQ-5D-5L. RESULTS: Between July 2015 and March 2018, 518 patients were randomized. The median follow-up for living patients was 12.1 months. The addition of HA to WBRT + memantine prevented cognitive failure (adjusted hazard ratio, 0.74, P = .016) and was associated with less deterioration in TMT-B at 4 months (P = .012) and HVLT-R recognition at 4 (P = .055) and 6 months (P = .011). Longitudinal modeling of imputed data showed better preservation of all HVLT-R domains (P < .005). Patients who received HA-WBRT + Memantine reported less symptom burden at 6 (P < .001 using imputed data) and 12 months (P = .026 using complete-case data; P < .001 using imputed data), less symptom interference at 6 (P = .003 using complete-case data; P = .0016 using imputed data) and 12 months (P = .0027 using complete-case data; P = .0014 using imputed data), and fewer cognitive symptoms over time (P = .043 using imputed data). Treatment arms did not differ significantly in overall survival, intracranial progression-free survival, or toxicity. CONCLUSIONS: With median follow-up exceeding 1 year, HA during WBRT + memantine for brain metastases leads to sustained preservation of cognitive function and continued prevention of patient-reported neurologic symptoms, symptom interference, and cognitive symptoms with no difference in survival or toxicity.

Prospective In Silico Evaluation of Cone-Beam Computed Tomography-Guided StereoTactic Adaptive Radiation Therapy (CT-STAR) for the Ablative Treatment of Ultracentral Thoracic Disease.

Purpose: We conducted a prospective, in silico study to evaluate the feasibility of cone-beam computed tomography (CBCT)-guided stereotactic adaptive radiation therapy (CT-STAR) for the treatment of ultracentral thoracic cancers (NCT04008537). We hypothesized that CT-STAR would reduce dose to organs at risk (OARs) compared with nonadaptive stereotactic body radiation therapy (SBRT) while maintaining adequate tumor coverage. Methods and Materials: Patients who were already receiving radiation therapy for ultracentral thoracic malignancies underwent 5 additional daily CBCTs on the ETHOS system as part of a prospective imaging study. These were used to simulate CT-STAR, in silico. Initial, nonadaptive plans (PI) were created based on simulation images and simulated adaptive plans (PA) were based on study CBCTs. 55 Gy/5 fractions was prescribed, with OAR constraint prioritization over PTV coverage under a strict isotoxicity approach. PI were applied to patients' anatomy of the day and compared with daily PA using dose-volume histogram metrics, with selection of superior plans for simulated delivery. Feasibility was defined as completion of the end-to-end adaptive workflow while meeting strict OAR constraints in ≥80% of fractions. CT-STAR was performed under time pressures to mimic clinical adaptive processes. Results: Seven patients were accrued, 6 with intraparenchymal tumors and 1 with a subcarinal lymph node. CT-STAR was feasible in 34 of 35 simulated fractions. In total, 32 dose constraint violations occurred when the PI was applied to anatomy-of-the-day across 22 of 35 fractions. These violations were resolved by the PA in all but one fraction, in which the proximal bronchial tree dose was still numerically improved through adaptation. The mean difference between the planning target volume and gross total volume V100% in the PI and the PA was -0.24% (-10.40 to 9.90) and -0.62% (-11.00 to 8.00), respectively. Mean end-to-end workflow time was 28.21 minutes (18.02-50.97). Conclusions: CT-STAR widened the dosimetric therapeutic index of ultracentral thorax SBRT compared with nonadaptive SBRT. A phase 1 protocol is underway to evaluate the safety of this paradigm for patients with ultracentral early-stage NSCLC.

ASTRO Radiation Therapy Summary of the ASCO Guideline on Management of Stage III Non-Small Cell Lung Cancer.

PURPOSE: To develop a radiation therapy summary of recommendations on the management of locally advanced non-small cell lung cancer (NSCLC) based on the Management of Stage III Non-Small Cell Lung Cancer: American Society of Clinical Oncology Guideline, which was endorsed by the American Society for Radiation Oncology (ASTRO). METHODS: The American Society of Clinical Oncology, ASTRO, and the American College of Chest Physicians convened a multidisciplinary panel to develop a guideline based on a systematic review of the literature and a formal consensus process, that has been separately published. A new panel consisting of radiation oncologists from the original guideline as well as additional ASTRO members was formed to provide further guidance to the radiation oncology community. A total of 127 articles met the eligibility criteria to answer 5 clinical questions. This summary focuses on the 3 radiation therapy questions (neoadjuvant, adjuvant, and unresectable settings). RESULTS: Radiation-specific recommendations are summarized with additional relevant commentary on specific questions regarding the management of preoperative radiation, postoperative radiation, and combined chemoradiation. CONCLUSIONS: Patients with stage III NSCLC who are planned for surgical resection, should receive either neoadjuvant chemotherapy or chemoradiation. The addition of neoadjuvant treatment is particularly important in patients planned for surgery in the N2 or superior sulcus settings. Postoperatively, patients who did not receive neoadjuvant chemotherapy should be offered adjuvant chemotherapy. The use of postoperative radiation for completely resected N2 disease is not routinely recommended. Unresectable patients with stage III NSCLC should ideally be managed with combined concurrent chemoradiation using a platinum-based doublet with a standard radiation dose of 60 Gy followed by consolidation durvalumab in patients without progression after initial therapy. Patients who cannot tolerate a concurrent chemoradiation approach can be managed either by sequential chemotherapy followed by radiation or by dose-escalated or hypofractionated radiation alone.

Short-term and long-term effects of noninvasive cardiac radioablation for ventricular tachycardia: A single-center case series.

Background: Noninvasive cardiac radioablation is reported to be effective and safe for the treatment of ventricular tachycardia (VT). Objective: This study aimed to analyze the acute and long-term effects of VT radioablation. Methods: Patients with intractable VT or premature ventricular contraction (PVC)-induced cardiomyopathy were included in this study and treated using a single-fraction 25-Gy dose of cardiac radioablation. To quantitatively analyze the acute response after treatment, continuous electrocardiography monitoring was performed from 24 hours before to 48 hours after irradiation and at the 1-month follow-up. Long-term clinical safety and efficacy were assessed 1-year follow-up. Results: From 2019 to 2020, 6 patients were treated with radioablation for ischemic VT (n = 3), nonischemic VT (n = 2), or PVC-induced cardiomyopathy (n = 1). In the short-term assessment, the total burden of ventricular beats decreased by 49% within 24 hours after radioablation and further decreased by 70% at 1 month. The VT component decreased earlier and more dramatically than the PVC component (decreased by 91% and 57% at 1 month, respectively). In the long-term assessment, 5 patients showed complete (n = 3) or partial (n = 2) remission of ventricular arrhythmias. One patient showed recurrence at 10 months, which was successfully suppressed with medical treatment. The posttreatment PVC coupling interval was prolonged (+38 ms at 1 month). Ischemic VT burden decreased more markedly than nonischemic VT burden after radioablation. Conclusion: In this small case series of 6 patients, without a comparison group, cardiac radioablation appeared to decrease the intractable VT burden. A therapeutic effect was apparent within 1-2 days after treatment but was variable by etiology of cardiomyopathy.

Knowledge-based adaptive planning quality assurance using dosimetric indicators for stereotactic adaptive radiotherapy for pancreatic cancer.

INTRODUCTION: We aimed to develop knowledge-based tools for robust adaptive radiotherapy (ART) planning to determine on-table adaptive DVH metric variations or planning process errors for stereotactic pancreatic ART. We developed volume-based dosimetric identifiers to identify deviations of ART plans from simulation plans. MATERIALS AND METHODS: Two patient cohorts who were treated on MR-Linac for pancreas cancer were included in this retrospective study; a training cohort and a validation cohort. All patients received 50 Gy in 5 fractions. PTV-OPT was generated by subtracting the critical organs plus a 5 mm-margin from PTV. Several metrics that potentially can identify failure-modes were calculated including PTV & PTV_OPT V95% and PTV & PTV_OPT D95%/D5%. The difference between each DVH metric in each adaptive plan with the DVH metric in simulation plan was calculated. The 95% confidence interval (CI) of the variations in each DVH metric was calculated for the patient training cohort. Variations in DVH metrics that exceeded the 95% CI for all fractions in training and validation cohort were flagged for retrospective investigation for root-cause analysis to determine their predictive power for identifying failure-modes. RESULTS: The CIs for the PTV & PTV_OPT V95% and PTV & PTV_OPT D95%/D5% were ± 13%, ± 5%, ± 0.1, ± 0.03, respectively. We estimated the positive predictive value and negative predictive value of our method to be 77% and 89%, respectively, for the training cohort, and 80% for both in the validation cohort. DISCUSSION: We developed dosimetric indicators for ART planning QA to identify population-based deviations or planning errors during online adaptive process for stereotactic pancreatic ART. This technology may be useful as an ART clinical trial QA tool and improve overall ART quality at an institution.

Pre-radiotherapy ctDNA liquid biopsy for risk stratification of oligometastatic non-small cell lung cancer.

The optimal treatment for patients with oligometastatic non-small cell lung cancer (NSCLC) remains unclear. Some patients with oligometastatic disease can experience prolonged remission after locally consolidative radiation therapy (RT), while others harbor micrometastatic disease (below current limits of detection by imaging) that may benefit from further prioritization of systemic therapy. To better risk-stratify this population and identify the patients most likely to benefit from locally consolidative radiation therapy, we performed a multi-institutional cohort study of patients with oligometastatic NSCLC undergoing liquid biopsy analysis of circulating tumor DNA (ctDNA). Among this real-world cohort of 1,487 patients undergoing analysis (using the Tempus xF assay), a total of 1,880 ctDNA liquid biopsies along with paired clinical data were obtained across various timepoints. Approximately 20% (n=309) of patients had ctDNA obtained prior to RT and after their diagnosis of oligometastatic disease. Samples were de-identified and analyzed for mutational burden and variant frequencies of detectable deleterious (or likely deleterious) mutations in plasma. Patients with undetectable ctDNA before RT had significantly improved progression-free survival and overall survival compared to patients with detectable ctDNA prior to RT. In patients that received RT, 598 pathogenic (or likely deleterious) variants were identified. ctDNA mutational burden pre-RT and ctDNA maximum variant allele frequency (VAF) pre-RT were both significantly inversely correlated with both progression-free (P = 0.0031 for mutational burden, P = 0.0084 for maximum VAF) and overall survival (P = 0.045 for mutational burden, P = 0.0073 for maximum VAF). Patients without detectable ctDNA prior to RT had significantly improved progression-free survival (P = 0.004) and overall survival (P = 0.03) compared to patients with detectable ctDNA prior to RT. These data suggest that in patients with oligometastatic NSCLC, pre-radiotherapy ctDNA analysis can potentially identify the patients most likely to benefit from locally consolidative RT and experience prolonged progression-free and overall survival. Similarly, ctDNA may be useful to identify those patients with undiagnosed micrometastatic disease, in whom it may be appropriate to prioritize systemic therapy.