The Role of Local Therapy for Oligo-Progressive Disease in Oncogene-Addicted Non-Small-Cell Lung Cancer.

Purpose: We first described the role of local radiation therapy (LT) for oligoprogressive disease (OPD) on targeted therapy in 2012. Here, we present an updated and larger data set and extend the analysis beyond EGFR and ALK. Methods: A retrospective review of patients with metastatic NSCLC harboring EGFR/BRAF V600E mutations, or ALK/ROS1/RET rearrangements, who had OPD on respective tyrosine-kinase inhibitor (TKI) and treated with LT was performed. OPD was defined as disease progression on therapy in ≤5 sites. PFS1 (progression-free survival 1) was defined as time from initiation of TKI-containing regimen to the first course of LT for OPD. Subsequent PFS times (eg, PFS2, PFS3) were defined as time from prior LT to subsequent LT, switch of systemic therapy, death, or loss to follow-up, whichever occurred first. Extended-PFS was defined as time from the first day of the first LT course to the day of change in systemic therapy, death, or loss to follow-up, whichever came first. Results: Eighty-nine patients were identified. In 75.4% of the LT courses, a single lesion was treated. Median PFS1 was 10.2 months (95% CI, 8.7-13.1) and median Extended-PFS was 6.7 months (95% CI, 4.9-8.3). Extended-PFS was similar across different oncogenic drivers; 51.4% of patients who underwent LT to a single site had only 1 site on next disease progression. Conclusions: LT is effective in prolonging treatment duration on TKI in oncogene-addicted NSCLC across multiple oncogenes.

Sex Differences in Odds of Brain Metastasis and Outcomes by Brain Metastasis Status after Advanced Melanoma Diagnosis.

Sex differences in cancer are well-established. However, less is known about sex differences in diagnosis of brain metastasis and outcomes among patients with advanced melanoma. Using a United States nationwide electronic health record-derived de-identified database, we evaluated patients diagnosed with advanced melanoma from 1 January 2011-30 July 2022 who received an oncologist-defined rule-based first line of therapy (n = 7969, 33% female according to EHR, 35% w/documentation of brain metastases). The odds of documented brain metastasis diagnosis were calculated using multivariable logistic regression adjusted for age, practice type, diagnosis period (pre/post-2017), ECOG performance status, anatomic site of melanoma, group stage, documentation of non-brain metastases prior to first-line of treatment, and BRAF positive status. Real-world overall survival (rwOS) and progression-free survival (rwPFS) starting from first-line initiation were assessed by sex, accounting for brain metastasis diagnosis as a time-varying covariate using the Cox proportional hazards model, with the same adjustments as the logistic model, excluding group stage, while also adjusting for race, socioeconomic status, and insurance status. Adjusted analysis revealed males with advanced melanoma were 22% more likely to receive a brain metastasis diagnosis compared to females (adjusted odds ratio [aOR]: 1.22, 95% confidence interval [CI]: 1.09, 1.36). Males with brain metastases had worse rwOS (aHR: 1.15, 95% CI: 1.04, 1.28) but not worse rwPFS (adjusted hazard ratio [aHR]: 1.04, 95% CI: 0.95, 1.14) following first-line treatment initiation. Among patients with advanced melanoma who were not diagnosed with brain metastases, survival was not different by sex (rwOS aHR: 1.06 [95% CI: 0.97, 1.16], rwPFS aHR: 1.02 [95% CI: 0.94, 1.1]). This study showed that males had greater odds of brain metastasis and, among those with brain metastasis, poorer rwOS compared to females, while there were no sex differences in clinical outcomes for those with advanced melanoma without brain metastasis.

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.

2D antiscatter grid and scatter sampling based CBCT method for online dose calculations during CBCT guided radiation therapy of pelvis.

BACKGROUND: Online dose calculations before the delivery of radiation treatments have applications in dose delivery verification, online adaptation of treatment plans, and simulation-free treatment planning. While dose calculations by directly utilizing CBCT images are desired, dosimetric accuracy can be compromised due to relatively lower HU accuracy in CBCT images. PURPOSE: In this work, we propose a novel CBCT imaging pipeline to enhance the accuracy of CBCT-based dose calculations in the pelvis region. Our approach aims to improve the HU accuracy in CBCT images, thereby improving the overall accuracy of CBCT-based dose calculations prior to radiation treatment delivery. METHODS: An in-house developed quantitative CBCT pipeline was implemented to address the CBCT raw data contamination problem. The pipeline combines algorithmic data correction strategies and 2D antiscatter grid-based scatter rejection to achieve high CT number accuracy. To evaluate the effect of the quantitative CBCT pipeline on CBCT-based dose calculations, phantoms mimicking pelvis anatomy were scanned using a linac-mounted CBCT system, and a gold standard multidetector CT used for treatment planning (pCT). A total of 20 intensity-modulated treatment plans were generated for five targets, using 6 and 10 MV flattening filter-free beams, and utilizing small and large pelvis phantom images. For each treatment plan, four different dose calculations were performed using pCT images and three CBCT imaging configurations: quantitative CBCT, clinical CBCT protocol, and a high-performance 1D antiscatter grid (1D ASG). Subsequently, dosimetric accuracy was evaluated for both targets and organs at risk as a function of patient size, target location, beam energy, and CBCT imaging configuration. RESULTS: When compared to the gold-standard pCT, dosimetric errors in quantitative CBCT-based dose calculations were not significant across all phantom sizes, beam energies, and treatment sites. The largest error observed was 0.6% among all dose volume histogram metrics and evaluated dose calculations. In contrast, dosimetric errors reached up to 7% and 97% in clinical CBCT and high-performance ASG CBCT-based treatment plans, respectively. The largest dosimetric errors were observed in bony targets in the large phantom treated with 6 MV beams. The trends of dosimetric errors in organs at risk were similar to those observed in the targets. CONCLUSIONS: The proposed quantitative CBCT pipeline has the potential to provide comparable dose calculation accuracy to the gold-standard planning CT in photon radiation therapy for the abdomen and pelvis. These robust dose calculations could eliminate the need for density overrides in CBCT images and enable direct utilization of CBCT images for dose delivery monitoring or online treatment plan adaptations before the delivery of radiation treatments.

A 2D antiscatter grid and scatter sampling based CBCT method for online dose calculations during CBCT guided radiation therapy of pelvis.

Online dose calculations before radiation treatment have applications in dose delivery verification, plan adaptation, and treatment planning. We propose a novel CBCT imaging pipeline to enhance accuracy. Our approach aims to improve HU accuracy in CBCT images for more precise dose calculations. A quantitative CBCT pipeline was implemented, combining data correction strategies and scatter rejection, achieving high CT number accuracy. We evaluated the pipeline's effect using pelvis anatomy phantoms and found that dosimetric errors in quantitative CBCT-based dose calculations were minimal. In contrast, clinical CBCT and high-performance ASG CBCT-based plans showed significant errors. The proposed quantitative CBCT pipeline offers comparable dose calculation accuracy to the gold-standard planning CT, eliminating the need for density overrides and enabling precise dose delivery monitoring or online plan adaptations in radiation therapy.

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.

Comparison of first-line radiosurgery for small-cell and non-small cell lung cancer brain metastases (CROSS-FIRE).

INTRODUCTION: Historical reservations regarding stereotactic radiosurgery (SRS) for small-cell lung cancer (SCLC) brain metastases include concerns for short-interval and diffuse central nervous system (CNS) progression, poor prognoses, and increased neurological mortality specific to SCLC histology. We compared SRS outcomes for SCLC and non-small cell lung cancer (NSCLC) where SRS is well established. METHODS: Multicenter first-line SRS outcomes for SCLC and NSCLC from 2000 to 2022 were retrospectively collected (n = 892 SCLC, n = 4785 NSCLC). Data from the prospective Japanese Leksell Gamma Knife Society (JLGK0901) clinical trial of first-line SRS were analyzed as a comparison cohort (n = 98 SCLC, n = 814 NSCLC). Overall survival (OS) and CNS progression were analyzed using Cox proportional hazard and Fine-Gray models, respectively, with multivariable adjustment for cofactors including age, sex, performance status, year, extracranial disease status, and brain metastasis number and volume. Mutation-stratified analyses were performed in propensity score-matched retrospective cohorts of epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) positive NSCLC, mutation-negative NSCLC, and SCLC. RESULTS: OS was superior for patients with NSCLC compared to SCLC in the retrospective dataset (median OS = 10.5 vs 8.6 months; P < .001) and in the JLGK0901 dataset. Hazard estimates for first CNS progression favoring NSCLC were similar in both datasets but reached statistical significance in the retrospective dataset only (multivariable hazard ratio = 0.82, 95% confidence interval = 0.73 to 0.92, P = .001). In the propensity score-matched cohorts, there were continued OS advantages for NSCLC patients (median OS = 23.7 [EGFR and ALK positive NSCLC] vs 13.6 [mutation-negative NSCLC] vs 10.4 months [SCLC], pairwise P values < 0.001), but no statistically significant differences in CNS progression were observed in the matched cohorts. Neurological mortality and number of lesions at CNS progression were similar for NSCLC and SCLC patients. Leptomeningeal progression was increased in patients with NSCLC compared to SCLC in the retrospective dataset only (multivariable hazard ratio = 1.61, 95% confidence interval = 1.14 to 2.26, P = .007). CONCLUSIONS: After SRS, SCLC histology was associated with shorter OS compared to NSCLC. CNS progression occurred earlier in SCLC patients overall but was similar in patients matched on baseline factors. SCLC was not associated with increased neurological mortality, number of lesions at CNS progression, or leptomeningeal progression compared to NSCLC. These findings may better inform clinical expectations and individualized decision making regarding SRS for SCLC patients.

CNS Downstaging: An Emerging Treatment Paradigm for Extensive Brain Metastases in Oncogene-Addicted Lung Cancer.

INTRODUCTION: For extensive brain metastases (BrM) presentations arising from oncogene-addicted lung cancer, tyrosine kinase inhibitors (TKIs) with high response rates in the central nervous system (CNS) could potentially downstage the CNS disease burden, allowing for the avoidance of upfront whole-brain radiotherapy (WBRT) and the conversion of some patients into candidates for focal stereotactic radiosurgery (SRS). METHODS: We describe the outcomes of patients with ALK, EGFR, and ROS1-driven NSCLC with extensive BrM presentations (defined as > 10 BrMs or leptomeningeal disease) treated with upfront newer generation CNS-active TKIs alone, including osimertinib, alectinib, brigatinib, lorlatinib, and entrectinib, from 2012 to 2021 at our institution. All BrMs were contoured at study entry, best CNS response (nadir), and first CNS progression. RESULTS: Twelve patients met criteria including 6 with ALK, 3 with EGFR, and 3 with ROS1-driven NSCLC. The median number and volume of BrMs at presentation were 49 and 19.6 cm3, respectively. Eleven patients (91.7 %) achieved a CNS response by modified-RECIST criteria to upfront TKI (10 partial responses, 1 complete response, 1 stable disease) with nadir observed at a median of 5.1 months. At nadir, the median number and volume of BrMs were 5 (median 91.7 % reduction per-patient) and 0.3 cm3(median 96.5 % reduction per-patient), respectively. Eleven patients (91.6 %) developed subsequent CNS progression (7 local failures, 3 local + distant, 1 distant) at a median of 17.9 months. At CNS progression, the median number and volume of BrMs were 7 and 0.7 cm3, respectively. Seven patients (58.3 %) received salvage SRS and no patients received salvage WBRT. The median overall survival from initiation of TKI for the extensive BrM presentation was 43.2 months. CONCLUSION: In this initial case series, we describe CNS downstaging as a promising multidisciplinary treatment paradigm involving the upfront administration CNS-active systemic therapy and close MRI surveillance for extensive BrMs as a strategy to avoid upfront WBRT and to convert some patients into SRS candidates.

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.

Development of a United States Radiation Oncology Curricular Framework: A Stakeholder Delphi Consensus.

PURPOSE: A United States (US) radiation oncology curriculum, developed using best practices for curriculum inquiry, is needed to guide residency education and qualifying examinations. Competency-based training, including entrustable professional activities (EPAs), provides an outcomes-based approach to modern graduate medical education. This study aimed to define US radiation oncology EPAs and curricular content domains using a deliberative process with input from multiple stakeholder groups. METHODS AND MATERIALS: The Radiation Oncology Education Collaborative Study Group Core Curriculum Project Leadership Committee developed initial content domains and EPAs. Following recruitment of stakeholders, a Delphi process was used to achieve consensus. In the first round, content domains and EPAs were reviewed for inclusion and exclusion, clarity, time allocation (content domains), and level of training (EPAs). Participants submitted additional content domains and EPAs for consideration. Any content domains or EPAs 1 standard deviation below the median for inclusion and exclusion underwent Leadership Committee review. All participants completing the first Delphi round were invited to the second round. Percent curriculum time allocated for content domains and a single subdomain were finalized. New EPAs or EPAs undergoing major revisions were reviewed. RESULTS: A total of 186 participants representing diverse stakeholder groups participated. One hundred fourteen completed the first Delphi round (61.3%). Of 114 invited, 77 participants completed the second round of the Delphi process (67.5%). Overall, 6 of 9 content domains met consensus, 1 content domain was removed, and 2 content domains were combined. Four subdomains of a single content domain were reviewed and met consensus. Consensus on percent time allocated per content domain and subdomain was reached. Of 55 initial EPAs, 52 final EPAs met consensus. CONCLUSIONS: Deliberative curriculum inquiry was successfully used to develop a consensus on US radiation oncology content domains and EPAs. These data can guide the allocation of educational time in training programs, help inform weighting for qualifying examinations, and help guide clinical training and resident assessment.

Concurrent kilovoltage CBCT imaging and megavoltage beam delivery: suppression of cross-scatter with 2D antiscatter grids and grid-based scatter sampling.

Objective. The concept of using kilovoltage (kV) and megavoltage (MV) beams concurrently has potential applications in cone beam computed tomography (CBCT) guided radiation therapy, such as single breath hold scans, metal artifact reduction, and simultaneous imaging during MV treatment delivery. However, MV cross-scatter generated during MV beam delivery degrades CBCT image quality. To address this, a 2D antiscatter grid and a cross-scatter correction method were investigated in the context of high dose MV treatment delivery.Approach. A 3D printed, tungsten 2D antiscatter grid prototype was utilized in kV CBCT scans to reduce MV cross-scatter fluence during concurrent MV beam delivery. Remaining cross-scatter in projections was corrected by using the 2D grid itself as a cross-scatter intensity sampling device, referred to as grid-based scatter sampling (GSS). To test this approach, kV CBCT acquisitions were performed while delivering 6 and 10 MV beams, mimicking high dose rate treatment delivery scenarios. kV and MV beam deliveries were not synchronized to eliminate MV beam delivery interruption. MV cross-scatter suppression performance of the proposed approach was evaluated in projections and CBCT images of phantoms.Main results. 2D grid reduced the intensity of MV cross-scatter in kV projections by a factor of 3 on the average, when compared to conventional antiscatter grid. Remaining cross scatter as measured by the GSS method was within 7% of measured reference intensity values, and subsequently corrected. CBCT image quality was improved substantially during concurrent kV-MV beam delivery. Median Hounsfield Unit (HU) inaccuracy was up to 182 HU without our methods, and it was reduced to a median 6.5 HU with our 2D grid and scatter correction approach. Our methods provided a factor of 2-6 improvement in contrast-to-noise ratio.Significance. This investigation demonstrates the utility of 2D antiscatter grids and grid-based scatter sampling in suppressing MV cross-scatter. Our approach successfully minimized the effects of MV cross-scatter in concurrent kV CBCT imaging and high dose MV treatment delivery scenarios. Hence, robust MV cross-scatter suppression is potentially feasible without MV beam delivery interruption or compromising kV image acquisition rate.

Evaluation of Radiation Oncologist and Trainee Opinions on Residency Expansion, Possible Actions, and Training Program Accreditation Changes in the United States.

PURPOSE: The objective of this study was to sample the opinions of radiation oncologists and trainees in the United States regarding residency expansion, what action(s) should be taken to limit residency supply, if any, and the proposed Accreditation Council for Graduate Medical Education (ACGME) changes. METHODS AND MATERIALS: An online survey was distributed to 1048 attending radiation oncologists by e-mail and approximately 800 residents through their program coordinators. The survey asked respondents to rank how strongly they agreed with certain statements regarding residency supply, possible solutions to address any perceived oversupply, and the proposed ACGME changes on a 1-to-10 disagreement-to-agreement scale. The 16% response rate yielded 294 responses for analysis. RESULTS: Of the respondents, 90 (30%) were residents, and 204 (70%) were attendings, of whom 117 (57%) were academic and 87 (43%) were nonacademic. Eighty-six percent agreed that there is a residency oversupply issue, and 91% agreed that actions should be taken to limit residency expansion. On χ2 test, residents and attendings were similarly likely to agree that there is a residency oversupply issue (93% and 89%, P = .27), although residents were more likely to agree that this oversupply should be acted upon compared with attendings (100% and 88%, P < .01). Regarding possible solutions, respondents were most likely to agree that further expansion should be limited (90%), program requirements should be made more stringent (76%), and the use of the Supplemental Offer and Acceptance Program should be limited (69%). Proposed ACGME changes that respondents were most likely to agree with included requiring that programs have modern image guidance, stereotactic radiation therapy, and brachytherapy techniques (98%) and have 4+ faculty members and maintain a faculty-to-resident ratio of >1.5:1 (86%). Case log minimums most supported to be increased were 4 uterus (65%) and 11 postmastectomy breast (61%) simulations. CONCLUSIONS: The majority of respondents agree that there is a residency oversupply issue and that actions should be taken to limit residency expansion and make program requirements more stringent.

Quality and Safety Considerations in Stereotactic Radiosurgery and Stereotactic Body Radiation Therapy: An ASTRO Safety White Paper Update.

PURPOSE: This updated report on stereotactic radiosurgery (SRS) and stereotactic body radiation therapy (SBRT) is part of a series of consensus-based white papers previously published addressing patient safety. Since the first white papers were published, SRS and SBRT technology and procedures have progressed significantly such that these procedures are now more commonly used. The complexity and submillimeter accuracy, and delivery of a higher dose per fraction requires an emphasis on best practices for technical, dosimetric, and quality assurance. Therefore, quality and patient safety considerations for these techniques remain an important area of focus. METHOD: The American Society for Radiation Oncology convened a task force to assess the original SRS/SBRT white paper and update content where appropriate. Recommendations were created using a consensus-building methodology and task force members indicated their level of agreement based on a 5-point Likert scale, from "strongly agree" to "strongly disagree." A prespecified threshold of ≥75% of raters who select "strongly agree" or "agree" indicated consensus. SUMMARY: This white paper builds on the previous version and uses of other guidance documents to broadly address SRS and SBRT delivery, primarily focusing on processes related to quality and safety. SRS and SBRT require a team-based approach, staffed by appropriately trained and credentialed specialists as well as significant personnel resources, specialized technology, and implementation time. A thorough feasibility analysis of resources is required to achieve the clinical and technical goals and thoroughly discussed with all personnel before undertaking new disease sites. A comprehensive quality assurance program must be developed, using established treatment guidelines, to ensure SRS and SBRT are performed in a safe and effective manner. Patient safety in SRS/SBRT is everyone's responsibility and professional organizations, regulators, vendors, and end-users must demonstrate a clear commitment to working together to ensure the highest levels of safety.

Repeated endo-tracheal tube disconnection generates pulmonary edema in a model of volume overload: an experimental study.

BACKGROUND: An abrupt lung deflation in rodents results in lung injury through vascular mechanisms. Ventilator disconnections during endo-tracheal suctioning in humans often cause cardio-respiratory instability. Whether repeated disconnections or lung deflations cause lung injury or oedema is not known and was tested here in a porcine large animal model. METHODS: Yorkshire pigs (~ 12 weeks) were studied in three series. First, we compared PEEP abruptly deflated from 26 cmH2O or from PEEP 5 cmH2O to zero. Second, pigs were randomly crossed over to receive rapid versus gradual PEEP removal from 20 cmH2O. Third, pigs with relative volume overload, were ventilated with PEEP 15 cmH2O and randomized to repeated ETT disconnections (15 s every 15 min) or no disconnection for 3 h. Hemodynamics, pulmonary variables were monitored, and lung histology and bronchoalveolar lavage studied. RESULTS: As compared to PEEP 5 cmH2O, abrupt deflation from PEEP 26 cmH2O increased PVR, lowered oxygenation, and increased lung wet-to-dry ratio. From PEEP 20 cmH2O, gradual versus abrupt deflation mitigated the changes in oxygenation and vascular resistance. From PEEP 15, repeated disconnections in presence of fluid loading led to reduced compliance, lower oxygenation, higher pulmonary artery pressure, higher lung wet-to-dry ratio, higher lung injury score and increased oedema on morphometry, compared to no disconnects. CONCLUSION: Single abrupt deflation from high PEEP, and repeated short deflations from moderate PEEP cause pulmonary oedema, impaired oxygenation, and increased PVR, in this large animal model, thus replicating our previous finding from rodents. Rapid deflation may thus be a clinically relevant cause of impaired lung function, which may be attenuated by gradual pressure release.

Factors associated with progression and mortality among patients undergoing stereotactic radiosurgery for intracranial metastasis: results from a national real-world registry.

OBJECTIVE: Stereotactic radiosurgery (SRS) has been increasingly employed in recent years to treat intracranial metastatic lesions. However, there is still a need for optimization of treatment paradigms to provide better local control and prevent progressive intracranial disease. In the current study, the authors utilized a national collaborative registry to investigate the outcomes of patients with intracranial metastatic disease who underwent SRS and to determine factors associated with lesion treatment response, overall progression, and mortality. METHODS: The NeuroPoint Alliance SRS registry was queried for all patients with intracranial metastatic lesions undergoing single- or multifraction SRS at participating institutions between 2016 and 2020. The main outcomes of interest included lesion response (lesion-level analysis), progression using Response Assessment for Neuro-Oncology criteria, and mortality (patient-level analysis). Kaplan-Meier analysis was used to report time to progression and overall survival, and multivariable Cox proportional hazards analysis was used to investigate factors associated with lesion response, progression, and mortality. RESULTS: A total of 501 patients (1447 intracranial metastatic lesions) who underwent SRS and had available follow-up were included in the current analyses. The most common primary tumor was lung cancer (49.5%, n = 248), followed by breast (15.4%, n = 77) and melanoma (12.2%, n = 61). Most patients had a single lesion (44.9%, n = 225), 29.3% (n = 147) had 2 or 3 lesions, and 25.7% (n = 129) had > 3 lesions. The mean sum of baseline measurements of the lesions according to Response Evaluation Criteria in Solid Tumors (RECIST) was 35.54 mm (SD 25.94). At follow-up, 671 lesions (46.4%) had a complete response, 631 (43.6%) had a partial response (≥ 30% decrease in longest diameter) or were stable (< 30% decrease but < 20% increase), and 145 (10%) showed progression (> 20% increase in longest diameter). On multivariable Cox proportional hazards analysis, melanoma-associated lesions (HR 0.48, 95% CI 0.34-0.67; p < 0.001) and larger lesion size (HR 0.94, 95% CI 0.93-0.96; p < 0.001) showed lower odds of lesion regression, while a higher biologically effective dose was associated with higher odds (HR 1.001, 95% CI 1.0001-1.00023; p < 0.001). A total of 237 patients (47.3%) had overall progression (local failure or intracranial progressive disease), with a median time to progression of 10.03 months after the index SRS. Factors found to be associated with increased hazards of progression included male sex (HR 1.48, 95% CI 1.108-1.99; p = 0.008), while administration of immunotherapy (before or after SRS) was found to be associated with lower hazards of overall progression (HR 0.62, 95% CI 0.460-0.85; p = 0.003). A total of 121 patients (23.95%) died during the follow-up period, with a median survival of 19.4 months from the time of initial SRS. A higher recursive partitioning analysis score (HR 21.3485, 95% CI 1.53202-3.6285; p < 0.001) was found to be associated with higher hazards of mortality, while single-fraction treatment compared with hypofractionated treatment (HR 0.082, 95% CI 0.011-0.61; p = 0.015), administration of immunotherapy (HR 0.385, 95% CI 0.233-0.64; p < 0.001), and presence of single compared with > 3 lesions (HR 0.427, 95% CI 0.187-0.98; p = 0.044) were found to be associated with lower risk of mortality. CONCLUSIONS: The comparability of results between this study and those of previously published clinical trials affirms the value of multicenter databases with real-world data collected without predetermined research purpose.

Results of a Multi-Institutional Phase 2 Clinical Trial for 4DCT-Ventilation Functional Avoidance Thoracic Radiation Therapy.

PURPOSE: Radiation pneumonitis remains a major limitation in the radiation therapy treatment of patients with lung cancer. Functional avoidance radiation therapy uses functional imaging to reduce pulmonary toxic effects by designing radiation therapy plans that reduce doses to functional regions of the lung. Lung functional imaging has been developed that uses 4-dimensional computed tomography (4DCT) imaging to calculate 4DCT-based lung ventilation (4DCT-ventilation). A phase 2 multicenter study was initiated to evaluate 4DCT-ventilation functional avoidance radiation therapy. The study hypothesis was that functional avoidance radiation therapy could reduce the rate of grade ≥2 radiation pneumonitis to 12% compared with a 25% historical rate, with the trial being positive if ≤16.4% of patients experienced grade ≥2 pneumonitis. METHODS AND MATERIALS: Lung cancer patients receiving curative-intent radiation therapy (prescription doses of 45-75 Gy) and chemotherapy were accrued. Patient 4DCT scans were used to generate 4DCT-ventilation images. The 4DCT-ventilation images were used to generate functional avoidance plans that reduced doses to functional portions of the lung while delivering the prescribed tumor dose. Pneumonitis was evaluated by a clinician at 3, 6, and 12 months after radiation therapy. RESULTS: Sixty-seven evaluable patients were accrued between April 2015 and December 2019. The median prescription dose was 60 Gy (range, 45-66 Gy) delivered in 30 fractions (range, 15-33 fractions). The average reduction in the functional volume of lung receiving ≥20 Gy with functional avoidance was 3.5% (range, 0%-12.8%). The median follow-up was 312 days. The rate of grade ≥2 radiation pneumonitis was 10 of 67 patients (14.9%; 95% upper CI, 24.0%), meeting the phase 2 criteria. CONCLUSIONS: 4DCT-ventilation offers an imaging modality that is convenient and provides functional imaging without an extra procedure necessary. This first report of a multicenter study of 4DCT-ventilation functional avoidance radiation therapy provided data showing that the trial met phase 2 criteria and that evaluation in a phase 3 study is warranted.

Impact of Reverse Triggering Dyssynchrony during Lung-Protective Ventilation on Diaphragm Function: An Experimental Model.

Rationale: Reverse triggering dyssynchrony (RT) is a patient-ventilator interaction where a respiratory muscle contraction is triggered by a passive mechanical insufflation. Its impact on diaphragm structure and function is unknown. Objectives: To establish an animal model of RT with lung injury receiving lung-protective ventilation and to assess its impact on the structure and function of the diaphragm. Methods: Lung injury was induced by surfactant depletion and high-stress ventilation in 32 ventilated pigs. Animals were allocated to receive passive mechanical ventilation (Vt: 10 ml/kg; respiratory rate [RR]: 30-35 breaths/min; n = 8) or a more lung-protective strategy (Vt: 6-8 ml/kg; n = 24) with adjustments in RR to facilitate the occurrence of RT for 3 hours. Diaphragm function (transdiaphragmatic pressure [Pdi] during phrenic nerve stimulation [force/frequency curve]) and structure (biopsies) were assessed. The impact of RT on diaphragm function was analyzed according to the breathing effort assessed by the pressure-time product. Measurements and Main Results: Compared with passive ventilation, the protective ventilation group with RT received significantly lower Vt (7 vs. 10 ml/kg) and higher RR (45 vs. 31 breaths/min). An entrainment pattern of 1:1 was the most frequently occurring in 83% of the animals. Breathing effort induced by RT was highly variable across animals. RT with the lowest tercile of breathing effort was associated with 23% higher twitch Pdi compared with passive ventilation, whereas RT with high breathing effort was associated with a 10% lower twitch Pdi and a higher proportion of abnormal muscle fibers. Conclusions: In a reproducible animal model of RT with variable levels of breathing effort and entrainment patterns, RT with high effort is associated with impaired diaphragm function, whereas RT with low effort is associated with preserved diaphragm force.

Practical Implementation of Emergent After-Hours Radiation Treatment Process Using Remote Treatment Planning on Optimized Diagnostic CT Scans.

The purpose of this report is to present the implementation of a process for after-hours radiation treatment (RT) utilizing remote treatment planning based on optimized diagnostic computed tomography (CT) scans for the urgent palliative treatment of inpatients. A standardized operating procedure was developed by an interprofessional panel to improve the quality of after-hours RT and minimize the risk of treatment errors. A new diagnostic CT protocol was created that could be performed after-hours on hospital scanners and would ensure a reproducible patient position and adequate field of view. An on-call structure for dosimetry staff was created utilizing remote treatment planning. The optimized CT protocol was developed in collaboration with the radiology department, and a novel order set was created in the electronic health system. The clinical workflow begins with the radiation oncologist notifying the on-call team (therapist, dosimetrist, and physicist) and obtaining an optimized diagnostic CT scan on a hospital-based scanner. The dosimetrist remotely creates a plan; the physicist checks the plan; and the patient is treated. Plans are intentionally simple (parallel opposed fields, symmetric jaws) to expedite care and reduce the risk of error. Education on the new process was provided for all relevant staff. Our process was successfully implemented with the use of an optimized CT protocol and remote treatment planning. This approach has the potential to improve the quality and safety of emergent after-hours RT by better approximating the normal process of care.