Characterization of Pediatric Infratentorial Arteriovenous Malformations: A Retrospective, Multicenter Cohort Study.

BACKGROUND AND OBJECTIVES: Infratentorial arteriovenous malformations (AVMs) harbor different characteristics compared with supratentorial AVMs. This study aims to explore the unique characteristics of pediatric infratentorial AVMs and their response to single session stereotactic radiosurgery (SRS). METHODS: The International Radiosurgery Research Foundation database of pediatric patients with AVM (age <18 years) who underwent SRS was retrospectively reviewed. Baseline demographics, AVM characteristics, outcomes, and complications post-SRS were compared between infratentorial and supratentorial pediatric AVMs. Unfavorable outcome was defined as the absence of AVM obliteration, post-SRS hemorrhage, or permanent radiation-induced changes at last follow-up. RESULTS: A total of 535 pediatric AVMs managed with SRS with a median follow-up of 67 months (IQR 29.0-130.6) were included, with 69 being infratentorial and 466 supratentorial. The infratentorial group had a higher proportion of deep location (58.4% vs 30.3%, P = <.001), deep venous drainage (79.8% vs 61.8%, P = .004), and prior embolization (26.1% vs 15.7%, P = .032). There was a higher proportion of hemorrhagic presentation in the infratentorial group (79.7% vs 71.3%, P = .146). There was no statistically significant difference in the odds of an unfavorable outcome (odds ratio [OR] = 1.36 [0.82-2.28]), AVM obliteration (OR = 0.85 [0.5-1.43]), post-SRS hemorrhage (OR = 0.83 [0.31-2.18]), or radiologic radiation-induced changes (OR = 1.08 [0.63-1.84]) between both cohorts. No statistically significant difference on the rates of outcomes of interest and complications were found in the adjusted model. CONCLUSION: Despite baseline differences between infratentorial and supratentorial pediatric AVMs, SRS outcomes, including AVM obliteration and post-SRS hemorrhage rates, were comparable amongst both groups. SRS appears to have a similar risk profile and therapeutic benefit to infratentorial pediatric AVMs as it does for those with a supratentorial location.

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.

Predictors of Early Hospice or Death in Patients With Inoperable Lung Cancer Treated With Curative Intent.

INTRODUCTION: Treatment for inoperable stage II to III non-small cell lung cancer (NSCLC) involves chemo-radiotherapy (CRT). However, some patients transition to hospice or die early during their treatment course. We present a model to prognosticate early poor outcomes in NSCLC patients treated with curative-intent CRT. METHODS AND MATERIALS: Across a statewide consortium, data was prospectively collected on stage II to III NSCLC patients who received CRT between 2012 and 2019. Early poor outcomes included hospice enrollment or death within 3 months of completing CRT. Logistic regression models were used to assess predictors in prognostic models. LASSO regression with multiple imputation were used to build a final multivariate model, accounting for missing covariates. RESULTS: Of the 2267 included patients, 128 experienced early poor outcomes. Mean age was 71 years and 59% received concurrent chemotherapy. The best predictive model, created parsimoniously from statistically significant univariate predictors, included age, ECOG, planning target volume (PTV), mean heart dose, pretreatment lack of energy, and cough. The estimated area under the ROC curve for this multivariable model was 0.71, with a negative predictive value of 95%, specificity of 97%, positive predictive value of 23%, and sensitivity of 16% at a predicted risk threshold of 20%. CONCLUSIONS: This multivariate model identified a combination of clinical variables and patient reported factors that may identify individuals with inoperable NSCLC undergoing curative intent chemo-radiotherapy who are at higher risk for early poor outcomes.

Stereotactic radiosurgery in the management of non-small cell lung cancer brain metastases: a prospective study using the NeuroPoint Alliance Stereotactic Radiosurgery Registry.

OBJECTIVE: The literature on non-small cell lung cancer (NSCLC) brain metastases (BMs) managed using stereotactic radiosurgery (SRS) relies mainly on single-institution studies or randomized controlled trials (RCTs). There is a literature gap on clinical and radiological outcomes of SRS for NSCLC metastases in real-world practice. The objective of this study was to benchmark mortality and progression outcomes in patients undergoing SRS for NSCLC BMs and identify risk factors for these outcomes using a national quality registry. METHODS: The SRS Registry of the NeuroPoint Alliance was used for this study. This registry included patients from 16 enrolling sites who underwent SRS from 2017 to 2022. Data are prospectively collected without a prespecified research purpose. The main outcomes of this analysis were overall survival (OS), out-of-field recurrence, local progression, and intracranial progression. All time-to-event investigations included Kaplan-Meier analyses and multivariable Cox regressions. RESULTS: Two hundred sixty-four patients were identified, with a mean age of 66.7 years and a female proportion of 48.5%. Most patients (84.5%) had a Karnofsky Performance Status (KPS) score of 80-100, and the mean baseline EQ-5D score was 0.539 quality-adjusted life years. A single lesion was present in 53.4% of the patients, and 29.1% of patients had 3 or more lesions. The median OS was 28.1 months, and independent predictors of mortality included no control of primary tumor (hazard ratio [HR] 2.1), KPS of 80 (HR 2.4) or lower (HR 2.4), coronary artery disease (HR 2.8), and 5 or more lesions present at the time of SRS treatment (HR 2.3). The median out-of-field progression-free survival (PFS) was 24.8 months, and the median local PFS was unreached. Intralesional hemorrhage was an independent risk factor of local progression, with an HR of 6.0. The median intracranial PFS was 14.0 months and was predicted by the number of lesions at the time of SRS (3-4 lesions, HR 2.2; 5-14 lesions, HR 2.5). CONCLUSIONS: In this real-world prospective study, the authors used a national quality registry and found favorable OS in patients with NSCLC BMs undergoing SRS compared with results from previously published RCTs. The intracranial PFS was mainly driven by the emergence of new lesions rather than local progression. A greater number of lesions at baseline was associated with out-of-field progression, while intralesional hemorrhage at baseline was associated with local progression.

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.

Stereotactic Radiosurgery for Vestibular Schwannoma in Neurofibromatosis Type 2: An International Multicenter Case Series of Response and Malignant Transformation Risk.

BACKGROUND: Vestibular schwannomas (VSs) related to neurofibromatosis type 2 (NF2) are challenging tumors. The increasing use of stereotactic radiosurgery (SRS) necessitates further investigations of its role and safety. OBJECTIVE: To evaluate tumor control, freedom from additional treatment (FFAT), serviceable hearing preservation, and radiation-related risks of patients with NF2 after SRS for VS. METHODS: We performed a retrospective study of 267 patients with NF2 (328 VSs) who underwent single-session SRS at 12 centers participating in the International Radiosurgery Research Foundation. The median patient age was 31 years (IQR, 21-45 years), and 52% were male. RESULTS: A total of 328 tumors underwent SRS during a median follow-up time of 59 months (IQR, 23-112 months). At 10 and 15 years, the tumor control rates were 77% (95% CI: 69%-84%) and 52% (95% CI: 40%-64%), respectively, and the FFAT rate were 85% (95% CI: 79%-90%) and 75% (95% CI: 65%-86%), respectively. At 5 and 10 years, the serviceable hearing preservation rates were 64% (95% CI: 55%-75%) and 35% (95% CI: 25%-54%), respectively. In the multivariate analysis, age (hazards ratio: 1.03 [95% CI: 1.01-1.05]; P = .02) and bilateral VSs (hazards ratio: 4.56 [95% CI: 1.05-19.78]; P = .04) were predictors for serviceable hearing loss. Neither radiation-induced tumors nor malignant transformation were encountered in this cohort. CONCLUSION: Although the absolute volumetric tumor progression rate was 48% at 15 years, the rate of FFAT related to VS was 75% at 15 years after SRS. None of the patients with NF2-related VS developed a new radiation-related neoplasm or malignant transformation after SRS.

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.

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.

Radionecrosis (RN) in patients with brain metastases treated with stereotactic radiosurgery (SRS) and immunotherapy.

OBJECTIVES: Limited data exist regarding radionecrosis (RN) rates when patients receive immunotherapy (IT) and SRS for brain metastases. This study assesses the influence of such treatments on the rate of RN. METHODS: We retrospectively reviewed 352 lesions from 105 patients with metastatic melanoma or NSCLC treated with SRS and IT from 2012 to 2018. Lesions were excluded from analysis if patients had received WBRT or prior GK to the same lesion, if RN occurred before IT, or if IT had been discontinued >6 months pre-SRS or initiated >1 year post-SRS. IT was delivered concurrently (±30 days of SRS) or sequentially. Overall survival and RN rates were assessed with Kaplan-Meier analysis. Univariate analysis and multivariate analysis were performed to identify characteristics predicting RN. RESULTS: Of 195 lesions from 63 patients included in analysis, the median prescription dose, IDL, lesion volume, and maximum tumor dimension (MTD) were 19 Gy, 50%, 0.15 cc and 0.8 cm, respectively. RN rates at 1, 2, and 3 years were 7.3%, 10.4% and 10.4%. On UVA, RN risk increased with, isodose volume (IDV), MTD, and tumor volume (TV) whereas conformity index was associated with a trend toward decreased RN risk. Two-year RN rates increased with TV ≥ 0.3 cc (16% vs 1.1% p = 0.001), MTD ≥ 1.3 cm (19.1% vs 1.8% p < 0.003), and IDV ≥ 1.5 cc (19.6% vs 1.7% p = 0.001). Concurrent vs sequential timing of IT did not predict for RN. CONCLUSIONS: Patients who received IT and SRS had acceptably low rates of RN. Timing of IT did not predict for RN. Further investigation is warranted to define RN risk with combined SRS and IT.

Introduce a rotational robust optimization framework for spot-scanning proton arc (SPArc) therapy.

Objective. Proton dosimetric uncertainties resulting from the patient's daily setup errors in rotational directions exist even with advanced image-guided radiotherapy techniques. Thus, we developed a new rotational robust optimization SPArc algorithm (SPArcrot) to mitigate the dosimetric impact of the rotational setup error in Raystation ver. 6.02 (RaySearch Laboratory AB, Stockholm, Sweden).Approach.The initial planning CT was rotated ±5° simulating the worst-case setup error in the roll direction. The SPArcrotuses a multi-CT robust optimization framework by taking into account of such rotational setup errors. Five cases representing different disease sites were evaluated. Both SPArcoriginaland SPArcrotplans were generated using the same translational robust optimized parameters. To quantitatively investigate the mitigation effect from the rotational setup errors, all plans were recalculated using a series of pseudo-CT with rotational setup error (±1°/±2°/±3°/±5°). Dosimetric metrics such as D98% of CTV, and 3D gamma analysis were used to assess the dose distribution changes in the target and OARs.Main results.The magnitudes of dosimetric changes in the targets due to rotational setup error were significantly reduced by the SPArcrotcompared to SPArc in all cases. The uncertainties of the max dose to the OARs, such as brainstem, spinal cord and esophagus were significantly reduced using SPArcrot. The uncertainties of the mean dose to the OARs such as liver and oral cavity, parotid were comparable between the two planning techniques. The gamma passing rate (3%/3 mm) was significantly improved for CTV of all tumor sites through SPArcrot.Significance.Rotational setup error is one of the major issues which could lead to significant dose perturbations. SPArcrotplanning approach can consider such rotational error from patient setup or gantry rotation error by effectively mitigating the dose uncertainties to the target and in the adjunct series OARs.

Redefine the Role of Spot-Scanning Proton Beam Therapy for the Single Brain Metastasis Stereotactic Radiosurgery.

Purpose: To explore the role of using Pencil Beam Scanning (PBS) proton beam therapy in single lesion brain stereotactic radiosurgery (SRS), we developed and validated a dosimetric in silico model to assist in the selection of an optimal treatment approach among the conventional Volumetric Modulated Arc Therapy (VMAT), Intensity Modulated Proton Therapy (IMPT) and Spot-scanning Proton Arc (SPArc). Material and Methods: A patient's head CT data set was used as an in silico model. A series of targets (volume range from 0.3 cc to 33.03 cc) were inserted in the deep central and peripheral region, simulating targets with different sizes and locations. Three planning groups: IMPT, VMAT, and SPArc were created for dosimetric comparison purposes and a decision tree was built based on this in silico model. Nine patients with single brain metastases were retrospectively selected for validation. Multiple dosimetric metrics were analyzed to assess the plan quality, such as dose Conformity Index (CI) (ratio of the target volume to 100% prescription isodose volume); R50 (ratio of 50% prescription isodose volume to the target volume); V12Gy (volume of brain tissue minus GTV receiving 12 Gy), and mean dose of the normal brain. Normal tissue complication probability (NTCP) of brain radionecrosis (RN) was calculated using the Lyman-Kutcher-Burman (LKB) model and total treatment delivery time was calculated. Six physicians from different institutions participated in the blind survey to evaluate the plan quality and rank their choices. Results: The study showed that SPArc has a dosimetric advantage in the V12Gy and R50 with target volumes > 9.00 cc compared to VMAT and IMPT. A significant clinical benefit can be found in deep centrally located lesions larger than 20.00 cc using SPArc because of the superior dose conformity and mean dose reduction in healthy brain tissue. Nine retrospective clinical cases and the blind survey showed good agreement with the in silico dosimetric model and decision tree. Additionally, SPArc significantly reduced the treatment delivery time compared to VMAT (SPArc 184.46 ± 59.51s vs. VMAT: 1574.78 ± 213.65s). Conclusion: The study demonstrated the feasibility of using Proton beam therapy for single brain metastasis patients utilizing the SPArc technique. At the current stage of technological development, VMAT remains the current standard modality of choice for single lesion brain SRS. The in silico dosimetric model and decision tree presented here could be used as a practical clinical decision tool to assist the selection of the optimal treatment modality among VMAT, IMPT, and SPArc in centers that have both photon and proton capabilities.

Trimodality therapy for patients with stage III non-small-cell lung cancer: A comprehensive surveillance, epidemiology, and end results analysis.

PURPOSE: Debate exists regarding the optimal management for patients with stage III non-small-cell lung cancer (NSCLC). Recent inclusion of chemotherapeutic data in the Surveillance, Epidemiology, and End Results (SEER) database has made it possible to identify patients with NSCLC who received chemotherapy. We hypothesized that patients with stage III NSCLC experience improved overall survival from trimodality therapy (TMT) versus definitive chemoradiation therapy (CRT) alone. MATERIALS AND METHODS: We analyzed the overall survival of stage III NSCLC patients based on the receipt of TMT versus CRT alone. This included crude and adjusted univariate models as well as crude and doubly robust adjusted multivariable analyses, both utilizing propensity score matching and inverse probability of treatment weighting. Factors included in the multivariable analyses included: age, sex, marital status, income, date of diagnosis, primary site, histology, grade, T stage, N stage, and intended treatment. Planned subset analyses were performed for stage III(N2) patients. RESULTS: Adult patients with stage III NSCLC (N = 9008) from the SEER database were included in our analyses. In our univariate analyses, an overall survival benefit was observed for TMT versus CRT (CrudeHR = 0.58, 95% CI = 0.55-0.61, p < 0.001; AdjHR = 0.58, 95% CI = 0.54-0.61, p < 0.001). This persisted in both crude and doubly robust multivariable analyses (CrudeHR = 0.57, 95% CI = 0.53-0.61, p < 0.001; AdjHR = 0.56, 95% CI = 0.53-0.59, p < 0.001). Patients with stage III(N2) disease also demonstrated a significant benefit to OS with TMT versus CRT alone. CONCLUSION: The significant difference in overall survival seen with TMT suggests this may be an effective treatment approach for select patients.

Using previously registered cone beam computerized tomography images to facilitate online computerized tomography to cone beam computerized tomography image registration in lung stereotactic body radiation therapy.

PURPOSE: In our conventional image registration workflow, the four-dimensional (4D) CBCT was directly registered to the reference helical CT (HCT) using a dual registration approach within the Elekta XVI software. In this study, we proposed a new HCT-CBCT auto-registration strategy using a previously registered CBCT (CBCTpre) as the reference image and tested its clinical feasibility. METHODS: From a previous CBCT session, the registered average 4D CBCT was selected as CBCTpre and the HCT-CBCTpre registration vector from the clinician's manual registration result was recorded. In the new CBCT session, auto-registration was performed between the new average 4D CBCT (CBCTtx) and CBCTpre (CBCTpre-CBCTtx). The overall HCT-CBCTtx registration result was then derived by combing the results from two registrations (i.e., HCT-CBCTpre + CBCTpre-CBCTtx). The results from the proposed method were compared with clinician's manually adjusted HCT-CBCTtx registration results ("ground truth") to evaluate its accuracy using a test dataset consisting of 32 challenging registration cases. RESULTS: The uncertainty of the proposed auto-registration method was -0.1 ± 0.5, 0.1 ± 1.0, and -0.1 ± 0.7 mm in three translational directions (lateral, longitudinal, and vertical) and 0.0° ± 0.9°, 0.3° ± 0.9°, and 0.4° ± 0.7° in three rotation directions, respectively. Two patients (6.3%) had translational uncertainty > 2 mm (max = 3.1 mm) and both occurred in the longitudinal direction. Meanwhile, the uncertainty of the conventional direct HCT-CBCTtx auto-registration was -0.4 ± 2.6, -0.2 ± 7.4, -1.4 ± 3.6 mm for translations and -0.3° ± 1.2°, 0.0° ± 1.6°, and 0.1 ± 1.1° for rotations. Eleven patients (34.4%) had translation uncertainty > 2 mm (max = 26.2 mm) in at least one direction. Accuracy in translation was improved with the new method, while rotation accuracy stayed in the same order. CONCLUSION: We demonstrated the feasibility of incorporating prior clinical registration knowledge into the online HCT-CBCT registration process. The proposed auto-registration method provides a quick and reliable starting solution for online HCT-CBCT registration.

Effect of Education and Standardization of Cardiac Dose Constraints on Heart Dose in Patients With Lung Cancer Receiving Definitive Radiation Therapy Across a Statewide Consortium.

PURPOSE: Cardiac radiation exposure is associated with an increased rate of adverse cardiac events in patients receiving radiation therapy for locally advanced non-small cell lung carcinoma (NSCLC). Previous analysis of practice patterns within the Michigan Radiation Oncology Quality Consortium (MROQC) revealed 1 in 4 patients received a mean heart dose >20 Gy and significant heterogeneity existed among treatment centers in using cardiac dose constraints. The purpose of this study is to analyze the effect of education and initiation of standardized cardiac dose constraints on heart dose across a statewide consortium. METHODS AND MATERIALS: From 2012 to 2020, 1681 patients from 27 academic and community centers who received radiation therapy for locally advanced NSCLC were included in this analysis. Dosimetric endpoints including mean heart dose (MHD), mean lung dose, and mean esophagus dose were calculated using data from dose-volume histograms. These dose metrics were grouped by year of treatment initiation for all patients. Education regarding data for cardiac dose constraints first occurred in small lung cancer working group meetings and then consortium-wide starting in 2016. In 2018, a quality metric requiring mean heart dose <20 Gy while maintaining dose coverage (D95) to the target was implemented. Dose metrics were compared before (2012-2016) versus after (2017-2020) initiation of interventions targeting cardiac constraints. Statistical analysis was performed using the Wilcoxon rank sum test. RESULTS: After education and implementation of the heart dose performance metric, mean MHD declined from an average of 12.2 Gy preintervention to 10.4 Gy postintervention (P < .0001), and the percentage of patients receiving MHD >20 Gy was reduced from 21.1% to 10.3% (P < .0001). Mean lung dose and mean esophagus dose did not increase, and target coverage remained unchanged. CONCLUSIONS: Education and implementation of a standardized cardiac dose quality measure across a statewide consortium was associated with a reduction of mean heart dose in patients receiving radiation therapy for locally advanced NSCLC. These dose reductions were achieved without sacrificing target coverage, increasing mean lung dose, or increasing mean esophagus dose. Analysis of the clinical ramifications of the reduction in cardiac doses is ongoing.

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.

Adverse radiation effects in volume-staged radiosurgery for large arteriovenous malformations: a multiinstitutional study.

OBJECTIVE: The optimal treatment paradigm for large arteriovenous malformations (AVMs) is controversial. One approach is volume-staged stereotactic radiosurgery (VS-SRS). The authors previously reported efficacy of VS-SRS for large AVMs in a multiinstitutional cohort; here they focus on risk of symptomatic adverse radiation effects (AREs). METHODS: This is a multicentered retrospective review of patients treated with a planned prospective volume staging approach to stereotactically treat the entire nidus of an AVM, with volume stages separated by intervals of 3-6 months. A total of 9 radiosurgical centers treated 257 patients with VS-SRS between 1991 and 2016. The authors evaluated permanent, transient, and total ARE events that were symptomatic. RESULTS: Patients received 2-4 total volume stages. The median age was 33 years at the time of the first SRS volume stage, and the median follow-up was 5.7 years after VS-SRS. The median total AVM nidus volume was 23.25 cm3 (range 7.7-94.4 cm3), with a median margin dose per stage of 17 Gy (range 12-20 Gy). A total of 64 patients (25%) experienced an ARE, of which 19 were permanent. Rather than volume, maximal linear dimension in the Z (craniocaudal) dimension was associated with toxicity; a threshold length of 3.28 cm was associated with an ARE, with a 72.5% sensitivity and a 58.3% specificity. In addition, parietal lobe involvement for superficial lesions and temporal lobe involvement for deep lesions were associated with an ARE. CONCLUSIONS: Size remains the dominant predictor of toxicity following SRS, but overall rates of AREs were lower than anticipated based on baseline features, suggesting that dose and size were relatively dissociated through volume staging. Further techniques need to be assessed to optimize outcomes.

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.

Association Between Physician- and Patient-Reported Symptoms in Patients Treated With Definitive Radiation Therapy for Locally Advanced Lung Cancer in a Statewide Consortium.

PURPOSE: Little data have been reported about the patient experience during curative radiation therapy (RT) for lung cancer in routine clinical practice or how this relates to treatment toxicity as reported by clinicians. The purpose of this study was to compare clinician-reported adverse events (AEs) with patient-reported outcomes (PROs), including both specific symptoms/side effects, as well as overall quality of life (QoL) during and after definitive RT for locally advanced lung cancer (LALC) in a large statewide cohort. METHODS AND MATERIALS: PROs were prospectively collected from patients treated with definitive RT for LALC at 24 institutions within the Michigan Radiation Oncology Quality Consortium between 2012 and 2018 using the Functional Assessment of Cancer Therapy trial outcome index. Physicians prospectively recorded AEs using the Common Terminology Criteria for Adverse Events, version 4.0. Patient-reported QoL changes from baseline were assessed during and after RT using the Functional Assessment of Cancer Therapy trial outcome index. Spearman correlation coefficients were calculated for AEs and similar PROs, and a multivariable analysis was used to assess associations with QoL. RESULTS: A total 1361 patients were included in the study, and 53% of respondents reported clinically meaningful declines in QoL at the end of RT. The correlation between clinician-reported esophagitis and patient-reported trouble swallowing was moderate (R = .67), but correlations between clinician-reported pneumonitis and patient-reported shortness of breath (R = .13) and cough (R = .09) were weak. Clinician-reported AEs were significantly associated with clinically meaningful declines in patient-reported QoL (R = - .46 for summary AE score). QoL was more strongly associated with fatigue (R = - .41) than lung-specific AEs. CONCLUSIONS: AEs are associated with clinically meaningful declines in QoL during and after RT for LALC, but associations between AEs and QoL are only modest. This highlights the importance of PRO data, and future research should assess whether earlier detection of PRO changes could allow for interventions that reduce the frequency of treatment-related clinically meaningful declines in QoL.