BRCA1 Protein Expression Predicts Survival in Glioblastoma Patients from an NRG Oncology RTOG Cohort.

PURPOSE: Glioblastoma, the most common malignant brain tumor, was associated with a median survival of <1 year in the pre-temozolomide (TMZ) era. Despite advances in molecular and genetic profiling studies identifying several predictive biomarkers, none has been translated into routine clinical use. Our aim was to investigate the prognostic significance of a panel of diverse cellular molecular markers of tumor formation and growth in an annotated glioblastoma tissue microarray (TMA). METHODS AND MATERIALS: A TMA composed of archived glioblastoma tumors from patients treated with surgery, radiation, and non-TMZ chemother-apy, was provided by RTOG. RAD51, BRCA-1, phosphatase and tensin homolog tumor suppressor gene (PTEN), and miRNA-210 expression levels were assessed using quantitative in situ hybridization and automated quantitative protein analysis. The objectives of this analysis were to determine the association of each biomarker with overall survival (OS), using the Cox proportional hazard model. Event-time distributions were estimated using the Kaplan-Meier method and compared by the log-rank test. RESULTS: A cohort of 66 patients was included in this study. Among the 4 biomarkers assessed, only BRCA1 expression had a statistically significant correlation with survival. From univariate analysis, patients with low BRCA1 protein expression showed a favorable outcome for OS (p = 0.04; hazard ratio = 0.56) in comparison with high expressors, with a median survival time of 18.9 versus 4.8 months. CONCLUSIONS: BRCA1 protein expression was an important survival predictor in our cohort of glioblastoma patients. This result may imply that low BRCA1 in the tumor and the consequent low level of DNA repair cause vulnerability of the cancer cells to treatment.

Radiation plus Procarbazine, CCNU, and Vincristine in Low-Grade Glioma.

BACKGROUND: Grade 2 gliomas occur most commonly in young adults and cause progressive neurologic deterioration and premature death. Early results of this trial showed that treatment with procarbazine, lomustine (also called CCNU), and vincristine after radiation therapy at the time of initial diagnosis resulted in longer progression-free survival, but not overall survival, than radiation therapy alone. We now report the long-term results. METHODS: We included patients with grade 2 astrocytoma, oligoastrocytoma, or oligodendroglioma who were younger than 40 years of age and had undergone subtotal resection or biopsy or who were 40 years of age or older and had undergone biopsy or resection of any of the tumor. Patients were stratified according to age, histologic findings, Karnofsky performance-status score, and presence or absence of contrast enhancement on preoperative images. Patients were randomly assigned to radiation therapy alone or to radiation therapy followed by six cycles of combination chemotherapy. RESULTS: A total of 251 eligible patients were enrolled from 1998 through 2002. The median follow-up was 11.9 years; 55% of the patients died. Patients who received radiation therapy plus chemotherapy had longer median overall survival than did those who received radiation therapy alone (13.3 vs. 7.8 years; hazard ratio for death, 0.59; P=0.003). The rate of progression-free survival at 10 years was 51% in the group that received radiation therapy plus chemotherapy versus 21% in the group that received radiation therapy alone; the corresponding rates of overall survival at 10 years were 60% and 40%. A Cox model identified receipt of radiation therapy plus chemotherapy and histologic findings of oligodendroglioma as favorable prognostic variables for both progression-free and overall survival. CONCLUSIONS: In a cohort of patients with grade 2 glioma who were younger than 40 years of age and had undergone subtotal tumor resection or who were 40 years of age or older, progression-free survival and overall survival were longer among those who received combination chemotherapy in addition to radiation therapy than among those who received radiation therapy alone. (Funded by the National Cancer Institute and others; ClinicalTrials.gov number, NCT00003375.).

Intermediate-grade carcinoma of the parotid and the impact of adjuvant radiation.

PURPOSE: To determine the influence of adjuvant radiotherapy on survival in surgically-managed early stage intermediate-grade mucoepidermoid and acinic cell carcinoma of the parotid. MATERIALS AND METHODS: The National Cancer Database was reviewed between 2004 and 2015 to identify patients with intermediate-grade, early T-stage, node-negative parotid carcinoma who underwent parotidectomy ± radiotherapy. RESULTS: There were 744 patients identified of which 81% had mucoepidermoid carcinoma and 19% had acinic cell carcinoma. Positive surgical margins were identified in 21% and adjuvant radiotherapy was administered in 38% of cases. Of the 159 patients with positive margins, 113 (71%) received adjuvant radiotherapy. Of the 585 patients with negative margins, 173 (30%) underwent adjuvant radiotherapy. In multivariable analysis, age (over 52 years: HR 5.19, 95%CI 2.33-11.57), insurance status (private insurance: HR 0.24 95%CI 0.13-0.43), and extent of parotidectomy (total parotidectomy: HR 2.02 95%CI 1.23-3.31) were significantly associated with overall survival, while adjuvant radiotherapy was not a significant predictive factor (HR 0.81, 95%CI 0.49-1.36). In patients with positive margin resections, however, adjuvant radiation was an independent predictor of improved survival when adjusted for age, insurance status, and extent of parotidectomy (HR 0.34, 95%CI 0.13-0.88). Conversely, in patients with negative margin resections, adjuvant radiation did not influence survival outcomes when adjusted for these covariates (HR 1.02, 95%CI 0.53-1.93). CONCLUSIONS AND RELEVANCE: In patients with early stage intermediate-grade parotid carcinoma, adjuvant radiotherapy significantly and independently improves survival in those with post-operative positive margins. Adjuvant therapy, however, does not appear to improve survival outcomes in those with negative margin resections.

NRG oncology RTOG 9006: a phase III randomized trial of hyperfractionated radiotherapy (RT) and BCNU versus standard RT and BCNU for malignant glioma patients.

From 1990 to 1994, patients with newly diagnosed malignant gliomas were enrolled and randomized between hyperfractionated radiation (HFX) of 72.0 Gy in 60 fractions given twice daily and 60.0 Gy in 30 fractions given once daily. All patients received 80 mg/m2 of 1,3 bis(2 chloroethyl)-1 nitrosourea on days 1-3 q8 weeks for 1 year. Patients were stratified by age, KPS, and histology. The primary endpoint was overall survival (OS), with secondary endpoints including progression-free survival (PFS) and toxicity. Out of the 712 patients accrued, 694 (97.5%) were analyzable cases (350 HFX, 344 standard arm). There was no significant difference between the arms on overall acute or late treatment-related toxicity. No statistically significant effect for HFX, as compared to standard therapy, was found on either OS, with a median survival time (MST) of 11.3 versus 13.1 months (p = 0.20) or PFS, with a median PFS time of 5.7 versus 6.9 months (p = 0.18). The treatment effect on OS remained insignificant based on the multivariate analysis (hazard ratio 1.16; p = 0.0682). When OS was analyzed by histology subgroup there was also no significant difference between the two arms for patients with glioblastoma multiforme (MST: 10.3 vs. 11.2 months; p = 0.34), anaplastic astrocytoma (MST: 69.8 vs. 50.0 months; p = 0.91) or anaplastic oligodendroglioma (MST: 92.1 vs. 66.5 months; p = 0.33). Though this trial provided many invaluable secondary analyses, there was no trend or indication of a benefit to HFX radiation to 72.0 Gy in any subset of malignant glioma patients.

Kinematic and Microphysical Significance of Lightning Jumps versus Non-Jump Increases in Total Flash Rate.

Thirty-nine thunderstorms are examined using multiple-Doppler, polarimetric and total lightning observations to understand the role of mixed phase kinematics and microphysics in the development of lightning jumps. This sample size is larger than those of previous studies on this topic. The principal result of this study is that lightning jumps are a result of mixed phase updraft intensification. Larger increases in intense updraft volume (≥ 10 m s-1) and larger changes in peak updraft speed are observed prior to lightning jump occurrence when compared to other non-jump increases in total flash rate. Wilcoxon-Mann-Whitney Rank Sum testing yields p-values ≤0.05, indicating statistical independence between lightning jump and non-jump distributions for these two parameters. Similar changes in mixed phase graupel mass magnitude are observed prior to lightning jumps and non-jump increases in total flash rate. The p-value for graupel mass change is p=0.096, so jump and non-jump distributions for graupel mass change are not found statistically independent using the p=0.05 significance level. Timing of updraft volume, speed and graupel mass increases are found to be 4 to 13 minutes in advance of lightning jump occurrence. Also, severe storms without lightning jumps lack robust mixed phase updrafts, demonstrating that mixed phase updrafts are not always a requirement for severe weather occurrence. Therefore, the results of this study show that lightning jump occurrences are coincident with larger increases in intense mixed phase updraft volume and peak updraft speed than smaller non-jump increases in total flash rate.

Cystic Brain Metastasis Outcomes After Gamma Knife Radiation Therapy.

Purpose: The response of cystic brain metastases (BMets) to radiation therapy is poorly understood, with conflicting results regarding local control, overall survival, and treatment-related toxicity. This study aims to examine the role of Gamma Knife (GK) in managing cystic BMets. Methods and Materials: Volumetric analysis was conducted to measure tumor and edema volume at the time of GK and follow-up magnetic resonance imaging studies. Survival was described using the Kaplan-Meier method, and the cumulative incidence of progression was described using the Aalen-Johansen estimator. We evaluated the association of 4 variables with survival using Cox regression analysis. Results: Between 2016 and 2021, 54 patients with 83 cystic BMets were treated with GK at our institution. Lung cancer was the most common pathology (51.9%), followed by breast cancer (13.0%). The mean target volume was 2.7 cm3 (range, 0.1-39.0 cm3), and the mean edema volume was 13.9 cm3 (range, 0-165.5 cm3). The median prescription dose of single-fraction and fractionated GK was 20 Gy (range, 14-27.5 Gy). With a median follow-up of 8.9 months, the median survival time (MST) was 11.1 months, and the 1-year local control rate was 75.9%. Gamma Knife was associated with decreased tumor and edema volumes over time, although 68.5% of patients required steroids after GK. Patients whose tumors grew beyond baseline after GK received significantly more whole-brain radiation therapy (WBRT) before GK than those whose tumors declined after GK. Higher age at diagnosis of BMets and pre-GK systemic therapy were associated with worse survival, with an MST of 7.8 months in patients who received it compared with 23.3 months in those who did not. Conclusions: Pre-GK WBRT may select for BMets with increased radioresistance. This study highlights the ability of GK to control cystic BMets with the cost of high posttreatment steroid use.

Safety and Tolerability of Online Adaptive High-Field Magnetic Resonance-Guided Radiotherapy.

Importance: In 2018, the first online adaptive magnetic resonance (MR)-guided radiotherapy (MRgRT) system using a 1.5-T MR-equipped linear accelerator (1.5-T MR-Linac) was clinically introduced. This system enables online adaptive radiotherapy, in which the radiation plan is adapted to size and shape changes of targets at each treatment session based on daily MR-visualized anatomy. Objective: To evaluate safety, tolerability, and technical feasibility of treatment with a 1.5-T MR-Linac, specifically focusing on the subset of patients treated with an online adaptive strategy (ie, the adapt-to-shape [ATS] approach). Design, Setting, and Participants: This cohort study included adults with solid tumors treated with a 1.5-T MR-Linac enrolled in Multi Outcome Evaluation for Radiation Therapy Using the MR-Linac (MOMENTUM), a large prospective international study of MRgRT between February 2019 and October 2021. Included were adults with solid tumors treated with a 1.5-T MR-Linac. Data were collected in Canada, Denmark, The Netherlands, United Kingdom, and the US. Data were analyzed in August 2023. Exposure: All patients underwent MRgRT using a 1.5-T MR-Linac. Radiation prescriptions were consistent with institutional standards of care. Main Outcomes and Measures: Patterns of care, tolerability, and technical feasibility (ie, treatment completed as planned). Acute high-grade radiotherapy-related toxic effects (ie, grade 3 or higher toxic effects according to Common Terminology Criteria for Adverse Events version 5.0) occurring within the first 3 months after treatment delivery. Results: In total, 1793 treatment courses (1772 patients) were included (median patient age, 69 years [range, 22-91 years]; 1384 male [77.2%]). Among 41 different treatment sites, common sites were prostate (745 [41.6%]), metastatic lymph nodes (233 [13.0%]), and brain (189 [10.5%]). ATS was used in 1050 courses (58.6%). MRgRT was completed as planned in 1720 treatment courses (95.9%). Patient withdrawal caused 5 patients (0.3%) to discontinue treatment. The incidence of radiotherapy-related grade 3 toxic effects was 1.4% (95% CI, 0.9%-2.0%) in the entire cohort and 0.4% (95% CI, 0.1%-1.0%) in the subset of patients treated with ATS. There were no radiotherapy-related grade 4 or 5 toxic effects. Conclusions and Relevance: In this cohort study of patients treated on a 1.5-T MR-Linac, radiotherapy was safe and well tolerated. Online adaptation of the radiation plan at each treatment session to account for anatomic variations was associated with a low risk of acute grade 3 toxic effects.

The role of pre-treatment white matter abnormalities in developing white matter changes following whole brain radiation: a volumetric study.

White matter injury is a known complication of whole brain radiation (WBRT). Little is known about the factors that predispose a patient to such injury. The current study used MR volumetrics to examine risk factors, in particular the influence of pre-treatment white matter health, in developing white matter change (WMC) following WBRT. Thirty-four patients with unilateral metastatic disease underwent FLAIR MRI pre-treatment and at several time points following treatment. The volume of abnormal FLAIR signal in the white matter was measured in the hemisphere contralateral to the diseased hemisphere at each time point. Analyses were restricted to the uninvolved hemisphere to allow for the measurement of WBRT effects without the potential confounding effects of the disease on imaging findings. The relationship between select pre-treatment clinical variables and the degree of WMC following treatment was examined using correlational and regression based analyses. Age when treated and volume of abnormal FLAIR prior to treatment were significantly associated with WMC following WBRT; however, pre-treatment FLAIR volume was the strongest predictor of post-treatment WMCs. Age did not add any predictive value once white matter status was considered. No significant relationships were found between biological equivalent dose and select cerebrovascular risk factors (total glucose, blood pressure, BMI) and development of WMCs. The findings from this study identify pre-treatment white matter health as an important risk factor in developing WMC following WBRT. This information can be used to make more informed decisions and counsel patients on their risk for treatment effects.

Incorporating uncertainty bounds in daily deformable dose accumulation for adaptive radiation therapy of head-and-neck cancer.

BACKGROUND: The widespread use of deformable dose accumulation (DDA) in adaptive radiotherapy (ART) has been limited due to the lack of clinically compatible methods to consider its related uncertainties. PURPOSE: We estimate dose reconstruction uncertainties in daily DDA during CT-guided radiotherapy of head-and-neck cancer (HNC). We project confidence intervals of cumulative dose-volume parameters to the parotids and determine threshold values to guide clinical decision-making in ART. METHODS: Doses from daily images (megavoltage CTs [MVCTs]) of 20 HNC patients treated with tomotherapy were reconstructed and accumulated in the planning CT (PCT) utilizing a commercial DDA algorithm (PreciseART, Accuray, Inc.). For each mapped fraction, we warped the planning contours to the MVCT. Dose-volume histograms (DVHs) calculated in the MVCT (with warped contour and native dose) and the PCT (with native contour and mapped dose) were compared; the observed inconsistencies were associated with dose reconstruction errors. We derived uncertainty bounds for the transferred dose to voxels within the structure of interest in the PCT. The confidence intervals of cumulative dose-volume parameters were mid-treatment projected and evaluated as predictors of the end of treatment cumulative metrics. The need for plan adaptation was tested by comparing the projected uncertainty bounds with the treatment constraint points. RESULTS: Among all cases, the uncertainty in mean values of daily dose distributions mapped to the reference parotid's contours averaged between 2.8% and 3.8% of typical single fraction planning values and less than 1% for the planning target volume (PTV) D95%. These daily inconsistencies were higher in the ipsilateral compared to the contralateral parotid and increased toward the end of treatment. The magnitude of the uncertainty bounds for the cumulative treatment mean dose, D50%, and V20 Gy to the parotids, and PTV D95% were on average 3.5%, 6.6%, 4.6%, and 0.4% of the planned or prescribed values, with confidence intervals of 97.1%-107.0%, 98.2%-110.4%, 95.6%-111.1%, and 98.2%-100.2% respectively. The uncertainty intervals projected at mid-treatment intersected with the end of treatment bounds in 82% of the parotid's metrics; half of them presented an overlapping percentage greater than 60%. In five patients, the cumulative mean doses were projected at mid-treatment to exceed the total treatment constraint point by at least 3%; this threshold was exceeded at the end of treatment in the five cases. Underdosing was projected in only one case; the cumulative PTV D95% at the end of treatment was below the clinical threshold. CONCLUSION: Uncertainty bounds were incorporated into the results of a commercial DDA tool. The cohort's statistics showed that the parotids' cumulative DVH metrics frequently exceeded the planning values if confidence intervals were included. Most of the uncertainty bounds of the PTV metrics were kept within the clinical thresholds. We verified that mid-treatment violation projections led to exceeding the constraint point at the end of the treatment. Based on a 3% threshold, approximately one fourth of the patients are expected to be replanned at mid-treatment for parotids sparing during HNC radiotherapy.

Development of a multi-layer quality assurance program to evaluate the uncertainty of deformable dose accumulation in adaptive radiotherapy.

PURPOSE: Deformable dose accumulation (DDA) has uncertainties which impede the implementation of DDA-based adaptive radiotherapy (ART) in clinic. The purpose of this study is to develop a multi-layer quality assurance (MLQA) program to evaluate uncertainties in DDA. METHODS: A computer program is developed to generate a pseudo-inverse displacement vector field (DVF) for each deformable image registration (DIR) performed in Accuray's PreciseART. The pseudo-inverse DVF is first used to calculate a pseudo-inverse consistency error (PICE) and then implemented in an energy and mass congruent mapping (EMCM) method to reconstruct a deformed dose. The PICE is taken as a metric to estimate DIR uncertainties. A pseudo-inverse dose agreement rate (PIDAR) is used to evaluate the consequence of the DIR uncertainties in DDA and the principle of energy conservation is used to validate the integrity of dose mappings. The developed MLQA program was tested using the data collected from five representative cancer patients treated with tomotherapy. RESULTS: DIRs were performed in PreciseART to generate primary DVFs for the five patients. The fidelity index and PICE of these DVFs on average are equal to 0.028 mm and 0.169 mm, respectively. With the criteria of 3 mm/3% and 5 mm/5%, the PIDARs of the PreciseART-reconstructed doses are 73.9 ± 4.4% and 87.2 ± 3.3%, respectively. The PreciseART and EMCM-based dose reconstructions have their deposited energy changed by 5.6 ± 3.9% and 2.6 ± 1.5% in five GTVs, and by 9.2 ± 7.8% and 4.7 ± 3.6% in 30 OARs, respectively. CONCLUSIONS: A pseudo-inverse map-based EMCM program has been developed to evaluate DIR and dose mapping uncertainties. This program could also be used as a sanity check tool for DDA-based ART.

Evolution in the Presence and Evidence Category of Radiation Therapy Treatment Recommendations in the National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology.

Purpose: The changes in the recommended use of radiation therapy (RT) in the presence of expanding systemic cancer therapies and technological advances are poorly characterized. We sought to understand the recommended utilization of RT across a broad range of malignancies by examining National Comprehensive Cancer Network (NCCN) Guidelines. Methods and Materials: We conducted a comprehensive review and categorization of RT recommendations, with their subsequent supporting evidence categories, in 3 versions of NCCN Guidelines, specifically years 2000, 2009, and 2019. These NCCN Guidelines were individually examined for RT-specific recommendations among the 10 most common tumors. The presence of RT as a recommended modality was recorded for each tumor type in each guideline. Recommendation categories including Category 1, 2A, 2B, and 3 were tallied and compared with examine totals and percentage distributions in each tumor type. Results: A total of 3858 NCCN recommendations were individually reviewed. The presence of a recommendation inclusive of RT increased from incidence of 205 in the year 2000 to 992 in the year 2019 (383%). In the 2019 NCCN Guidelines, the most Category 1 RT recommendations were found within small cell lung (13%), non-small cell lung (5%), breast (5%), bladder (2%), rectal (2%), and non-Hodgkin lymphoma (1%). Pancreatic, uterine, prostate, melanoma, kidney, and colon cancer guidelines had no Category 1 RT recommendations. Rectal cancer had 31 (27%) preferred recommendations. The majority (89%) of 2019 RT recommendations were for initial therapy, and 9% were specific to salvage therapy. Tumor sites with the highest proportion of RT Category 1 evidence were small cell lung (29%), non-small cell lung (24%), and breast cancer (24%). Conclusions: The frequency of recommendations for using RT in NCCN Guidelines has increased by >300% in the past 20 years among the 10 most common malignancies. Consideration of the quality of evidence supporting these recommendations by tumor type is useful to identify specific malignancies in need of higher-level evidence supporting the role of RT.

Assessment of Differences in Academic Rank and Compensation by Gender and Race/Ethnicity Among Academic Radiation Oncologists in the United States.

Purpose: Advancing equity, diversity, and inclusion in the physician workforce is essential to providing high-quality and culturally responsive patient care and has been shown to improve patient outcomes. To better characterize equity in the field of radiation oncology, we sought to describe the current academic radiation oncology workforce, including any contemporary differences in compensation and rank by gender and race/ethnicity. Methods and Materials: We conducted a retrospective cohort study using data from the Society of Chairs of Academic Radiation Oncology Programs (SCAROP) 2018 Financial Survey. Multivariable logistic regression models were used to identify factors associated with associate or full professor rank. Compensation was compared by gender and race/ethnicity overall and stratified by rank and was further analyzed using multivariable linear regression models. Results: Of the 858 academic radiation oncologists from 63 departments in the United States in the sample, 33.2% were female, 65.2% were White, 27.2% were Asian, and 7.6% were underrepresented in medicine (URiM). There were 44.0% assistant professors, 32.0% associate professors, and 22.8% full professors. Multivariable logistic regression analysis for factors associated with associate or full professor rank did not reveal statistically significant associations between gender or race/ethnicity with academic rank (odds ratio [OR], 0.86; 95% confidence interval [CI], 0.56-1.32; P = .48 for gender; OR, 0.81; 95% CI, 0.5-1.30; P = .37 for Asian vs White; and OR, 0.69; 95% CI, 0.31-1.55; P = .37 for URiM vs White), but CIs were wide due to sample size, and point estimates were <1. Similarly, multivariable linear regression analysis modeling the log relative total compensation did not detect statistically significant differences between radiation oncologists by gender (-1.7%; 95% CI, -6.8% to 3.4%; P = .51 for female vs male) or race/ethnicity (-1.6%; 95% CI, -7.3% to 4.0%; P = .57 for Asian vs White and -3.0%; 95% CI, -12.1% to 6.0%; P = .51 for URiM vs White). Conclusions: The low numbers of women and faculty with URiM race/ethnicity in this radiation oncology faculty sample limits the ability to compare career trajectory and compensation by those characteristics. Given that point estimates were <1, our findings do not contradict larger multispecialty studies that suggest an ongoing need to monitor equity.

Case report: Fractional brain tumor burden magnetic resonance mapping to assess response to pulsed low-dose-rate radiotherapy in newly-diagnosed glioblastoma.

Background: Pulsed low-dose-rate radiotherapy (pLDR) is a commonly used reirradiation technique for recurrent glioma, but its upfront use with temozolomide (TMZ) following primary resection of glioblastoma is currently under investigation. Because standard magnetic resonance imaging (MRI) has limitations in differentiating treatment effect from tumor progression in such applications, perfusion-weighted MRI (PWI) can be used to create fractional tumor burden (FTB) maps to spatially distinguish active tumor from treatment-related effect. Methods: We performed PWI prior to re-resection in four patients with glioblastoma who had undergone upfront pLDR concurrent with TMZ who had radiographic suspicion for tumor progression at a median of 3 months (0-5 months or 0-143 days) post-pLDR. The pathologic diagnosis was compared to retrospectively-generated FTB maps. Results: The median patient age was 55.5 years (50-60 years). All were male with IDH-wild type (n=4) and O6-methylguanine-DNA methyltransferase (MGMT) hypermethylated (n=1) molecular markers. Pathologic diagnosis revealed treatment effect (n=2), a mixture of viable tumor and treatment effect (n=1), or viable tumor (n=1). In 3 of 4 cases, FTB maps were indicative of lesion volumes being comprised predominantly of treatment effect with enhancing tumor volumes comprised of a median of 6.8% vascular tumor (6.4-16.4%). Conclusion: This case series provides insight into the radiographic response to upfront pLDR and TMZ and the role for FTB mapping to distinguish tumor progression from treatment effect prior to redo-surgery and within 20 weeks post-radiation.

Characterization of Underrepresented Populations in Modern Era Clinical Trials Involving Radiation Therapy.

PURPOSE: The demographic composition of modern radiation therapy (RT) clinical trials is incompletely studied. Understanding and minimizing disparities in clinical trials is critical to ensure health equity and the generalizability of research findings. METHODS AND MATERIALS: Clinicaltrials.gov was searched to identify RT clinical trials that occurred from 1996 to 2019. A total of 1242 trials were reviewed for patient characteristics. The demographic composition of the studies was summarized by the frequency and percentage of patients by race, gender, and ethnicity. The racial composition of the study population was compared with the 2018 US Census using a 1-sample χ2 test. Subgroup racial composition was compared using χ2 tests of independence. Analyses used a complete case approach. RESULTS: A total of 122 trials met the inclusion criteria, and 121 of these (99.1%) reported race. Trial subgroups included 63 trials in the United States (51.6%), 9 proton therapy trials (7.4%), 34 RT toxicity mitigation or prevention trials (27.9%), 24 trials for female cancer (19.7%), and 17 trials for male cancer (13.9%). US clinical trials overall, US RT toxicity mitigation or prevention trials, US trials for female cancer, and US trials for male cancer had significantly different racial compositions compared with the 2018 US Census data (P < .001 for all). Compared with all clinical trials, those for proton therapy had the largest magnitude of significantly lower enrollment of participants who identified their race as Black, Asian, or other (P < .001). CONCLUSIONS: This study characterized the racial composition of prospective RT clinical trials in a modern cohort. The racial population represented across multiple categories in the United States differed significantly from US census data and was most pronounced in trials evaluating proton therapy. This is a benchmark study for future efforts to characterize and balance the participation of underrepresented populations in RT clinical trials.

The impact of age on outcome in phase III NRG Oncology/RTOG trials of radiotherapy (XRT) +/- systemic therapy in locally advanced head and neck cancer.

PURPOSE: To examine the role age plays in the treatment and prognosis of locally advanced head and neck cancer (LAHNC) treated definitively with radiation alone or combined modality therapy. METHODS: A retrospective analysis was performed of three NRG/RTOG trials examining either radiation alone or combined radiation and systemic therapy for LAHNC. The effect of age (≥70 yrs.) on cause-specific survival (CSS), overall survival (OS), and toxicity was evaluated. RESULTS: A total of 2688 patients were analyzed, of whom 309 patients (11.5%) were ≥ 70. For all studies combined, the hazard ratio (HR) for CSS for patients age ≥ 70 vs. those <70 was 1.33 (95%CI: 1.14-1.55, p < 0.001). For OS, the HR for patients age ≥ 70 vs. those <70 for all studies combined was 1.55 (95% CI 1.35-1.77, p < 0.001). After adjustment for all covariates, age ≥ 70 was associated with worse OS regardless of adjustment for smoking and p16 status. The survival difference was more pronounced in those receiving combined radiation and systemic therapy. Hematologic and renal toxicities were increased in combined modality trials in patients ≥70 years old. CONCLUSIONS: Patients age ≥ 70 with LAHNC were underrepresented in these clinical trials. Their CSS and OS proved inferior to patients <70 years old.

Patterns of Care, Tolerability, and Safety of the First Cohort of Patients Treated on a Novel High-Field MR-Linac Within the MOMENTUM Study: Initial Results From a Prospective Multi-Institutional Registry.

PURPOSE: High-field magnetic resonance-linear accelerators (MR-Linacs), linear accelerators combined with a diagnostic magnetic resonance imaging (MRI) scanner and online adaptive workflow, potentially give rise to novel online anatomic and response adaptive radiation therapy paradigms. The first high-field (1.5T) MR-Linac received regulatory approval in late 2018, and little is known about clinical use, patient tolerability of daily high-field MRI, and toxicity of treatments. Herein we report the initial experience within the MOMENTUM Study (NCT04075305), a prospective international registry of the MR-Linac Consortium. METHODS AND MATERIALS: Patients were included between February 2019 and October 2020 at 7 institutions in 4 countries. We used descriptive statistics to describe the patterns of care, tolerability (the percentage of patients discontinuing their course early), and safety (grade 3-5 Common Terminology Criteria for Adverse Events v.5 acute toxicity within 3 months after the end of treatment). RESULTS: A total 943 patients participated in the MOMENTUM Study, 702 of whom had complete baseline data at the time of this analysis. Patients were primarily male (79%) with a median age of 68 years (range, 22-93) and were treated for 39 different indications. The most frequent indications were prostate (40%), oligometastatic lymph node (17%), brain (12%), and rectal (10%) cancers. The median number of fractions was 5 (range, 1-35). Six patients discontinued MR-Linac treatments, but none due to an inability to tolerate repeated high-field MRI. Of the 415 patients with complete data on acute toxicity at 3-month follow-up, 18 (4%) patients experienced grade 3 acute toxicity related to radiation. No grade 4 or 5 acute toxicity related to radiation was observed. CONCLUSIONS: In the first 21 months of our study, patterns of care were diverse with respect to clinical utilization, body sites, and radiation prescriptions. No patient discontinued treatment due to inability to tolerate daily high-field MRI scans, and the acute radiation toxicity experience was encouraging.

Observations of lightning in relation to transitions in volcanic activity during the 3 June 2018 Fuego Eruption.

Satellite and ground-based remote sensing are combined to characterize lightning occurrence during the 3 June 2018 Volcán de Fuego eruption in Guatemala. The combination of the space-based Geostationary Lightning Mapper (GLM) and ground-based Earth Networks Total Lightning Network observed two distinct periods of lightning during this eruption totaling 75 unique lightning flash occurrences over five hours (57 in cloud, 18 cloud-to-ground). The first period of lightning coincided with the rapid growth of the ash cloud, while the second maxima occurred near the time of a deadly pyroclastic density current (PDC) and thunderstorm. Ninety-one percent of the lightning during the event was observed by only one of the lightning sensors, thus showing the importance of combining lightning datasets across multiple frequencies to characterize electrical activity in volcanic eruptions. GLM flashes during the event had a median total optical energy and flash length of 16 fJ, and 12 km, respectively. These median GLM flash energies and lengths observed in the volcanic plume are on the lower end of the flash spectrum because flashes observed in surrounding thunderstorms on 3 June had larger median total optical energy values (130 fJ) and longer median flash lengths (20 km). All 18 cloud-to-ground flashes were negative polarity, supportive of net negative charge within the plume. Mechanisms for the generation of the secondary lightning maxima are discussed based on the presence and potential interaction between ash plume, thunderstorm, and PDC transport during this secondary period of observed lightning.

Pulsed Reduced Dose Rate Radiotherapy in Conjunction With Bevacizumab or Bevacizumab Alone in Recurrent High-grade Glioma: Survival Outcomes.

PURPOSE: Dismal prognosis and limited treatment options for recurrent high-grade glioma have provoked interest in various forms of reirradiation. Pulsed reduced dose rate radiation therapy (pRDR) is a promising technique that exploits low-dose hyper-radiosensitivity of proliferating tumor cells while sparing adjacent nonproliferating normal brain tissue. Large radiation treatment volumes can thus be used to target both contrast-enhancing and FLAIR abnormalities thought to harbor recurrent gross and microscopic disease, respectively. The aim of this retrospective study was to determine whether the addition of pRDR to bevacizumab improves survival over bevacizumab alone for recurrent high-grade glioma. METHODS AND MATERIALS: Eighty patients with recurrent high-grade glioma were included in this study; 47 patients received bevacizumab monotherapy (BEV), and 33 patients received pRDR with bevacizumab (BEV/pRDR). Progression-free survival (PFS) and overall survival were compared between the BEV and BEV/pRDR groups. Regression analysis was performed to identify and control for confounding influences on survival analyses. RESULTS: Significant (P < .05) advantages in PFS (12 vs 4 months; hazard ratio = 2.37) and OS (16 vs. 9 months; hazard ratio = 1.68) were observed with BEV/pRDR compared with BEV alone. CONCLUSIONS: This retrospective analysis suggests that treatment with pRDR in addition to bevacizumab could significantly prolong PFS and overall survival compared with bevacizumab alone for recurrent high-grade glioma.

Lymph node yield from neck dissection in HPV-associated oropharyngeal cancer.

OBJECTIVES: To determine the influence of nodal yield during neck dissection on survival in surgically managed human papillomavirus (HPV)-associated oropharyngeal cancer. METHODS: The National Cancer Database was used to identify patients with HPV-associated tumor T1 to T2 oropharyngeal squamous cell carcinoma who underwent upfront surgery with or without adjuvant therapy. Patients were stratified by lymph node yield (<26 vs. ≥26 nodes). Multivariable Cox proportional hazards regression analysis was used to identify factors associated with overall survival. Models were stratified by pathologically positive node number. RESULTS: There were 2,554 patients identified with previously untreated T1 to T2 oropharyngeal squamous cell carcinoma who underwent resection of the primary tumor and neck dissection between 2010 and 2015. Fifty-two percent had zero to one pathologically involved lymph node. Among all study patients, lymph node harvest of ≥26 was not associated with survival when adjusted for relevant covariates (hazard ratio [HR] 0.70, 95% confidence interval [CI] 0.49-1.00). However, in patients with zero to one pathologically involved node, lymph node harvest of ≥26 was significantly associated with improved overall survival (HR 0.29, 95% CI 0.20-0.78). This survival benefit was lost in patients with two or more positive nodes (2-4 positive nodes: HR 0.89, 95% CI 0.52-1.51; 5 or more positive nodes: HR 1.01, 95% CI 0.47-2.20). CONCLUSION: For patients with surgically managed early T-stage HPV-associated oropharyngeal squamous cell carcinoma, lymph node yield was not associated with survival outcomes for patients with multiple positive lymph nodes. Those with a more limited burden of regional metastatic disease, however, may benefit harvest of at least 26 nodes during neck dissection. LEVEL OF EVIDENCE: 4 Laryngoscope, 130:666-671, 2020.

Comprehensive Genomic Analysis in NRG Oncology/RTOG 9802: A Phase III Trial of Radiation Versus Radiation Plus Procarbazine, Lomustine (CCNU), and Vincristine in High-Risk Low-Grade Glioma.

PURPOSE: NRG Oncology/RTOG 9802 (ClinicalTrials.gov Identifier: NCT00003375) is a practice-changing study for patients with WHO low-grade glioma (LGG, grade II), as it was the first to demonstrate a survival benefit of adjuvant chemoradiotherapy over radiotherapy. This post hoc study sought to determine the prognostic and predictive impact of the WHO-defined molecular subgroups and corresponding molecular alterations within NRG Oncology/RTOG 9802. METHODS: IDH1/2 mutations were determined by immunohistochemistry and/or deep sequencing. A custom Ion AmpliSeq panel was used for mutation analysis. 1p/19q codeletion and MGMT promoter methylation were determined by copy-number arrays and/or Illumina 450K array, respectively. Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method. Hazard ratios (HRs) were calculated using the Cox proportional hazard model and tested using the log-rank test. Multivariable analyses (MVAs) were performed incorporating treatment and common prognostic factors as covariates. RESULTS: Of the eligible patients successfully profiled for the WHO-defined molecular groups (n = 106/251), 26 (24%) were IDH-wild type, 43 (41%) were IDH-mutant/non-codeleted, and 37(35%) were IDH-mutant/codeleted. MVAs demonstrated that WHO subgroup was a significant predictor of PFS after adjustment for clinical variables and treatment. Notably, treatment with postradiation chemotherapy (PCV; procarbazine, lomustine (CCNU), and vincristine) was associated with longer PFS (HR, 0.32; P = .003; HR, 0.13; P < .001) and OS (HR, 0.38; P = .013; HR, 0.21; P = .029) in the IDH-mutant/non-codeleted and IDH-mutant/codeleted subgroups, respectively. In contrast, no significant difference in either PFS or OS was observed with the addition of PCV in the IDH-wild-type subgroup. CONCLUSION: This study is the first to report the predictive value of the WHO-defined diagnostic classification in a set of uniformly treated patients with LGG in a clinical trial. Importantly, this post hoc analysis supports the notion that patients with IDH-mutant high-risk LGG regardless of codeletion status receive benefit from the addition of PCV.