Immune checkpoint inhibition and single fraction stereotactic radiosurgery in brain metastases from non-small cell lung cancer: an international multicenter study of 395 patients.

PURPOSE: Approximately 80% of brain metastases originate from non-small cell lung cancer (NSCLC). Immune checkpoint inhibitors (ICI) and stereotactic radiosurgery (SRS) are frequently utilized in this setting. However, concerns remain regarding the risk of radiation necrosis (RN) when SRS and ICI are administered concurrently. METHODS: A retrospective study was conducted through the International Radiosurgery Research Foundation. Logistic regression models and competing risks analyses were utilized to identify predictors of any grade RN and symptomatic RN (SRN). RESULTS: The study included 395 patients with 2,540 brain metastases treated with single fraction SRS and ICI across 11 institutions in four countries with a median follow-up of 14.2 months. The median age was 67 years. The median margin SRS dose was 19 Gy; 36.5% of patients had a V12 Gy ≥ 10 cm3. On multivariable analysis, V12 Gy ≥ 10 cm3 was a significant predictor of developing any grade RN (OR: 2.18) and SRN (OR: 3.95). At 1-year, the cumulative incidence of any grade and SRN for all patients was 4.8% and 3.8%, respectively. For concurrent and non-concurrent groups, the cumulative incidence of any grade RN was 3.8% versus 5.3%, respectively (p = 0.35); and for SRN was 3.8% vs. 3.6%, respectively (p = 0.95). CONCLUSION: The risk of any grade RN and symptomatic RN following single fraction SRS and ICI for NSCLC brain metastases increases as V12 Gy exceeds 10 cm3. Concurrent ICI and SRS do not appear to increase this risk. Radiosurgical planning techniques should aim to minimize V12 Gy.

Accelerated hypofractionated radiation for elderly or frail patients with a newly diagnosed glioblastoma: A pooled analysis of patient-level data from 4 prospective trials.

BACKGROUND: The standard of care for elderly or frail patients with glioblastoma (GBM) is 40 Gy in 15 fractions of radiotherapy. However, this regimen has a lower biological effective dose (BED) compared with the Stupp regimen of 60 Gy in 30 fractions. It is hypothesized that accelerated hypofractionated radiation of 52.5 Gy in 15 fractions (BED equivalent to Stupp) is safe and efficacious. METHODS: Elderly or frail patients with GBM treated with 52.5 Gy in 15 fractions were pooled from 3 phase 1/2 studies and a prospective observational study. Overall survival (OS) and progression-free survival (PFS) were defined time elapsing between surgery/biopsy and death from any cause or progression of disease. RESULTS: Sixty-two newly diagnosed patients were eligible for this pooled analysis of individual patient data. The majority (66%) had a Karnofsky performance status (KPS) score <70. The median age was 73 years. The median OS and PFS were 10.3 and 6.9 months, respectively. Patients with KPS scores ≥70 and <70 had a median OS of 15.3 and 9.5 months, respectively. Concurrent chemotherapy was an independent prognostic factor for improved PFS and OS. Grade 3 neurologic toxicity was seen in 2 patients (3.2%). There was no grade 4/5 toxicity. CONCLUSIONS: This is the only analysis of elderly/frail patients with GBM prospectively treated with a hypofractionated radiation regimen that is isoeffective to the Stupp regimen. Treatment was well tolerated and demonstrated excellent OS and PFS compared with historical studies. This regimen gives the elderly/frail population an alternative to regimens with a lower BED. Randomized trials are needed to validate these results.

Radiation necrosis in renal cell carcinoma brain metastases treated with checkpoint inhibitors and radiosurgery: An international multicenter study.

BACKGROUND: Patients with renal cell carcinoma (RCC) brain metastases are frequently treated with immune checkpoint inhibitors (ICIs) and stereotactic radiosurgery (SRS). However, data reporting on the risk of developing radiation necrosis (RN) are limited. METHODS: RN rates were compared for concurrent therapy (ICI/SRS administration within 4 weeks of one another) and nonconcurrent therapy with the χ2 test. Univariable logistic regression was used to identify factors associated with developing RN. RESULTS: Fifty patients (23 concurrent and 27 nonconcurrent) with 395 brain metastases were analyzed. The median follow-up was 12.1 months; the median age was 65 years. The median margin dose was 20 Gy, and 4% underwent prior whole-brain radiation therapy (WBRT). The median treated tumor volume was 3.32 cm3 (range, 0.06-42.38 cm3 ); the median volume of normal brain tissue receiving a dose of 12 Gy or higher (V12 Gy) was 8.42 cm3 (range, 0.27-111.22 cm3 ). Any-grade RN occurred in 17.4% and 22.2% in the concurrent and nonconcurrent groups, respectively (P = .67). Symptomatic RN occurred in 4.3% and 14.8% in the concurrent and nonconcurrent groups, respectively (P = .23). Increased tumor volume during SRS (odds ratio [OR], 1.08; 95% confidence interval [CI], 1.01-1.19; P = .04) was associated with developing RN, although V12 Gy (OR, 1.03; 95% CI, 0.99-1.06; P = .06), concurrent therapy (OR, 0.74; 95% CI, 0.17-2.30; P = .76), prior WBRT, and ICI agents were not statistically significant. CONCLUSIONS: Symptomatic RN occurs in a minority of patients with RCC brain metastases treated with ICI/SRS. The majority of events were grade 1 to 3 and were managed medically. Concurrent ICI/SRS does not appear to increase this risk. Attempts to improve dose conformality (reduce V12) may be the most successful mitigation strategy in single-fraction SRS.

Fractionated pre-operative stereotactic radiotherapy for patients with brain metastases: a multi-institutional analysis.

BACKGROUND: The current standard of care for patients with a large brain metastasis and limited intracranial disease burden is surgical resection and post-operative single fraction stereotactic radiosurgery (SRS). However, post-operative SRS can still lead to substantial rates of local failure (LF), radiation necrosis (RN), and meningeal disease (MD). Pre-operative SRS may reduce the risk of RN and MD, while fractionated treatments may improve local control by allowing delivery of higher biological effective dose. We hypothesize that pre-operative fractionated stereotactic radiation therapy (FSRT) can minimize rates of LF, RN, and MD. METHODS: A retrospective, multi-institutional analysis was conducted and included patients who had pre-operative FSRT for a large or symptomatic brain metastasis. Pertinent demographic, clinical, radiation, surgical, and follow up data were collected for each patient. A primary measurement was the rate of a composite endpoint of (1) LF, (2) MD, and/or (3) Grade 2 or higher (symptomatic) RN. RESULTS: 53 patients with 55 lesions were eligible for analysis. FSRT was prescribed to a dose of 24-25 Gy in 3-5 fractions. There were 0 LFs, 3 Grade 2-3 RN events, and 1 MD occurrence, which corresponded to an 8% per-patient composite endpoint event rate. CONCLUSIONS: In this study, the composite endpoint of 8% for pre-operative FSRT was improved compared to previously reported rates with post-operative SRS of 49-60% (N107C, Mahajan etal. JCOG0504) and pre-operative SRS endpoints of 20.6% (PROPS-BM). Pre-operative FSRT appears to be safe, effective, and may decrease the incidence of adverse outcomes. Prospective validation is needed.

A genome-wide analysis of colorectal cancer in a child with Noonan syndrome.

Noonan syndrome (NS) is a developmental syndrome caused by germline mutations in the Ras signaling pathway. No association has been shown between NS and pediatric colorectal cancer (CRC). We report the case of CRC in a pediatric patient with NS. The patient underwent whole genome sequencing. A germline SOS1 mutation c.1310T>C (p. Ile437Thr) confirmed NS diagnosis. No known hereditary cancer syndromes were identified. Tumor analysis revealed two mutations: a TP53 missense mutation c.481G>A (p. Ala161Tyr) and NCOR1 nonsense mutation c.6052C>T (p. Arg2018*). This report highlights the complexity of Ras signaling and the interplay between developmental syndromes and cancer.

Real-time vascular mechanosensation through ex vivo artery perfusion.

BACKGROUND: Cell-based perfusion studies have provided great insight into fluid-sensing mechanisms, such as primary cilia in the renal and vascular systems. However, the intrinsic limitations of in vitro cell culture, such as the inability to reflect cellular organization within tissues, has distanced observed paradigms from possible clinical developments. Here we describe a protocol that applies ex vivo artery perfusion and calcium imaging to observe real-time cellular responses to fluid-shear stress. RESULTS: Through our ex vivo artery perfusion method, we were able to simulate physiological flow and initiate distinct fluid shear stress mechanosensory responses, as well as induced acetylcholine responses in mouse aortic tissue. The observed calcium profiles confirm results found through previous in vitro cell culture experiments. The overall procedure, including dissection, sample preparation and perfusion, takes around 3 hours to complete. CONCLUSION: Through our unique method, we are able to induce laminar flow within intact mouse aortic tissue and illicit subsequent cellular responses. This method of ex vivo artery perfusion provides the opportunity to bridge the novel findings of in vitro studies with subsequent physiological models of fluid-shear stress mechanosensation in vascular tissues.

Three types of ependymal cells with intracellular calcium oscillation are characterized by distinct cilia beating properties.

Ependymal cells are multiciliated epithelial cells that line the ventricles in the adult brain. Abnormal function or structure of ependymal cilia has been associated with various neurological deficits. For the first time, we report three distinct ependymal cell types, I, II, and III, based on their unique ciliary beating frequency and beating angle. These ependymal cells have specific localizations within the third ventricle of the mouse brain. Furthermore, neither ependymal cell types nor their localizations are altered by aging. Our high-speed fluorescence imaging analysis reveals that these ependymal cells have an intracellular pacing calcium oscillation property. Our study further shows that alcohol can significantly repress the amplitude of calcium oscillation and the frequency of ciliary beating, resulting in an overall decrease in volume replacement by the cilia. Furthermore, the pharmacological agent cilostazol could differentially increase cilia beating frequency in type II, but not in type I or type III, ependymal cells. In summary, we provide the first evidence of three distinct types of ependymal cells with calcium oscillation properties.

Accuracy of ringless casting and accelerated wax-elimination technique: a comparative in vitro study.

PURPOSE: The purpose of this study was to determine whether the ringless casting and accelerated wax-elimination techniques can be combined to offer a cost-effective, clinically acceptable, and time-saving alternative for fabricating single unit castings in fixed prosthodontics. MATERIALS AND METHODS: Sixty standardized wax copings were fabricated on a type IV stone replica of a stainless steel die. The wax patterns were divided into four groups. The first group was cast using the ringless investment technique and conventional wax-elimination method; the second group was cast using the ringless investment technique and accelerated wax-elimination method; the third group was cast using the conventional metal ring investment technique and conventional wax-elimination method; the fourth group was cast using the metal ring investment technique and accelerated wax-elimination method. The vertical marginal gap was measured at four sites per specimen, using a digital optical microscope at 100× magnification. The results were analyzed using two-way ANOVA to determine statistical significance. RESULTS: The vertical marginal gaps of castings fabricated using the ringless technique (76.98 ± 7.59 µm) were significantly less (p < 0.05) than those castings fabricated using the conventional metal ring technique (138.44 ± 28.59 µm); however, the vertical marginal gaps of the conventional (102.63 ± 36.12 µm) and accelerated wax-elimination (112.79 ± 38.34 µm) castings were not statistically significant (p > 0.05). CONCLUSIONS: The ringless investment technique can produce castings with higher accuracy and can be favorably combined with the accelerated wax-elimination method as a vital alternative to the time-consuming conventional technique of casting restorations in fixed prosthodontics.

Hypofractionated Radiation Therapy: A Cross-sectional Survey Study of US Radiation Oncologists.

OBJECTIVES: For many malignancies, hypofractionated radiotherapy (HFRT) is an accepted standard associated with decreased treatment time and costs. United States provider beliefs regarding HFRT likely impact its adoption but are poorly studied. We surveyed US-based radiation oncologists (ROs) to gauge HFRT utilization rates for prostate (PC), breast (BC), and rectal cancer (RC) and to characterize the beliefs governing these decisions. METHODS: From July to October 2021, an anonymized, online survey was electronically distributed to ROs actively practicing in the United States. Demographic and practice characteristic information was collected. Questions assessing rates of offering HFRT for PC, BC, and RC and perceived limitations towards using HFRT were administered. RESULTS: A total of 203 eligible respondents (72% male, 72% White, 53% nonacademic practice, 69% with 11+ years in practice) were identified. Approximately 50% offered stereotactic body radiation therapy (SBRT) for early/favorable intermediate risk PC. Although >90% of ROs offered whole-breast HFRT for early-stage BC, only 33% offered accelerated partial-breast irradiation (APBI). Overall, 41% of ROs offered short-course neoadjuvant RT for RC. The primary reported barriers to HFRT utilization were lack of data, inexperience, and referring provider concerns. CONCLUSIONS: HFRT is safe, effective, and beneficial, yet underutilized-particularly prostate SBRT, APBI, and short-course RT for RC. Skills retraining and education of ROs and referring providers may increase utilization rates.

Targeting DHX9 Triggers Tumor-Intrinsic Interferon Response and Replication Stress in Small Cell Lung Cancer.

Activating innate immunity in cancer cells through cytoplasmic nucleic acid sensing pathways, a phenomenon known as "viral mimicry," has emerged as an effective strategy to convert immunologically "cold" tumors into "hot." Through a curated CRISPR-based screen of RNA helicases, we identified DExD/H-box helicase 9 (DHX9) as a potent repressor of double-stranded RNA (dsRNA) in small cell lung cancers (SCLC). Depletion of DHX9 induced accumulation of cytoplasmic dsRNA and triggered tumor-intrinsic innate immunity. Intriguingly, ablating DHX9 also induced aberrant accumulation of R-loops, which resulted in an increase of DNA damage-derived cytoplasmic DNA and replication stress in SCLCs. In vivo, DHX9 deletion promoted a decrease in tumor growth while inducing a more immunogenic tumor microenvironment, invigorating responsiveness to immune-checkpoint blockade. These findings suggest that DHX9 is a crucial repressor of tumor-intrinsic innate immunity and replication stress, representing a promising target for SCLC and other "cold" tumors in which genomic instability contributes to pathology. SIGNIFICANCE: One promising strategy to trigger an immune response within tumors and enhance immunotherapy efficacy is by inducing endogenous "virus-mimetic" nucleic acid accumulation. Here, we identify DHX9 as a viral-mimicry-inducing factor involved in the suppression of double-stranded RNAs and R-loops and propose DHX9 as a novel target to enhance antitumor immunity. See related commentary by Chiappinelli, p. 389. This article is featured in Selected Articles from This Issue, p. 384.

AIDS-Related Kaposi Sarcoma Associated with Steroid-Unresponsive Periorbital Lymphedema that Responded to Chemotherapy.

BACKGROUND As an AIDS-defining illness, the neoplasm Kaposi sarcoma (KS) classically presents as cutaneous lesions that are often associated with periorbital edema. This association with KS is important because it frequently leads to the misuse of steroids in HIV-infected patients. This report presents 2 cases of AIDS-related Kaposi sarcoma (AIDS-KS) associated with severe steroid-unresponsive periorbital lymphedema that responded to chemotherapy. CASE REPORT Case 1: A 30-year-old African-American man with KS-related periorbital edema suffered progression after receiving multiple corticosteroids for a presumed hypersensitivity reaction. After multiple hospitalizations, the patient's KS had disseminated, and he eventually opted for hospice. Case 2: A 29-year-old White male with recurrent facial edema had been repeatedly treated with corticosteroids for impending anaphylaxis reactions. He had multiple admissions with similar presentations, and it was found that his KS had progressed. After receiving chemotherapy, his facial edema has not recurred. CONCLUSIONS The failure to recognize periorbital edema as tumor-associated edema has direct consequences for the management of AIDS-KS. In addition to a delay in administering chemotherapy, the mischaracterization of periorbital edema as a hypersensitivity/allergic reaction often prompts the use of corticosteroids, potentially exacerbating the underlying AIDS-KS. Despite the current evidence, clinicians continue to order steroids in advanced AIDS-KS patients presenting with periorbital edema. Although that management is started with the best intentions and done with concerns for airway compromise, this anchoring bias could lead to devastating consequences and a rather poor prognosis.

Prostate brachytherapy utilization in the COVID-19 era: A cross-sectional study of radiation oncologists in the United States.

PURPOSE: Despite advantages such as abbreviated treatment course, brachytherapy (BT) utilization rates for prostate cancer (PC) in the United States (US) are declining. We surveyed practicing US radiation oncologists (ROs) to determine the proportion who offer BT for PC and whether the COVID-19 pandemic influenced practice patterns. MATERIALS AND METHODS: From July-October 2021, we surveyed practicing US ROs. Provider demographic and practice characteristics were collected. Questions assessing utilization of BT and external beam (EBRT) for patients of varying risk groups and the effect of the pandemic on practice patterns were administered. Descriptive statistics were reported. The bivariate relationships between provider characteristics and likelihood of offering BT were assessed using the Chi-square test (α < 0.05). RESULTS: Six percent of surveyed ROs responded, with 203 meeting inclusion criteria (72% male, 72% white, 53% non-academic, 69% >10 years in practice) and 156 (77%) treating PC. For low-risk, fewer providers offered BT (41% total; 25% low dose rate [LDR], 10% high dose rate [HDR], 6% both) than stereotactic body (SBRT) (54%) and moderately hypofractionated radiation therapy (MHFRT) (83%). For favorable intermediate risk, fewer offered BT (37% total; 21% LDR, 10% HDR, 6% both) than SBRT (48%), MHFRT (87%), and conventionally fractionated EBRT (38%). For high (44%) and very-high (37%) risk, fewer offered EBRT+BT than EBRT alone. For every risk group, academic ROs were significantly more likely to offer BT (all p-values<0.05). <1% of respondents reported increased pandemic-related BT usage. CONCLUSIONS: US ROs, particularly in non-academic settings, do not routinely offer BT monotherapy or boost (<50%). Practice patterns were unaffected by COVID-19. Retraining may be critical to increasing utilization.

Exposure to radon and heavy particulate pollution and incidence of brain tumors.

BACKGROUND: Global incidence for brain tumors varies substantially without explanation. Studies correlating radon exposure and incidence are inconclusive. Particulate pollution has been linked to increased tumor incidence. Particulates may disrupt the blood-brain barrier allowing intracranial exposure to oncogenic radon. We investigated the relationship between exposure to residential radon, particulate pollution, and brain tumor incidence in the United States (US). METHODS: County-level median radon testing results and annual air quality index values were obtained and divided into tertiles. Counties without both values were excluded. Four groups of counties were generated: high particulate/high radon (high/high), high/low, low/high, and low/low. Using incidence data from the Central Brain Tumor Registry of the US (provided by CDC's National Program of Cancer Registries and NCI's SEER), annual age-adjusted incidence rates (AAAIRs) by group were generated by behavior. Incidence rate ratios were calculated to examine for significant differences (α = .05). Poisson regression accounting for possible confounders was conducted. RESULTS: Counties with available data included 83% of the US population. High/high exposure was significantly associated with increased AAAIR of all non-malignant tumors (up to 26% higher, including most meningiomas) even after accounting for potential confounders. An increased AAAIR was noted for all malignant tumors (up to 10% higher), including glioblastoma, but was negated after accounting for demographic/socioeconomic differences. CONCLUSIONS: We present the first report suggesting increased non-malignant brain tumor incidence in regions with high particulate and radon exposure. These findings provide insight into unexplained variation in tumor incidence. Future studies are needed to validate these findings in other populations.

Comparing pre-operative versus post-operative single and multi-fraction stereotactic radiotherapy for patients with resectable brain metastases.

Background: The standard treatment for patients with large brain metastases and limited intracranial disease is surgical resection and post-operative stereotactic radiosurgery (SRS). However, post-operative SRS still has elevated rates of local failure (LF) and is complicated by radiation necrosis (RN), and meningeal disease (MD). Pre-operative SRS may reduce the risk of RN and MD, while fractionated therapy may improve local control through delivering a higher biological effective dose. We hypothesize that pre-operative fractionated stereotactic radiation therapy (FSRT) will have less toxicity compared to patients who receive post-operative SRS or FSRT. Methods: A multi-institutional analysis was conducted and included patients who had surgical resection and stereotactic radiation therapy to treat at least one brain metastasis. Pertinent demographic, clinical, radiation, surgical, and follow up data were collected for each patient. The primary outcome was a composite endpoint defined as patients with one of the following adverse events: 1) LF, 2) MD, and/or 3) Grade 2 or higher (symptomatic) RN. Results: 279 patients were eligible for analysis. The median follow-up time was 9 months. 87 % of patients received fractionated treatment. 29 % of patients received pre-operative treatment. The composite endpoint incidences for post-operative SRS (n = 10), post-operative FSRT (n = 189), pre-operative SRS (n = 27), and pre-operative FSRT (n = 53) were 0 %, 17 %, 15 %, and 7.5 %, respectively. Conclusions: In our study, the composite endpoint of 7.5% for pre-operative FSRT compares favorably to our post-operative FSRT rate of 17%. Pre-operative FSRT was observed to have low rates of LF, MD, and RN. Prospective validation is needed.

Imaging-defined necrosis after treatment with single-fraction stereotactic radiosurgery and immune checkpoint inhibitors and its potential association with improved outcomes in patients with brain metastases: an international multicenter study of 697 patients.

OBJECTIVE: Immune checkpoint inhibitors (ICIs) and stereotactic radiosurgery (SRS) are commonly utilized in the management of brain metastases. Treatment-related imaging changes (TRICs) are a frequently observed clinical manifestation and are commonly classified as imaging-defined radiation necrosis. However, these findings are not well characterized and may predict a response to SRS and ICIs. The objective of this study was to investigate predictors of TRICs and their impact on patient survival. METHODS: This retrospective multicenter cohort study was conducted through the International Radiosurgery Research Foundation. Member institutions submitted de-identified clinical and dosimetric data for patients with non-small cell lung cancer (NSCLC), melanoma, and renal cell carcinoma (RCC) brain metastases that had been treated with SRS and ICIs. Data were collected from March 2020 to February 2021. Univariable and multivariable Cox and logistic regression analyses were performed. The Kaplan-Meier method was used to evaluate overall survival (OS). The diagnosis-specific graded prognostic assessment was used to guide variable selection. TRICs were determined on the basis of MRI, PET/CT, or MR spectroscopy, and consensus by local clinical providers was required. RESULTS: The analysis included 697 patients with 4536 brain metastases across 11 international institutions in 4 countries. The median follow-up after SRS was 13.6 months. The median age was 66 years (IQR 58-73 years), 54.1% of patients were male, and 57.3%, 36.3%, and 6.4% of tumors were NSCLC, melanoma, and RCC, respectively. All patients had undergone single-fraction radiosurgery to a median margin dose of 20 Gy (IQR 18-20 Gy). TRICs were observed in 9.8% of patients. The median OS for all patients was 24.5 months. On univariable analysis, Karnofsky Performance Status (KPS; HR 0.98, p < 0.001), TRICs (HR 0.67, p = 0.03), female sex (HR 0.67, p < 0.001), and prior resection (HR 0.60, p = 0.03) were associated with improved OS. On multivariable analysis, KPS (HR 0.98, p < 0.001) and TRICs (HR 0.66, p = 0.03) were associated with improved OS. A brain volume receiving ≥ 12 Gy of radiation (V12Gy) ≥ 10 cm3 (OR 2.78, p < 0.001), prior whole-brain radiation therapy (OR 3.46, p = 0.006), and RCC histology (OR 3.10, p = 0.01) were associated with an increased probability of developing TRICs. The median OS rates in patients with and without TRICs were 29.0 and 23.1 months, respectively (p = 0.03, log-rank test). CONCLUSIONS: TRICs following ICI and SRS were associated with a median OS benefit of approximately 6 months in this retrospective multicenter study. Further prospective study and additional stratification are needed to validate these findings and further elucidate the role and etiology of this common clinical scenario.

Concurrent Administration of Immune Checkpoint Inhibitors and Single Fraction Stereotactic Radiosurgery in Patients With Non-Small Cell Lung Cancer, Melanoma, and Renal Cell Carcinoma Brain Metastases.

PURPOSE: Stereotactic radiosurgery (SRS) and immune checkpoint inhibitors (ICI) are highly effective treatments for brain metastases, particularly when these therapies are administered concurrently. However, there are limited data reporting the risk of radiation necrosis (RN) in this setting. METHODS AND MATERIALS: Patients with brain metastases from primary non-small cell lung cancer, renal cell carcinoma, or melanoma treated with SRS and ICI were considered. Time-to-event analyses were conducted for any grade RN and symptomatic RN (SRN) with death incorporated as a competing risk. As a secondary analysis, recursive partitioning analysis (RPA) was used for model development, and a loop of potential models was analyzed, with the highest-fidelity model selected. Brain V12 Gy thresholds identified on RPA were then incorporated into the competing risks analysis. Concurrent SRS and ICI administration. RESULTS: Six hundred fifty-seven patients with 4182 brain metastases across 11 international institutions were analyzed. The median follow-up for all patients was 13.4 months. The median follow-up was 12.8 months and 14.1 months for the concurrent and nonconcurrent groups, respectively (P = .03). The median patient age was 66 years, and the median Karnofsky Performance Status was 90. In patients with any grade RN, 1- and 2-year rates were 6.4% and 9.9%, respectively. In patients with SRN, 1- and 2-year rates were 4.8% and 7.2%, respectively. On RPA, the highest-fidelity models consistently identified V12 Gy as the dominant variable predictive of RN. Three risk groups were identified by V12 Gy: (1) < 12 cm3; (2) 20 cm3 ≥ V12 Gy ≥ 12 cm3; (3) V12 Gy > 20 cm3. In patients with any grade RN, 1-year rates were 3.7% (V12 Gy < 12 cm3), 10.3% (20 cm3 ≥ V12 Gy ≥ 12 cm3), and 12.6% (V12 Gy > 20 cm3); the 2-year rates were 7.5% (V12 Gy < 12 cm3), 13.8% (20 cm3 ≥ V12 Gy ≥ 12 cm3), and 15.4% (V12 Gy > 20 cm3) (P < 0.001). In patients with any SRN, 1-year rates were 2.4% (V12 Gy < 12 cm3), 8.9% (20 cm3 ≥ V12 Gy ≥ 12 cm3), and 10.3% (V12 Gy > 20 cm3); the 2-year rates were 4.4% (V12 Gy < 12 cm3), 12.4% (20 cm3 ≥ V12 Gy ≥ 12 cm3), and 13.1% (V12 Gy > 20 cm3; P < 0.001). There were no statistically significant differences in rates of any grade RN or SRN when accounting for therapy timing for all patients and by V12 risk group identified on RPA. CONCLUSIONS: The use of SRS and ICI results in a low risk of any grade RN and SRN. This risk is not increased with concurrent administration. Therefore, ICI can safely be administered within 4-weeks of SRS. Three risk groups based on V12 Gy were identified, which clinicians may consider to further reduce rates of RN.

COVID-19 Booster Vaccine Equity for Patients With Cancer.

COVID-19 has caused greater than 300 million documented infections worldwide including over 5 million confirmed deaths. Patients with cancer are particularly vulnerable due to a combination of disease and therapy-related effects. Available vaccines were highly effective against the original viral strains in clinical trials. However, initial vaccination efforts in this vulnerable population were impacted by federal policy that created substantial vaccine scarcity and allocation difficulties by recommending prioritization of unmanageably large patient populations including the entire elderly population and patients over the age of 16 with broadly defined, high-risk medical conditions (including cancer). We found that these overly broad recommendations led nearly two-thirds of states to elect not to give adequate vaccination priority to patients with cancer, exposing this vulnerable population to potentially preventable infection. With the virulent omicron variant spreading rapidly, there is newfound concern about waning immunity, particularly in immunocompromised populations. To address this issue, the Centers for Disease Control is recommending boosters for patients who meet age, occupational exposure, or medical criteria, in similar fashion to recommendations during the initial vaccination phase. Thus, this approach raises the question of whether state-level decisions on how to sub prioritize may inadvertently once again result in delayed immunizations for particularly vulnerable subgroups - such as patients with cancer. We discuss the implications of this public health policy on the likelihood of timely re-vaccination of patients with cancer. With the omicron variant continuing its unchecked global spread, equitable distribution of booster immunizations is critical to minimizing inherent medical and socioeconomic inequities in COVID-related morbidity and mortality.

Lack of Cardiotoxicity Endpoints in Prospective Trials Involving Chest Radiation Therapy: A Review of Registered, Latter-Phase Studies.

BACKGROUND: Chest radiation therapy (RT) has been associated with increased cardiac morbidity and mortality in numerous studies including the landmark Darby study published in 2013 demonstrating a linear increase in cardiac mortality with increasing mean heart radiation dose. However, the extent to which cardiotoxicity has been incorporated as an endpoint in prospective RT studies remains unknown. METHODS: We queried clincaltrials.gov to identify phase II/III trials in lung, esophageal, lymphoma, mesothelioma, thymoma, or breast cancer from 1/1/2006-2/1/2021 enrolling greater than 100 patients wherein chest RT was delivered in at least one treatment arm. The primary endpoint was the rate of inclusion of cardiotoxicity as a specific primary or secondary endpoint in the pre- (enrollment started prior to 1/1/2014) versus post-Darby era using the Chi-square test (p<0.05 considered significant). We also analyzed clinical trial factors associated with the inclusion of cardiotoxicity as an endpoint using logistic regression analysis. RESULTS: In total, 1,822 trials were identified, of which 256 merited inclusion. 32% were for esophageal, 31% lung, 28% breast, and 7% lymphoma/thymoma/mesothelioma cancers, respectively. 5% (N=13) included cardiotoxicity as an endpoint: 6 breast cancer, 3 lung cancer, 3 esophageal cancer, and 1 lymphoma study. There was no difference in the inclusion of cardiotoxicity endpoints in the pre-Darby versus post-Darby era (3.9% vs. 5.9%, P=0.46). The greatest absolute increase in inclusion of cardiotoxicity as an endpoint was seen for lung cancer (0% vs. 6%, p=0.17) and breast cancer (5.7% vs. 10.8%, p=0.43) studies, though these increases remained statistically non-significant. We found no clinical trial factors associated with the inclusion of cardiotoxicity as an endpoint. CONCLUSIONS: Among prospective trials involving chest RT, cardiotoxicity remains an uncommon endpoint despite its prevalence as a primary source of toxicity following treatment. In order to better characterize cardiac toxicities, future prospective studies involving chest RT should include cardiotoxicity endpoints.

Financial Toxicity as an End Point in Prospective Clinical Trials Involving Radiation Therapy.

Prior research, predominately retrospective, has increased awareness that patients with cancer are at elevated risk for financial toxicity (FT). Radiation therapy (RT) can be particularly disruptive due to weeks of daily treatments. Yet, FT in patients receiving RT is less studied, and the extent to which FT has been incorporated as an end point in prospective clinical trials involving RT is unknown. Clinicaltrials.gov was queried to identify all observational or interventional studies from 2001 to 2020 wherein RT was administered for cancer. Studies with primary, secondary, or exploratory FT end points were identified through keyword search. For trials incorporating FT outcomes, pertinent study characteristics were collected. Detailed information regarding FT measures was recorded. Descriptive statistics, including frequency counts and proportions, were performed. The overall rate of inclusion of FT end points was calculated, and rates over 5-year intervals were compared using the χ2 test (α = 0.05). Overall, 10,550 studies involving RT were identified, of which 88 reported FT end points (0.8%). Included FT end points were typically secondary (78%), with just 15 studies (17%), including primary end points. Notably, only 19 studies (22%) reported a standalone FT end point. The majority measured FT as part of a larger quality of life (QoL) questionnaire. The rate of inclusion of FT end points significantly increased over time from 0.1% from 2001 to 2005 to 1.5% from 2016 to 2020, (P < .0001). FT is a major stressor for patients with cancer, yet even after a relative increase over time, the absolute rate of inclusion of FT end points remains low among RT-based trials. When included, FT outcomes were typically a single question within a QoL assessment not validated as a standalone measure of FT, preventing meaningful study and inference. To characterize and mitigate this burden more accurately, future prospective studies should include FT end points with greater frequency.

Cost Comparison From a Patient Perspective for Intracranial Stereotactic Radiation Therapy.

PURPOSE: Historically, opaque health care pricing in the US has prevented patients from identifying opportunities to lower costs. Attempting to promote price transparency, the US government recently mandated that hospitals publish prices for all services in a document called a chargemaster. Patients often travel to tertiary centers for intracranial stereotactic radiation therapy (SRT), but cost comparison is complicated by multiple delivery systems and fractionation schemes. We hypothesized that prices published in chargemasters vary widely between SRT techniques and institutions. METHODS AND MATERIALS: We obtained chargemasters published online by National Cancer Institute-designated clinical centers. Technical charges for Gamma Knife single-fraction stereotactic radiosurgery (GK), single-fraction linear-accelerator stereotactic radiation surgery (SRS), and 3-fraction fractionated stereotactic radiation therapy (FSRT) were obtained from chargemasters by billing code and keyword searches. Prices were adjusted by the Medicare geographic cost price index (GPCI). Pairwise comparisons were conducted to compare prices between modalities and geographic regions. Relationships with cost index were examined using Spearman correlations, as was the price interrelationship between modalities across institutions. RESULTS: Of 62 chargemasters obtained, 58 listed SRT prices. Median prices were $49,529 for GK, $31,834 for FSRT, and $22,915 for SRS. Prices varied widely, with large ranges corresponding to 2 to 9 times the magnitude of median prices (GK, $111,298; FSRT, $312,480; and SRS, $104,396). Adjusting for GPCI, GK (P = .0003) and FSRT (P = .001) were more expensive than SRS, and no difference in price was noted between regions. The FSRT price was positively correlated with GPCI (P = .033), but prices for the other techniques were not. Modality prices were all positively correlated (all P < .001), meaning that institutions with prices greater than the median price for SRS were similarly expensive for GK and FSRT. CONCLUSIONS: Published prices for SRT vary by delivery system, fractionation, and institution without a clear explanation. Obtaining personalized price estimates may offer cost savings for patients. Policy changes encouraging reliable access to insurer-negotiated cost estimates for SRT are needed.