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.

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.

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.

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.

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.

Feasibility, safety, and efficacy of circumferential spine stereotactic body radiotherapy.

Background: With advances in systemic therapy translating to improved survival in metastatic malignancies, spine metastases have become an increasingly common source of morbidity. Achieving durable local control (LC) for patients with circumferential epidural disease can be particularly challenging. Circumferential stereotactic body radiotherapy (SBRT) may offer improved LC for circumferential vertebral and/or epidural metastatic spinal disease, but prospective (and retrospective) data are extremely limited. We sought to evaluate the feasibility, toxicity, and cancer control outcomes with this novel approach to circumferential spinal disease. Methods: We retrospectively identified all circumferential SBRT courses delivered between 2013 and 2019 at a tertiary care institution for post-operative or intact spine metastases. Radiotherapy was delivered to 14-27.5 Gy in one to five fractions. Feasibility was assessed by determining the proportion of plans for which ≥95% planning target volume (PTV) was coverable by ≥95% prescription dose. The primary endpoint was 1-year LC. Factors associated with increased likelihood of local failure (LF) were explored. Acute and chronic toxicity were assessed. Detailed dosimetric data were collected. Results: Fifty-eight patients receiving 64 circumferential SBRT courses were identified (median age 61, KPS ≥70, 57% men). With a median follow-up of 15 months, the 12-month local control was 85% (eight events). Five and three recurrences were in the epidural space and bone, respectively. On multivariate analysis, increased PTV and uncontrolled systemic disease were significantly associated with an increased likelihood of LF; ≥95% PTV was covered by ≥95% prescription dose in 94% of the cases. The rate of new or progressive vertebral compression fracture was 8%. There were no myelitis events or any grade 3+ acute or late toxicities. Conclusions: For patients with circumferential disease, circumferential spine SBRT is feasible and may offer excellent LC without significant toxicity. A prospective evaluation of this approach is warranted.

Concurrent Administration of Immune Checkpoint Inhibitors and Stereotactic Radiosurgery Is Well-Tolerated in Patients With Melanoma Brain Metastases: An International Multicenter Study of 203 Patients.

BACKGROUND: Melanoma brain metastases are commonly treated with stereotactic radiosurgery (SRS) and immune checkpoint inhibitors (ICIs). However, the toxicity of these 2 treatments is largely unknown when administered concurrently. OBJECTIVE: To evaluate the risk of radiation necrosis (RN) with concurrent and nonconcurrent SRS and ICIs. METHODS: The guidelines from the Strengthening the Reporting of Observational Studies in Epidemiology checklist were used. Inverse probability of treatment weighting, univariable and multivariable logistic regression, and the Kaplan-Meier method was utilized. RESULTS: There were 203 patients with 1388 brain metastases across 11 international institutions in 4 countries with a median follow-up of 15.6 months. The rates of symptomatic RN were 9.4% and 8.2% in the concurrent and nonconcurrent groups, respectively ( P =.766). On multivariable logistic regression, V12 ≥ 10 cm 3 (odds ratio [OR]: 2.76; P =.006) and presence of BRAF mutation (OR: 2.20; P =.040) were associated with an increased risk of developing symptomatic RN; the use of concurrent over nonconcurrent therapy was not associated with an increased risk (OR: 1.06; P =.877). There were 20 grade 3 toxic events reported, and no grade 4 events reported. One patient experienced a grade 5 intracranial hemorrhage. The median overall survival was 36.1 and 19.8 months for the concurrent and nonconcurrent groups (log-rank P =.051), respectively. CONCLUSION: Concurrent administration of ICIs and SRS are not associated with an increased risk of RN. Tumors harboring BRAF mutation, or perhaps prior exposure to targeted agents, may increase this risk. Radiosurgical optimization to maintain V12 < 10 cm 3 is a potential strategy to reduce the risk of RN.

Craniospinal irradiation for respiratory failure secondary to central nervous system Erdheim-Chester disease.

Erdheim-Chester disease (ECD) is a rare non-Langerhans cell histiocytosis typically featuring lower extremity osteosclerosis (96%) from Langerin-negative histiocytes with fibrosis. Central nervous system (CNS)-only disease is extremely rare, and particularly difficult to diagnose and manage. Neurologic complaints may be refractory to systemic therapy (ST), and the role of radiation therapy (RT) is undefined. We present a patient with ECD of the medulla complicated by respiratory failure and strength deficits with disseminated leptomeningeal disease (LMD) but not systemic disease, representing the first report of CNS-limited ECD with LMD. He received upfront craniospinal irradiation (CSI), representing a rare account of CSI for ESD, with marked clinical improvement resulting in extubation and improved strength. CSI facilitated excellent preservation of quality of life, and no treatment-related toxicity was observed prior to eventual, unrelated cardiopulmonary arrest. Thus, palliative CSI may augment ST by safely offering improved local control and symptomatic relief for CNS ECD.

Spine Stereotactic Body Radiotherapy to Three or More Contiguous Vertebral Levels.

Background: With survival improving in many metastatic malignancies, spine metastases have increasingly become a source of significant morbidity; achieving durable local control (LC) is critical. Stereotactic body radiotherapy (SBRT) may offer improved LC and/or symptom palliation. However, due to setup concerns, SBRT is infrequently offered to patients with ≥3 contiguous involved levels. Because data are limited, we sought to evaluate the feasibility, toxicity, and cancer control outcomes of spine SBRT delivered to ≥3 contiguous levels. Methods: We retrospectively identified all SBRT courses delivered between 2013 and 2019 at a tertiary care institution for postoperative or intact spine metastases. Radiotherapy was delivered to 14-35 Gy in 1-5 fractions. Patients were stratified by whether they received SBRT to 1-2 or ≥3 contiguous levels. The primary endpoint was 1-year LC and was compared between groups. Factors associated with increased likelihood of local failure (LF) were explored. Acute and chronic toxicity was assessed. In-depth dosimetric data were collected. Results: Overall, 165 patients with 194 SBRT courses were identified [54% were men, median age was 61 years, 93% had Karnofsky Performance Status (KPS) ≥70, and median follow-up was 15 months]. One hundred thirteen patients (68%) received treatment to 1-2 and 52 to 3-7 (32%) levels. The 1-year LC was 88% (89% for 1-2 levels vs. 84% for ≥3 levels, p = 0.747). On multivariate analysis, uncontrolled systemic disease was associated with inferior LC for patients with ≥3 treated levels. No other demographic, disease, treatment, or dosimetric variables achieved significance. Rates of new/progressive fracture were equivalent (8% vs. 9.5%, p = 0.839). There were no radiation-induced myelopathy or grade 3+ acute or late toxicities in either group. Coverage of ≥95% of the planning target volume with ≥95% prescription dose was similar between groups (96% 1-2 levels vs. 89% ≥3 levels, p = 0.078). Conclusions: For patients with ≥3 contiguous involved levels, spine SBRT is feasible and may offer excellent LC without significant toxicity. Prospective evaluation is warranted.

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.

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.

List Prices for Proton Radiation Therapy.

PURPOSE: Some patients elect for self-pay proton radiation therapy (PT) in the United States, but price transparency is a significant concern. The U.S. government recently declared that hospitals must provide a comprehensive list of "standard" charges for all services. Yet, the proportion of compliant proton centers is unknown, as is the extent to which prices vary nationally. METHODS AND MATERIALS: We obtained online chargemasters from U.S. proton centers. Technical charges for per fraction delivery of PT of varying complexity were obtained by billing code (77520, 77522, 77523, 77525) and keyword searches. Prices were adjusted for cost-of-living differences using the Medicare geographic cost price index. The relationship between prices for each PT billing code and cost of living was assessed. The interrelationship in cost between codes was examined. The effect of geographic region and other key variables on pricing was explored. RESULTS: Thirty-six proton centers were identified. Twenty-eight (78%) had accessible chargemasters with 20 (56%) listing at least one PT charge. The median prices for billing codes 77520, 77522, 77523, 77525 were $4707, $4712, $5904, and $6690, respectively, with a trend toward greater cost for more complex therapy (77523, 77525; P = .056). Large ranges ($16,863, $16,059, $18,414, $22,143) resulted in ratios of maximum/minimum prices of 5 to 10x. Only prices for code 77522 were associated with cost of living (P = .039). Across institutions, prices for all 4 codes were positively interrelated (all P < .0001). Prices differed between regions (P < .0001) but not by National Cancer Institute designation. CONCLUSIONS: List prices for PT differ dramatically between institutions and regions without obvious explanation, raising the concerning possibility that such variation is largely arbitrary. Policy solutions that promote rationalized pricing would greatly benefit this patient population.

Phase I study of trametinib in combination with whole brain radiation therapy for brain metastases.

INTRODUCTION: Trametinib is a MEK inhibitor with intracranial activity indicated for BRAF-mutant metastatic malignancies. Yet, the safety of trametinib concurrent with whole brain radiation therapy (WBRT) is unknown. We performed a single-institution, prospective, 3 + 3, phase I clinical trial to determine the maximum tolerated dose (MTD) of trametinib with WBRT. METHODS AND MATERIALS: Patients with brain metastases (BM) received daily trametinib for 28 days, starting 7 days prior to and continuing through WBRT (37.5 Gy/15 fractions). Dose levels (DL)1-3 were 1.0, 1.5, and 2.0 mg. The MTD of trametinib plus WBRT, the max dose where ≤1 of 6 patients experienced a dose limiting toxicity (DLT), was the primary endpoint. RESULTS: 10 patients were enrolled (median age-59 [47-64], BM-5 [1-10], 50% melanoma). Three and 7 patients were assigned to DL1 and 2. One DL2 patient withdrew. 89% of remaining patients completed therapy per protocol, but 1 DL2 patient with systemic progression discontinued therapy at 30 Gy. Thirteen grade (G)3-4 toxicities were observed, of which 12 occurred at DL2 (4/6 of patients). DLT was reached at DL2 (G4 thrombocytopenia and G3 diarrhea, 1 each). There were no G5 toxicities. Median overall survival was 2.2 months. During the study period, changing practice patterns favored utilization of stereotactic radiosurgery (SRS). Thus, the trial closed early prior to completion. CONCLUSIONS: In a patient population representative of modern candidates for WBRT, trametinib plus WBRT is highly toxic with a MTD <1.5 mg. The safety of trametinib with SRS remains an important question for future study.

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.

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.

Cardiovascular Event Reporting in Modern Cancer Radiation Therapy Trials.

PURPOSE: Cardiovascular disease (CVD) is the leading cause of morbidity and mortality in cancer survivors, particularly after chest radiation therapy (RT). However, the extent to which CVD events are consistently reported in contemporary prospective trials is unknown. METHODS AND MATERIALS: From 10 high-impact RT, oncology, and medicine journals, we identified all latter phase trials from 2000 to 2019 enrolling patients with breast, lung, lymphoma, mesothelioma, or esophageal cancer wherein chest-RT was delivered. The primary outcome was the report of major adverse cardiac events (MACEs), defined as incident myocardial infarction, heart failure, coronary revascularization, arrhythmia, stroke, or CVD death across treatment arms. The secondary outcome was the report of any CVD event. Multivariable regression was used to identify factors associated with CVD reporting. Pooled annualized incidence rates of MACEs across RT trials were compared with contemporary population rates using relative risks (RRs). RESULTS: The 108 trials that met criteria enrolled 59,070 patients (mean age, 58.0 ± 10.2 years; 46.0% female), with 273,587 person-years of available follow-up. During a median follow-up of 48 months, 468 MACEs were reported (including 96 heart failures, 75 acute coronary syndrome, 1 revascularization, 94 arrhythmias, 28 strokes, and 20 CVD deaths; 307 occurred in the intervention arms vs 144 in the control arms; RR, 1.96; P < .001). Altogether, 50.0% of trials did not report MACEs, and 37.0% did not report any CVD. The overall weighted-trial incidence was 376 events per 100,000 person-years compared with 1408 events per 100,000 person-years in similar nontrial patients (RR, 0.27; P < .001). There were no RT factors associated with CVD reporting. CONCLUSION: In contemporary chest RT-based clinical trials, reported CVD rates were lower than expected population rates.

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.