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Magnetic resonance-guided radiation therapy (MRgRT) utilization is rapidly expanding worldwide, driven by advanced capabilities including continuous intrafraction visualization, automatic triggered beam delivery, and on-table adaptive replanning (oART). Our objective was to describe patterns of 0.35Tesla(T)-MRgRT (MRIdian) utilization in the United States (US) among early adopters of this novel technology.Anonymized administrative data from all US MRIdian treatment systems were extracted for patients completing treatment from 2014 to 2020. Detailed treatment information was available for all MRIdian linear accelerator (linac) systems and some cobalt systems.Seventeen systems at 16 centers delivered 5736 courses and 36,389 fractions (fraction details unavailable for 1223 cobalt courses), of which 21.1% were adapted. Ultra-hypofractionation (UHfx) (1-5 fractions) was used in 70.3% of all courses. At least one adaptive fraction was used for 38.5% of courses (average 1.7 adapted fractions/course), with higher oART use in UHfx dose schedules (47.7% of courses, average 1.9 adapted fractions per course). The most commonly treated organ sites were pancreas (20.7%), liver (16.5%), prostate (12.5%), breast (11.5%), and lung (9.4%). Temporal trends show a compounded annual growth rate (CAGR) of 59.6% in treatment courses delivered, with a dramatic increase in use of UHfx to 84.9% of courses in 2020 and similar increase in use of oART to 51.0% of courses.This is the first comprehensive study reporting patterns of utilization among early adopters of MRIdian in the US. Intrafraction MR image-guidance, advanced motion management, and increasing adoption of adaptive radiation therapy has led to a substantial transition to ultra-hypofractionated regimens. 0.35

Deep learning-based algorithms have been shown to be able to automatically detect and segment brain metastases (BMs) in magnetic resonance imaging, mostly based on single-institutional data sets. This work aimed to investigate the use of deep convolutional neural networks (DCNN) for BM detection and segmentation on a highly heterogeneous multi-institutional data set.A total of 407 patients from 98 institutions were randomly split into 326 patients from 78 institutions for training/validation and 81 patients from 20 institutions for unbiased testing. The data set contained T1-weighted gadolinium and T2-weighted fluid-attenuated inversion recovery magnetic resonance imaging acquired on diverse scanners using different pulse sequences and various acquisition parameters. Several variants of 3-dimensional U-Net based DCNN models were trained and tuned using 5-fold cross validation on the training set. Performances of different models were compared based on Dice similarity coefficient for segmentation and sensitivity and false positive rate (FPR) for detection. The best performing model was evaluated on the test set.A DCNN with an input size of 64 × 64 × 64 and an equal number of 128 kernels for all convolutional layers using instance normalization was identified as the best performing model (Dice similarity coefficient 0.73, sensitivity 0.86, and FPR 1.9) in the 5-fold cross validation experiments. The best performing model demonstrated consistent behavior on the test set (Dice similarity coefficient 0.73, sensitivity 0.91, and FPR 1.7) and successfully detected 7 BMs (out of 327) that were missed during manual delineation. For large BMs with diameters greater than 12 mm, the sensitivity and FPR improved to 0.98 and 0.3, respectively.The DCNN model developed can automatically detect and segment brain metastases with reasonable accuracy, high sensitivity, and low FPR on a multi-institutional data set with nonprespecified and highly variable magnetic resonance imaging sequences. For large BMs, the model achieved clinically relevant results. The model is robust and may be potentially used in real-world situations.

Stereotactic radiosurgery (SRS) is increasingly used for brain metastases (BM) patients, but distant intracranial failure (DIF) remains the principal disadvantage of this focal therapeutic approach. The objective of this study was to determine if dedicated SRS imaging would improve lesion detection and reduce DIF.Between 02/2020 and 01/2021, SRS patients at a tertiary care institution underwent dedicated treatment planning MRIs of the brain including MPRAGE and SPACE post-contrast sequences. DIF was calculated using the Kaplan-Meier method; comparisons were made to a historical consecutive cohort treated using MPRAGE alone (02/2019-01/2020).134 patients underwent 171 SRS courses for 821 BM imaged with both MPRAGE and SPACE (primary cohort). MPRAGE sequence evaluation alone detected 679 lesions. With neuroradiologists evaluating SPACE and MPRAGE, an additional 108 lesions were identified (p 0.001). Upon multidisciplinary review, 34 additional lesions were identified. Compared to the historical cohort (103 patients, 135 SRS courses, 479 BM), the primary cohort had improved median time to DIF (13.5 vs. 5.1 months, p = 0.004). The benefit was even more pronounced for patients treated for their first SRS course (18.4 vs. 6.3 months, p = 0.001). SRS using MPRAGE and SPACE was associated with a 60% reduction in risk of DIF compared to the historical cohort (HR: 0.40; 95% CI: 0.28-0.57, p 0.001).Among BM patients treated with SRS, a treatment planning SPACE sequence in addition to MPRAGE substantially improved lesion detection and was associated with a statistically significant and clinically meaningful prolongation in time to DIF, especially for patients undergoing their first SRS course.

Background Approximately 50% of newly diagnosed glioblastomas (GBMs) harbor epidermal growth factor receptor gene amplification (EGFR-amp). Preclinical and early-phase clinical data suggested efficacy of depatuxizumab mafodotin (depatux-m), an antibody–drug conjugate comprised of a monoclonal antibody that binds activated EGFR (overexpressed wild-type and EGFRvIII-mutant) linked to a microtubule-inhibitor toxin in EGFR-amp GBMs. Methods In this phase III trial, adults with centrally confirmed, EGFR-amp newly diagnosed GBM were randomized 1:1 to radiotherapy, temozolomide, and depatux-m/placebo. Corneal epitheliopathy was treated with a combination of protocol-specified prophylactic and supportive measures. There was 85% power to detect a hazard ratio (HR) ≤0.75 for overall survival (OS) at a 2.5% 1-sided significance level (ie traditional two-sided p ≤ 0.05) by log-rank testing. Results There were 639 randomized patients (median age 60, range 22–84; 62% men). Prespecified interim analysis found no improvement in OS for depatux-m over placebo (median 18.9 vs. 18.7 months, HR 1.02, 95% CI 0.82–1.26, 1-sided p = 0.63). Progression-free survival was longer for depatux-m than placebo (median 8.0 vs. 6.3 months; HR 0.84, 95% confidence interval [CI] 0.70–1.01, p = 0.029), particularly among those with EGFRvIII-mutant (median 8.3 vs. 5.9 months, HR 0.72, 95% CI 0.56–0.93, 1-sided p = 0.002) or MGMT unmethylated (HR 0.77, 95% CI 0.61–0.97; 1-sided p = 0.012) tumors but without an OS improvement. Corneal epitheliopathy occurred in 94% of depatux-m-treated patients (61% grade 3–4), causing 12% to discontinue. Conclusions Interim analysis demonstrated no OS benefit for depatux-m in treating EGFR-amp newly diagnosed GBM. No new important safety risks were identified.

Background Three- and five-year progression-free survival (PFS) for low-risk meningioma managed with surgery and observation reportedly exceeds 90%. Herewith we summarize outcomes for low-risk meningioma patients enrolled on NRG/RTOG 0539. Methods This phase II trial allocated patients to one of three groups per World Health Organization grade, recurrence status, and resection extent. Low-risk patients had either gross total (GTR) or subtotal resection (STR) for a newly diagnosed grade 1 meningioma and were observed after surgery. The primary endpoint was 3-year PFS. Adverse events (AEs) were scored using Common Terminology Criteria for Adverse Events (CTCAE) version 3. Results Among 60 evaluable patients, the median follow-up was 9.1 years. The 3-, 5-, and 10-year rates were 91.4% (95% CI, 84.2 to 98.6), 89.4% (95% CI, 81.3 to 97.5), 85.0% (95% CI, 75.3 to 94.7) for PFS and 98.3% (95% CI, 94.9 to 100), 98.3%, (95% CI, 94.9 to 100), 93.8% (95% CI, 87.0 to 100) for overall survival (OS), respectively. With centrally confirmed GTR, 3/5/10y PFS and OS rates were 94.3/94.3/87.6% and 97.1/97.1/90.4%. With STR, 3/5/10y PFS rates were 83.1/72.7/72.7% and 10y OS 100%. Five patients reported one grade 3, four grade 2, and five grade 1 AEs. There were no grade 4 or 5 AEs. Conclusions These results prospectively validate high PFS and OS for low-risk meningioma managed surgically but raise questions regarding optimal management following STR, a subcohort that could potentially benefit from adjuvant therapy.

The primary objective of this study is to evaluate the utility and value of an institutional, multi-disciplinary radiation oncology team review process prior to radiotherapy (RT) simulation.Over a period of 3 months and through an iterative team-based process, a standardized simulation requisition directive (SSRD) was developed, piloted, modified, and subsequently implemented for all patients treated with external beam RT at a single tertiary care institution from January to December 2020. The SSRDs were reviewed at a daily multi-disciplinary radiation oncology team review conference; modifications consequential to the review were prospectively recorded in a quality database.1500 consecutive SSRDs were prospectively reviewed for this study. 397 modifications on 290 (19.3%) SSRDs were recorded and parsed into 5 main categories and 18 subcategories. The most common modifications resulted from changes in immobilization device (n = 88, 22.2%), RT care path (n = 56, 14.1%), and arm positioning (n = 43, 10.8%). On univariate analysis, modifications were associated with RT intent, scan parameters, tumor site, and consultation type. An increased rate modifications was observed for patients had telemedicine consults (n = 101, 22.7%) compared to in-person consultations (n = 189, 17.9%) (p = 0.032). Using logistic regression analysis, there was also a statistically significant relationship between postoperative RT delivery and modification rates (OR: 2.913, 95% CI: 1.014-8.372) (p = 0.0126). Overall, only 14 patients (0.9%) needed re-simulation during the entire study period.Prospective multi-disciplinary radiation oncology team review prior to simulation identifies actionable change in approximately 19% of procedures, and results in an extremely low rate (1%) of re-simulation. As departmental processes transition to virtual platforms, thorough attention is needed to identify patients at higher risk of simulation modifications.

We evaluated the effect of lesion number and volume for brain metastasis treated with SRS using GammaKnife® ICON™ (GK) and CyberKnife® M6™ (CK). Four sets of lesion sizes (10–15 mm, and >15 mm) were contoured and prescribed a dose of 20 Gy/1 fraction. The number of lesions was increased until a threshold mean brain dose of 8 Gy was reached; then individually optimized to achieve maximum conformity. Across GK plans, mean brain dose was linearly proportional to the number of lesions and total GTV for all sizes. The numbers of lesions needed to reach this threshold for GK were 177, 57, 29, and 10 for each size group, respectively; corresponding total GTVs were 3.62 cc, 20.37 cc, 30.25 cc, and 57.96 cc, respectively. For CK, the threshold numbers of lesions were 135, 35, 18, and 8, with corresponding total GTVs of 2.32 cc, 12.09 cc, 18.24 cc, and 41.52 cc respectively. Mean brain dose increased linearly with number of lesions and total GTV while V8 Gy, V10 Gy, and V12 Gy showed quadratic correlations to the number of lesions and total GTV. Modern dedicated intracranial SRS systems allow for treatment of numerous brain metastases especially for ≤10 mm; clinical evidence to support this practice is critical to expansion in the clinic.

Background/purpose Glioblastoma (GBM) is the most common primary malignant brain tumor. Sex has been shown to be an important prognostic factor for GBM. The purpose of this study was to develop and independently validate sex-specific nomograms for estimation of individualized GBM survival probabilities using data from 2 independent NRG Oncology clinical trials. Methods This analysis included information on 752 (NRG/RTOG 0525) and 599 (NRG/RTOG 0825) patients with newly diagnosed GBM. The Cox proportional hazard models by sex were developed using NRG/RTOG 0525 and significant variables were identified using a backward selection procedure. The final selected models by sex were then independently validated using NRG/RTOG 0825. Results Final nomograms were built by sex. Age at diagnosis, KPS, MGMT promoter methylation and location of tumor were common significant predictors of survival for both sexes. For both sexes, tumors in the frontal lobes had significantly better survival than tumors of multiple sites. Extent of resection, and use of corticosteroids were significant predictors of survival for males. Conclusions A sex specific nomogram that assesses individualized survival probabilities (6-, 12- and 24-months) for patients with GBM could be more useful than estimation of overall survival as there are factors that differ between males and females. A user friendly online application can be found here—https://npatilshinyappcalculator.shinyapps.io/SexDifferencesInGBM/.

Survival is dismal for bevacizumab refractory high-grade glioma patients. We prospectively investigated the efficacy of re-irradiation, bevacizumab, and temozolomide in bevacizumab-naive and bevacizumab-exposed recurrent high-grade glioma, without volume limitations, in a single arm trial. Recurrent high-grade glioma patients were stratified based on WHO grade (4 vs. grade 3 lymphopenia and 2 with > grade 3 thrombocytopenia. No radiographic or clinical radiation necrosis occurred. Re-irradiation with bevacizumab and temozolomide is a safe and feasible salvage treatment for patients with large volume bevacizumab-refractory high-grade glioma. Patients further from their initial radiotherapy may derive greater benefit with this regimen.

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related deaths in the United States (US), with substantial disparities observed in cancer incidence and survival among racial groups. This study provides analyses on race and ethnicity disparities for patients with HCC.This is a cross-sectional analysis of data from the National Inpatient Sample (NIS) between 2011 and 2016, utilizing the STROBE guidelines. Multivariate logistic regression analyses were used to examine the risk-adjusted associations between race and pre-treatment clinical presentation, surgical procedure allocation, and post-treatment hospital outcomes. All clinical parameters were identified using ICD-9-CM and ICD-10-CM diagnosis and procedure codes.83,876 weighted HCC hospitalizations were reported during the study period. Patient demographics were divided according to NIS racial/ethnic categorization, which includes Caucasian (57.3%), African American (16.9%), Hispanic (15.7%), Asian or Pacific Islanders (9.3%), and Native American (0.8%). Association between greater odds of hospitalization and Elixhauser Comorbidity Index 4 was significantly higher among Native Americans (aOR=1.79; 95% CI: 1.23-2.73), African Americans (aOR=1.24; 95% CI: 1.12-1.38), and Hispanics (aOR=1.11; 95% CI, 1.01-1.24). Risk-adjusted association between race and receipt of surgical procedures demonstrated that the odds of having surgery was significantly lower for African Americans (aOR=0.64; 95% CI: 0.55-0.73) and Hispanics (aOR=0.70; 95% CI: 0.59-0.82), while significantly higher for Asians/Pacific Islanders (aOR=1.36; 95% CI: 1.28-1.63). Post-operative complications were significantly lower for African Americans (aOR=0.68; 95% CI: 0.55-0.86) while the odds of in-hospital mortality were significantly higher for African Americans (aOR=1.28; 95% CI: 1.11-1.49) and Asians/Pacific Islanders (aOR=1.26; 95% CI: 1.13-1.62).After controlling for potential confounders, there were significant racial disparities in pre-treatment presentations, surgical procedure allocations, and post-treatment outcomes among patients with HCC. Further studies are needed to determine the underlying factors for these disparities to develop targeted interventions to reduce these disparities of care.

Purpose Although peer review in radiation oncology (RO) has been recommended to improve quality of care, an analysis of modifications resulting from an RO multidisciplinary presimulation standardized review process has yet to be empirically demonstrated. Methods and Materials A standardized simulation directive was used for patients undergoing simulation for external beam radiation therapy at a single tertiary care institution. The simulation directives were presented, and all aspects were reviewed by representatives from key RO disciplines. Modifications to the original directives were prospectively captured in a quality improvement registry. Association between key variables and the incidence of modifications were performed using Fisher exact test and t test. Results A registry of 500 consecutive simulations for patients undergoing radiation therapy was reviewed. A median of 105 simulations occurred per month. All simulation directives were entered by a physician a median of 3 days before simulation (range, 1-76 days). The treatment intent was curative for 269 patients (53.8%), palliative for 203 patients (40.6%), and benign for 3 patients (0.6%). Twenty-five (5%) patients did not have a treatment intent selected. Based on RO multidisciplinary review, 105 directives (21%) were modified from the original intent, with 29 (5.8%) requiring more than 1 modification. A total of 149 modifications were made and categorized as changes to patient positioning and immobilization (n = 100, 20%), treatment site and care path (n = 34, 6.8%), simulation coordination activities (n = 6, 1.2%), and treatment technique and planning instructions (n = 9, 1.8%). A higher proportion of modifications occurred at the time of multidisciplinary review in patients receiving more complex treatments (intensity modulated radiation therapy/stereotactic radiosurgery/stereotactic body radiation therapy [IMRT/SRS/SBRT] vs 3-dimensional radiation therapy [3DCRT] radiation therapy, 25% vs 16%, P Conclusions Given the complexity of radiation therapy simulation, standardization of directives with prospective RO multidisciplinary presimulation peer review is critical to optimizing department processes and reducing errors. Approximately 1 in 5 patients benefits from this peer review process, especially patients treated with IMRT/SRS/SBRT.

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the basis of the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported. Anaplastic oligodendroglial tumors (AOTs) are chemotherapy-sensitive brain tumors. We report the final very long-term survival results from European Organization for the Research and Treatment of Cancer 26951 and Radiation Therapy Oncology Group 9402 phase III trials initiated in 1990s, which both studied radiotherapy with/without neo/adjuvant procarbazine, lomustine, and vincristine (PCV) for newly diagnosed anaplastic oligodendroglial tumors. The median follow-up duration in both was 18-19 years. For European Organization for the Research and Treatment of Cancer 26951, median, 14-year, and probable 20-year overall survival rates without versus with PCV were 2.6 years, 13.4%, and 10.1% versus 3.5 years, 25.1%, and 16.8% (N = 368 overall; hazard ratio [HR] 0.78; 95% CI, 0.63 to 0.98; P = .033), with 1p19q codeletion 9.3 years, 26.2%, and 13.6% versus 14.2 years, 51.0%, and 37.1% (n = 80; HR 0.60; 95% CI, 0.35 to 1.03; P = .063), respectively. For Radiation Therapy Oncology Group 9402, analogous results were 4.8 years, 16.5%, and 11.2% versus 4.8 years, 29.1%, and 24.6% (N = 289 overall; HR 0.79; 95% CI, 0.61 to 1.03; P = .08), with codeletion 7.3 years, 25.0%, and 14.9% versus 13.2 years, 46.1%, and 37% (n = 125; HR 0.61; 95% CI, 0.40 to 0.94; P = .02), respectively. With that, the studies show similar long-term survival even without tumor recurrence in a significant proportion of patients after first-line treatment with radiotherapy/PCV.

Recurrent meningiomas remain a substantial treatment challenge given the lack of effective therapeutic options aside from surgery and radiation therapy, which yield limited results in the retreatment situation. Systemic therapies have little effect, and responses are rare; the search for effective systemic therapeutics remains elusive. In this case report, we provide data regarding significant responses in two radiographically diagnosed intracranial meningiomas in a patient with concurrent thyroid carcinoma treated with cabozantinib, an oral multitarget tyrosine kinase inhibitor with potent activity against MET and VEGF receptor 2. Given the clinical experience supporting the role of VEGF agents as experimental therapeutics in meningioma and the current understanding of the biological pathways underlying meningioma growth, this may represent a new oral therapeutic alternative, warranting prospective evaluation.

PURPOSE: Community-academic partnerships have the potential to improve access to clinical trials for under-represented minority patients who more often receive cancer treatment in community settings. In 2017, the Memorial Sloan Kettering (MSK) Cancer Center began opening investigator-initiated clinical trials in radiation oncology in targeted community-based partner sites with a high potential to improve diverse population accrual. This study evaluates the effectiveness of a set of implementation strategies for increasing overall community-based enrollment and the resulting proportional enrollment of Hispanic patients on trials on the basis of availability in community-based partner sites. METHODS: An interrupted time series analysis evaluating implementation strategies was conducted from April 2018 to September 2021. Descriptive analysis ofHispanic enrollment on investigator-initiated randomized therapeutic radiation trials open at community-based sites was compared with those open only at themain academic center. RESULTS: Overall, 84 patients were enrolled in clinical trials in the MSK Alliance, of which 48 (56%) identified as Hispanic. The quarterly patient enrollment pre- vs postimplementation increased from 1.39 (95% CI, –3.67 to 6.46) to 9.42 (95% CI, 2.05 to 16.78; P5 .017). In the investigator-initiated randomized therapeutic radiation trials open in the MSK Alliance, Hispanic representation was 11.5% and 35.9% in twometastatic trials and 14.2% in a proton versus photon trial. Inmatched trials open only at the main academic center, Hispanic representation was 5.6%, 6.0%, and 4.0%, respectively. CONCLUSION: A combination of practice-level and physician-level strategies implemented at community-based partner sites was associated with increased clinical trial enrollment, which translated to improved Hispanic representation. This supports the role Q:2 of strategic community-academic partnerships in addressing disparities in clinical trial enrollment.

Purpose: Compared with computed tomography, magnetic resonance (MR) image guidance offers significant advantages for radiation therapy (RT) that may be particularly beneficial for reirradiation (reRT). However, clinical outcomes of MR-guided reRT are not well described in the published literature. Methods and Materials: We performed a single-institution retrospective safety and efficacy analysis of reRT patients treated on the MRIdian Linac to targets within the abdomen or pelvis using continuous intrafraction MR-based motion management with automatic beam triggering. Fiducial markers were not used. Results: We evaluated 11 patients who received prior RT to a median of 50 Gy (range, 30-58.8 Gy) in 25 fractions (range, 5-28 fractions). The median interval to reRT was 26.8 months. The most frequently retreated sites were nodal metastases (36.4%) and pancreatic cancer (27.3%). The median reRT dose was 40 Gy (range, 25-54 Gy) in 6 fractions (range, 5-36 fractions); ultrahypofractionation (63.6%) was more common than hyperfractionation (36.4%). Daily on-table adaptive replanning was used for 3 patients (27.3%). With a median of 14 months’ follow-up from reRT completion (range, 6-32 months), the median and 1-year freedom from local progression were 29 months and 88.9%, respectively, and the median and 1-year overall survival were 17.5 months and 70.0%, respectively. One patient (9.1%) experienced acute grade 2 toxic effects; there were no acute or late treatment-related toxic effects of grade 3 or greater. Conclusions: Magnetic resonance–guided reRT appeared to be feasible and may facilitate safe dose escalation. Additional follow-up is needed to better assess long-term efficacy and late toxic effects. Prospective evaluation of this novel treatment strategy is warranted.

PURPOSE Conventional wisdom has rendered patients with brain metastases ineligible for clinical trials for fear that poor survival could mask the benefit of otherwise promising treatments. Our group previously published the diagnosis-specific Graded Prognostic Assessment (GPA). Updates with larger contemporary cohorts using molecular markers and newly identified prognostic factors have been published. The purposes of this work are to present all the updated indices in a single report to guide treatment choice, stratify research, and define an eligibility quotient to expand eligibility. METHODS A multi-institutional database of 6,984 patients with newly diagnosed brain metastases underwent multivariable analyses of prognostic factors and treatments associated with survival for each primary site. Significant factors were used to define the updated GPA. GPAs of 4.0 and 0.0 correlate with the best and worst prognoses, respectively. RESULTS Significant prognostic factors varied by diagnosis and new prognostic factors were identified. Those factors were incorporated into the updated GPA with robust separation ( P < .01) between subgroups. Survival has improved, but varies widely by GPA for patients with non–small-cell lung, breast, melanoma, GI, and renal cancer with brain metastases from 7-47 months, 3-36 months, 5-34 months, 3-17 months, and 4-35 months, respectively. CONCLUSION Median survival varies widely and our ability to estimate survival for patients with brain metastases has improved. The updated GPA (available free at brainmetgpa.com) provides an accurate tool with which to estimate survival, individualize treatment, and stratify clinical trials. Instead of excluding patients with brain metastases, enrollment should be encouraged and those trials should be stratified by the GPA to ensure those trials make appropriate comparisons. Furthermore, we recommend the expansion of eligibility to allow for the enrollment of patients with previously treated brain metastases who have a 50% or greater probability of an additional year of survival (eligibility quotient > 0.50).

PurposeBrain metastases are a common sequelae of breast cancer. Survival varies widely based on diagnosis-specific prognostic factors (PF). We previously published a prognostic index (Graded Prognostic Assessment [GPA]) for patients with breast cancer with brain metastases (BCBM), based on cohort A (1985-2007, n = 642), then updated it, reporting the effect of tumor subtype in cohort B (1993-2010, n = 400). The purpose of this study is to update the Breast GPA with a larger contemporary cohort (C) and compare treatment and survival across the 3 cohorts.Methods and materialsA multi-institutional (19), multinational (3), retrospective database of 2473 patients with breast cancer with newly diagnosed brain metastases (BCBM) diagnosed from January 1, 2006, to December 31, 2017, was created and compared with prior cohorts. Associations of PF and treatment with survival were analyzed. Kaplan-Meier survival estimates were compared with log-rank tests. PF were weighted and the Breast GPA was updated such that a GPA of 0 and 4.0 correlate with the worst and best prognoses, respectively.ResultsMedian survival (MS) for cohorts A, B, and C improved over time (from 11, to 14 to 16 months, respectively; P < .01), despite the subtype distribution becoming less favorable. PF significant for survival were tumor subtype, Karnofsky Performance Status, age, number of BCBMs, and extracranial metastases (all P < .01). MS for GPA 0 to 1.0, 1.5-2.0, 2.5-3.0, and 3.5-4.0 was 6, 13, 24, and 36 months, respectively. Between cohorts B and C, the proportion of human epidermal receptor 2 + subtype decreased from 31% to 18% (P < .01) and MS in this subtype increased from 18 to 25 months (P < .01).ConclusionsMS has improved modestly but varies widely by diagnosis-specific PF. New PF are identified and incorporated into an updated Breast GPA (free online calculator available at brainmetgpa.com). The Breast GPA facilitates clinical decision-making and will be useful for stratification of future clinical trials. Furthermore, these data suggest human epidermal receptor 2-targeted therapies improve clinical outcomes in some patients with BCBM.

PURPOSE Radiation dose to the neuroregenerative zone of the hippocampus has been found to be associated with cognitive toxicity. Hippocampal avoidance (HA) using intensity-modulated radiotherapy during whole-brain radiotherapy (WBRT) is hypothesized to preserve cognition. METHODS This phase III trial enrolled adult patients with brain metastases to HA-WBRT plus memantine or WBRT plus memantine. The primary end point was time to cognitive function failure, defined as decline using the reliable change index on at least one of the cognitive tests. Secondary end points included overall survival (OS), intracranial progression-free survival (PFS), toxicity, and patient-reported symptom burden. RESULTS Between July 2015 and March 2018, 518 patients were randomly assigned. Median follow-up for alive patients was 7.9 months. Risk of cognitive failure was significantly lower after HA-WBRT plus memantine versus WBRT plus memantine (adjusted hazard ratio, 0.74; 95% CI, 0.58 to 0.95; P = .02). This difference was attributable to less deterioration in executive function at 4 months (23.3% v 40.4%; P = .01) and learning and memory at 6 months (11.5% v 24.7% [ P = .049] and 16.4% v 33.3% [ P = .02], respectively). Treatment arms did not differ significantly in OS, intracranial PFS, or toxicity. At 6 months, using all data, patients who received HA-WBRT plus memantine reported less fatigue ( P = .04), less difficulty with remembering things ( P = .01), and less difficulty with speaking ( P = .049) and using imputed data, less interference of neurologic symptoms in daily activities ( P = .008) and fewer cognitive symptoms ( P = .01). CONCLUSION HA-WBRT plus memantine better preserves cognitive function and patient-reported symptoms, with no difference in intracranial PFS and OS, and should be considered a standard of care for patients with good performance status who plan to receive WBRT for brain metastases with no metastases in the HA region.

Background Targeting vascular endothelial growth factor (VEGF) alone does not improve overall survival (OS) in recurrent glioblastoma (rGBM). The angiopoiein (Ang)-TIE2 system may play a role in tumor survival under VEGF inhibition. We conducted a phase 2, double-blinded, placebo-controlled trial of bevacizumab plus trebananib (a novel Fc fusion protein that sequesters Ang1/Ang2) over bevacizumab alone in rGBM. Methods Patients ≥18 years of age with a Karnofsky performance status ≥70 and GBM or variants in first or second relapse were randomized to bevacizumab 10 mg/kg every 2 weeks plus trebananib 15 mg/kg every week or bevacizumab plus placebo. The primary endpoint was 6-month progression-free survival (PFS). Results After an initial 6-patient lead-in cohort confirmed the safety of combining bevacizumab and trebananib, 115 eligible patients were randomized to the control (n = 58) or experimental treatment (n = 57). In the control arm, 6-month PFS was 41.1%, median survival time was 11.5 months (95% CI, 8.4-14.2 months), median PFS was 4.8 months (95% CI, 3.8-7.1 months), and radiographic response (RR) was 5.9%. In the experimental arm, 6-month PFS was 22.6%, median survival time was 7.5 months (95% CI, 6.8-10.1 months), median PFS was 4.2 months (95% CI, 3.7-5.6 months), and RR was 4.2%. The rate of severe toxicities was not significantly different between arms. Conclusion The combination of bevacizumab and trebananib was well tolerated but did not significantly improve 6-month PFS rate, PFS, or OS for patients with rGBM over bevacizumab alone. The shorter PFS in the experimental arm with a hazard ratio of 1.51 (P = .04) suggests that the addition of trebananib to bevacizumab is detrimental.

BACKGROUND: Phase 2 cooperative group meningioma trial assessing the safety and efficacy of risk-adaptive management strategies. This is the initial analysis of the high-risk cohort. METHODS AND MATERIALS: High-risk patients were those with a new or recurrent World Health Organization (WHO) grade III meningioma of any resection extent, recurrent WHO grade II of any resection extent, or new WHO grade II after subtotal resection. Patients received intensity-modulated radiotherapy (IMRT) using a simultaneous integrated boost technique (60 Gy high dose and 54 Gy low dose in 30 fractions). Three-year progression-free survival (PFS) was the primary endpoint. Adverse events (AEs) were scored per NCI Common Terminology Criteria for Adverse Events version 3. RESULTS: Of 57 enrolled patients, 53 received protocol treatment. Median follow-up was 4.0 years (4.8 years for living patients). Two patients withdrew without progression before year 3; for the remaining 51 patients, 3-year PFS was 58.8%. Among all 53 protocol-treated patients, 3-year PFS was 59.2%. Three-year local control was 68.9%, and overall survival was 78.6%. Of 51 patients, 1 patient (1.9%) experienced a late grade-5 necrosis-related AE. All other acute (23 of 53 patients) and late (21 of 51 patients) AEs were grades 1 to 3. CONCLUSIONS: Patients with high-risk meningioma treated with IMRT (60 Gy/30) experienced 3-year PFS of 58.8%. Combined acute and late AEs were limited to grades 1 to 3, except for a single necrosis-related grade 5 event. These results support postoperative IMRT for high-risk meningioma and invite ongoing investigations to improve outcomes further. © 2019 Elsevier Inc. All rights reserved.

Background Breast cancer treatment is based on estrogen receptors (ERs), progesterone receptors (PRs), and human epidermal growth factor receptor 2 (HER2). At the time of metastasis, receptor status can be discordant from that at initial diagnosis. The purpose of this study was to determine the incidence of discordance and its effect on survival and subsequent treatment in patients with breast cancer brain metastases (BCBM). Methods A retrospective database of 316 patients who underwent craniotomy for BCBM between 2006 and 2017 was created. Discordance was considered present if the ER, PR, or HER2 status differed between the primary tumor and the BCBM. Results The overall receptor discordance rate was 132/316 (42%), and the subtype discordance rate was 100/316 (32%). Hormone receptors (HR, either ER or PR) were gained in 40/160 (25%) patients with HR-negative primary tumors. HER2 was gained in 22/173 (13%) patients with HER2-negative primary tumors. Subsequent treatment was not adjusted for most patients who gained receptors—nonetheless, median survival (MS) improved but did not reach statistical significance (HR, 17–28 mo, P = 0.12; HER2, 15–19 mo, P = 0.39). MS for patients who lost receptors was worse (HR, 27–18 mo, P = 0.02; HER2, 30–18 mo, P = 0.08). Conclusions Receptor discordance between primary tumor and BCBM is common, adversely affects survival if receptors are lost, and represents a missed opportunity for use of effective treatments if receptors are gained. Receptor analysis of BCBM is indicated when clinically appropriate. Treatment should be adjusted accordingly. Key Points 1. Receptor discordance alters subtype in 32% of BCBM patients. 2. The frequency of receptor gain for HR and HER2 was 25% and 13%, respectively. 3. If receptors are lost, survival suffers. If receptors are gained, consider targeted treatment.

OBJECTIVE The objective of this study was to understand recent trends in direct health care expenditures among cancer survivors using novel cost-estimation methods and a nationally representative database. MATERIALS AND METHODS This study was a retrospective analysis of 193,003 adults, ≥18 years of age, using the Medical Expenditure Panel Survey during the years 2009-2016. Manning and Mullahy two-part model was used to calculate adjusted mean and incremental medical expenditures after adjusting for covariates. RESULTS The mean direct annual health care expenditure among cancer survivors ($13,025.0 [$12,572.0 to $13,478.0]) was nearly 3 times greater than noncancer participants ($4689.3 [$4589.2 to $4789.3]) and were mainly spent on inpatient services, office-based visits, and prescription medications. Cancer survivors had an additional health care expenditure of $4407.6 ($3877.6, $4937.6) per person per year, compared with noncancer participants after adjusting for covariates (P

IMPORTANCE: Nearly 96% of patients with high-grade glioma (HGG) report moderate-to-severe fatigue. Armodafinil is a psychostimulant that might help cancer-related fatigue in patients with HGG. OBJECTIVE: To determine whether armodafinil reduces fatigue in patients with HGG and moderate-to-severe fatigue. DESIGN, SETTING, AND PARTICIPANTS: In this randomized multicenter, phase 3, double-blinded, placebo-controlled clinical trial, adults with HGG and moderate-to-severe fatigue who were clinically stable at least 4 weeks after completing radiation therapy were randomized to receive armodafinil daily (150 mg or 250 mg) or placebo over 8 weeks. A score of at least 6 out of 10 on severity scale for the brief fatigue inventory scale, with 10 being the worst, was required to suggest moderate-to-severe fatigue. Patients were allowed stable doses of corticosteroids but were excluded if they required increasing amounts of corticosteroids, were receiving some other treatment for fatigue, or had an uncontrolled seizure disorder. The study was conducted from June 2013 to December 15, 2019. INTERVENTIONS: Patients were randomized to 150 mg of armodafinil, 250 mg of armodafinil, or placebo for a total of 8 weeks with assessments at weeks 4 and 8. MAIN OUTCOMES AND MEASURES: The primary outcome was efficacy in treating cancer-related fatigue. Secondary outcomes included safety, neurocognitive function, and quality of life. Patients were evaluated at baseline and at weeks 4 and 8. Efficacy between the placebo and the 2 doses of study drug was determined by an improvement by 2 points on the 0 to 10 brief fatigue inventory scale. Kruskal-Wallis and χ(2) tests were used and followed by confirmatory analyses. RESULTS: A total of 328 patients were enrolled, of whom 297 had evaluable end point data. Of these, 103 received 150 mg of armodafinil (mean [SD] age, 58.5 [11.9] years; 42 women [40.8%]), 97 250 mg of armodafinil (mean [SD] age, 56.6 [12.5] years; 37 women [38.1%]), and 97 placebo (mean [SD] age, 57.1 [12.5] years; 39 women [40.2%]). There was no difference in the proportion of patients who achieved clinically meaningful fatigue reduction between arms (28% [95% CI 20%-30%] for 150 mg of armodafinil, 28% [95% CI 19%-38%] for 250 mg of armodafinil, and 30% [95% CI 21%-40%] for placebo). There was a statistically significant reduction in global fatigue for corticosteroid users compared with nonusers (−0.7 [95% CI, −1.5 to −0.3] vs −1.7 [95% CI, −2.1 to −1.3]; P

Patients with lung cancer and brain metastases represent a markedly heterogeneous population. Accurate prognosis is essential to optimally individualize care. In prior publications, we described the graded prognostic assessment (GPA), but a GPA for patients with small cell lung cancer (SCLC) has never been reported, and in non-small cell lung cancer (NSCLC), the effect of programmed death ligand 1 (PD-L1) was unknown. The 3-fold purpose of this work is to provide the initial report of an SCLC GPA, to evaluate the effect of PD-L1 on survival in patients with NSCLC, and to update the Lung GPA accordingly.A multivariable analysis of prognostic factors and treatments associated with survival was performed on 4183 patients with lung cancer (3002 adenocarcinoma, 611 nonadenocarcinoma, 570 SCLC) with newly diagnosed brain metastases between January 1, 2015, and December 31, 2020, using a multi-institutional retrospective database. Significant variables were used to update the Lung GPA.Overall median survival for lung adenocarcinoma, SCLC, and nonadenocarcinoma was 17, 10, and 8 months, respectively, but varied widely by GPA from 2 to 52 months. In SCLC, the significant prognostic factors were age, performance status, extracranial metastases, and number of brain metastases. In NSCLC, the distribution of molecular markers among patients with lung adenocarcinoma and known primary tumor molecular status revealed alterations/expression in PD-L1 50% to 100%, PD-L1 1% to 49%, epidermal growth factor receptor, and anaplastic lymphoma kinase in 32%, 31%, 30%, and 7%, respectively. Median survival of patients with lung adenocarcinoma and brain metastases with 0, 1% to 49%, and ≥50% PD-L1 expression was 17, 19, and 24 months, respectively (P.01), confirming PD-L1 is a prognostic factor. Previously identified prognostic factors for NSCLC (epidermal growth factor receptor and anaplastic lymphoma kinase status, performance status, age, number of brain metastases, and extracranial metastases) were reaffirmed. These factors were incorporated into the updated Lung GPA with robust separation between subgroups for all histologies.Survival for patients with lung cancer and brain metastases has improved but varies widely. The initial report of a GPA for SCLC is presented. For patients with NSCLC-adenocarcinoma and brain metastases, PD-L1 is a newly identified significant prognostic factor, and the previously identified factors were reaffirmed. The updated indices establish unique criteria for SCLC, NSCLC-nonadenocarcinoma, and NSCLC-adenocarcinoma (incorporating PD-L1). The updated Lung GPA, available for free at brainmetgpa.com, provides an accurate tool to estimate survival, individualize treatment, and stratify clinical trials.

Background Treatment paradigms for metastatic non-small cell lung cancer are increasingly based on biomarker-driven therapies, with the most common alteration being mutation in the epidermal growth factor receptor (EGFR). Change in expression of such biomarkers could have a profound impact on the choice and efficacy of a selected targeted therapeutic, and hence the objective of this study was to analyze discordance in EGFR status in patients with lung cancer brain metastasis (LCBM). Methods Using PRISMA guidelines, a systematic review was performed of series in the Medline database of biopsied or resected LCBM published before May, 2020. Key words included “lung cancer” and “brain metastasis” combined with “epidermal growth factor receptor/EGFR,” and “receptor conversion/discordance or concordance.” Weighted random effects models were used to calculate pooled estimates. Results We identified 501 patients from 19 full-text articles for inclusion in this study. All patients underwent biopsy or resection of at least one intracranial lesion to compare to the primary tumor. On primary/LCBM comparison, the weighted pooled estimate for overall EGFR receptor discordance was 10% (95% CI 5–17%). The weighted effects model estimated a gain of an EGFR mutation in a brain metastases in patients with negative primary tumors was 7% (95% CI 4–12%). Alternatively, the weighted effects model estimate of loss of an EGFR mutation in patients with detected mutations in the primary tumor was also 7% (95% CI 4–10%). KRAS testing was also performed on both primary tumors and LCBM in a subset of 148 patients. The weighted effects estimate of KRAS-mutation discordance among LCBM compared to primary tumors was 13% (95% CI 5–27%). The weighted effects estimated of KRAS gain and loss in LCBM was 10% (95% CI 6–18%) and 8% (95% CI 4–15%), respectively. Meta-regression analysis did not find any association with any factors that could be associated with discordances. Conclusions EGFR and KRAS mutation status discordance between primary tumor and LCBM occurs in approximately 10% and 13% of patients, respectively. Evaluation of LCBM receptor status is key to biomarker-driven targeted therapy for intracranial disease and awareness of subtype switching is critical for those patients treated with systemic therapy alone for intracranial disease.

PURPOSE This study sought to determine the prognostic significance of the WHO-defined glioma molecular subgroups along with additional alterations, including MGMT promoter methylation and mutations in ATRX, CIC, FUBP1, TERT, and TP53, in NRG/RTOG 0424 using long-term follow-up data. METHODS Mutations were determined using an Ion Torrent sequencing panel. 1p/19q co-deletion and MGMT promoter methylation were determined by Affymetrix OncoScan and Illumina 450K arrays. Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method and tested using the log-rank test. Hazard ratios were calculated using the Cox proportional hazard model. Multivariable analyses (MVAs) included patient pretreatment characteristics. RESULTS We obtained complete molecular data to categorize 80/129 eligible patients within the WHO subgroups. Of these, 26 (32.5%) were IDHmutant/co-deleted, 28 (35%) were IDHmutant/non-co-deleted, and 26 (32.5%) were IDHwild-type. Upon single-marker MVA, both IDHmutant subgroups were associated with significantly better OS and PFS ( P values < .001), compared with the IDHwild-type subgroup. MGMT promoter methylation was obtained on 76 patients, where 58 (76%) were methylated and 18 (24%) were unmethylated. Single-marker MVAs demonstrated that MGMT promoter methylation was statistically significant for OS ( P value < .001) and PFS ( P value = .003). In a multimarker MVA, one WHO subgroup comparison ( IDHmutant/co-deleted v IDHwild-type) was significant for OS ( P value = .045), whereas MGMT methylation did not retain significance. CONCLUSION This study reports the long-term prognostic effect of the WHO molecular subgroups, MGMT promoter methylation, and other mutations in NRG/RTOG 0424. These results demonstrate that the WHO molecular classification and MGMT both serve as strong prognostic indicators, but that MGMT does not appear to add statistically significant prognostic value to the WHO subgrouping, above and beyond IDH and 1p/19q status.

Hippocampal volume (HV) is an established predicting factor for neurocognitive function (NCF) in neurodegenerative disease. Whether the same phenomenon exists with hippocampal-avoidant whole brain radiation therapy is not known; therefore, we assessed the association of baseline HV with NCF among patients enrolled on RTOG 0933.Hippocampal volume and total brain volume were calculated from the radiation therapy plan. Hippocampal volume was correlated with baseline and 4-month NCF scores (Hopkins Verbal Learning Test-Revised [HVLT-R] Total Recall [TR], Immediate Recognition, and Delayed Recall [DR]) using Pearson correlation. Deterioration in NCF was defined per the primary endpoint of RTOG 0933(mean 4-month relative decline in HVLT-R DR). Comparisons between patients with deteriorated and nondeteriorated NCF were made using the Wilcoxon test.Forty-two patients were evaluable. The median age was 56.5 years (range, 28-83 years), and 81% had a class II recursive partitioning analysis. The median total, right, and left HVs were 5.4 cmLarger HV was positively associated with improved performance on baseline and 4-month HVLT-R TR and DR scores in patients with brain metastases undergoing hippocampal-avoidant whole brain radiation therapy but was not associated with a change in NCF.

Purpose: Randomized data show a survival benefit of stereotactic ablative body radiation therapy in selected patients with oligometastases (OM). Stereotactic magnetic resonance guided adaptive radiation therapy (SMART) may facilitate the delivery of ablative dose for OM lesions, especially those adjacent to historically dose-limiting organs at risk, where conventional approaches preclude ablative dosing. Methods and Materials: The RS Search Registry was queried for OM patients (1-5 metastatic lesions) treated with SMART. Freedom from local progression (FFLP), freedom from distant progression (FFDP), progression-free survival (PFS), and overall survival (LS) were estimated using the Kaplan-Meier method. FFLP was evaluated using RECIST 1.1 criteria. Toxicity was evaluated using Common Terminology Criteria for Adverse Events version 4 criteria. Results: Ninety-six patients with 108 OM lesions were treated on a 0.35 T MR Linac at 2 institutions between 2018 and 2020. SMART was delivered to mostly abdominal or pelvic lymph nodes (48.1\%), lung (18.5\%), liver and intrahepatic bile ducts (16.7\%), and adrenal gland (11.1\%). The median prescribed radiation therapy dose was 48.5 Gy (range, 30-60 Gy) in 5 fractions (range, 3-15). The median biologically effective dose corrected using an alpha/beta value of 10 was 100 Gy10 (range, 48-180). No acute or late grade 3+ toxicities were observed with median 10 months (range, 3-25) follow-up. Estimated 1-year FFLP, FFDP, PFS, and OS were 92.3\%, 41.1\%, 39.3\%, and 89.6\%, respectively. Median FFDP and PFS were 8.9 months (95\% confidence interval, 5.2-12.6 months) and 7.6 months (95\% confidence interval, 4.5-10.6 months), respectively. Conclusions: To our knowledge, this represents the largest analysis of SMART using ablative dosing for non-bone OM. A median prescribed biologically effective dose of 100 Gy10 resulted in excellent early FFLP and no significant toxicity, likely facilitated by continuous intrafraction MR visualization, breath hold delivery, and online adaptive replanning. Additional prospective evaluation of dose-escalated SMART for OM is warranted. (C) 2022 The Author(s). Published by Elsevier Inc. on behalf of American Society for Radiation Oncology.

Immunotherapy has revolutionized treatment for many hard-to-treat cancers but has yet to produce significant improvement in outcomes for patients with glioblastoma. This reflects the multiple and unique mechanisms of immune evasion and escape in this highly heterogeneous tumor. Glioblastoma engenders profound local and systemic immunosuppression and is remarkably effective at inducing T-cell dysfunction, posing a challenge to any immunotherapy-based approach. To overcome these mechanisms, multiple disparate modes of immune-oriented therapy will be required. However, designing trials that can evaluate these combinatorial approaches requires careful consideration. In this review, we explore the immunotherapy resistance mechanisms that have been encountered to date and how combinatorial approaches may address these. We also describe the unique aspects of trial design in both preclinical and clinical settings and consider endpoints and markers of response best suited for an intervention involving multiple agents.

Simple Summary In the multi-modal treatment of brain metastasis (BM), the role of systemic therapy has undergone a recent revolution. Due to the development of multiple agents with modest central nervous system penetration of the blood-brain barrier, targeted therapies and immune checkpoint inhibitors are increasingly being utilized alone or in combination with radiation therapy. However, the adoption of sequential or concurrent strategies varies considerably, and treatment strategies employed in clinical practice have rapidly outpaced evidence development. Therefore, this review critically analyzes the data regarding combinatorial approaches for a variety of systemic therapeutics with stereotactic radiosurgery and provides an overview of ongoing clinical trials. Abstract Brain metastasis (BM) represents a common complication of cancer, and in the modern era requires multi-modal management approaches and multi-disciplinary care. Traditionally, due to the limited efficacy of cytotoxic chemotherapy, treatment strategies are focused on local treatments alone, such as whole-brain radiotherapy (WBRT), stereotactic radiosurgery (SRS), and resection. However, the increased availability of molecular-based therapies with central nervous system (CNS) penetration now permits the individualized selection of tailored systemic therapies to be used alongside local treatments. Moreover, the introduction of immune checkpoint inhibitors (ICIs), with demonstrated CNS activity has further revolutionized the management of BM patients. The rapid introduction of these cancer therapeutics into clinical practice, however, has led to a significant dearth in the published literature about the optimal timing, sequencing, and combination of these systemic therapies along with SRS. This manuscript reviews the impact of tumor biology and molecular profiles on the management paradigm for BM patients and critically analyzes the current landscape of SRS, with a specific focus on integration with systemic therapy. We also discuss emerging treatment strategies combining SRS and ICIs, the impact of timing and the sequencing of these therapies around SRS, the effect of corticosteroids, and review post-treatment imaging findings, including pseudo-progression and radiation necrosis.

Purpose: Postoperative radiation therapy (RT) is commonly used for World Health Organization grade II-III intracranial ependymoma. Clinicians generally aim to begin RT ≤5 weeks after surgery, but postoperative recovery and need for second look surgery can delay the initiation of adjuvant therapy. On ACNS 0831, patients were required to enroll ≤8 weeks after initial surgery and begin adjuvant therapy within 3 weeks after enrollment. The purpose of this study was to determine the optimal timing of RT after surgery. Methods and Materials: The National Cancer Database was queried for patients (aged 1-39 years) with localized World Health Organization grade II-III intracranial ependymoma treated with surgery and postoperative RT. Overall survival (OS) curves were plotted based on RT timing (≤5 weeks, 5-8 weeks, and >8 weeks after surgery) and were compared by log-rank test. Factors associated with OS were identified by multivariate analysis. After 2009, complete data were available on whether patients underwent gross total resection or subtotal resection. Planned subset analysis was performed to examine the effect of RT timing on OS in patients with known extent of resection. Results: In the final analytical data set of 1043 patients, no difference in 3-year OS was observed in patients who initiated RT ≤5 weeks, 5 to 8 weeks, and >8 weeks after surgery (89.8% vs 89.1% vs 88.4%; P = .796). On multivariate analysis, grade III tumors (hazard ratio, 2.752; 95% confidence interval, 1.969-3.846, P < .001) and subtotal resection (hazard ratio, 2.253; 95% confidence interval, 1.405-3.611, P < .001) were significantly associated with reduced OS. Timing of RT, total RT dose, age, and other factors were not significant. These findings were affirmed in the subset of patients treated between 2010 and 2016, when extent of resection was routinely recorded. Conclusions: Delayed postoperative RT was not associated with inferior survival in patients with intracranial ependymoma. Delayed RT initiation may be acceptable in patients who require longer postoperative recovery or referral to an appropriate RT center, but should be minimized whenever practical.

Background and Purpose To quantify the indication for adaptive, gated breath-hold (BH) MR-guided radiotherapy (MRgRTBH) versus BH or free-breathing (FB) CT-based image-guided radiotherapy (CT-IGRT) for the ablative treatment of adrenal malignancies. Materials and Methods Twenty adrenal patients underwent adaptive IMRT MRgRTBH to a median dose of 50 Gy/5 fractions. Each patient was replanned for VMAT CT-IGRTBH and CT-IGRTFB on a c-arm linac. Only CT-IGRTFB used an ITV, summed from GTVs of all phases of the 4DCT respiratory evaluation. All used the same 5 mm GTV/ITV to PTV expansion. Metrics evaluated included: target volume and coverage, conformality, mean ipsilateral kidney and 0.5 cc gastrointestinal organ-at-risk (OAR) doses (D0.5cc). Adaptive dose for MRgRTBH and predicted dose (i.e., initial plan re-calculated on anatomy of the day) was performed for CT-IGRTBH and MRgRTBH to assess frequency of OAR violations and coverage reductions for each fraction. Results The more common VMAT CT-IGRTFB, with its significantly larger target volumes, proved inferior to MRgRTBH in mean PTV and ITV/GTV coverage, as well as small bowel D0.5cc. Conversely, VMAT CT-IGRTBH delivered a dosimetrically superior initial plan in terms of statistically significant (p≤0.02) improvements in target coverage, conformality and D0.5cc to the large bowel, duodenum and mean ipsilateral kidney compared to IMRT MRgRTBH. However, non-adaptive CT-IGRTBH had a 71.8% frequency of predicted indications for adaptation and was 2.8 times more likely to experience a coverage reduction in PTV D95% than predicted for MRgRTBH. Conclusion Breath-hold VMAT radiotherapy provides superior target coverage and conformality over MRgRTBH, but the ability of MRgRTBH to safely provide ablative doses to adrenal lesions near mobile luminal OAR through adaptation and direct, real-time motion tracking is unmatched.

Survival prediction models may serve as decision-support tools for clinicians who have to assign the right treatment to each patient, in a manner whereby harmful over- or undertreatment is avoided as much as possible. Current models differ regarding their components, the overall number of components and the weighting of individual components. Some of the components are easy to assess, such as age or primary tumor type. Others carry the risk of inter-assessor inconsistency and time-dependent variation. The present publication focuses on issues related to assessment of extracranial metastases and potential surrogates, e.g. blood biomarkers. It identifies areas of controversy and provides recommendations for future research projects, which may contribute to prognostic models with improved accuracy. (c) 2021 Elsevier B.V. All rights reserved. Radiotherapy and Oncology 159 (2021) 17-20

Background ONC201 is a dopamine receptor D2 (DRD2) antagonist that penetrates the blood–brain barrier. ONC201 efficacy has been shown in glioblastoma animal models and is inversely correlated with dopamine receptor DRD5 expression. ONC201 is well tolerated in adult recurrent glioblastoma patients with dosing every 3 weeks and has achieved an objective radiographic response in a patient harboring the H3 K27M mutation. Methods In a window-of-opportunity arm, 6 adult subjects initiated ONC201 prior to re-resection of recurrent glioblastoma with intratumoral concentrations as the primary endpoint. An additional 20 adults with recurrent glioblastoma received single agent weekly oral ONC201 at 625 mg, with progression-free survival at 6 months (PFS6) by Response Assessment in Neuro-Oncology (RANO) criteria as the primary endpoint. Results The window-of-opportunity arm achieved its primary endpoint with intratumoral ONC201 concentrations at ~24 hours following the second weekly dose ranging from 600 nM to 9.3 µM. Intratumoral pharmacodynamics assessed by activating transcriptional factor 4, death receptor 5, and apoptosis induction relative to archival samples were observed with the strongest intensity and uniformity among patients with low DRD5 tumor expression. The primary endpoint of PFS6 by RANO was not achieved at 5% in this molecularly unselected cohort; however, 1 of 3 patients enrolled with the H3 K27M mutation had a complete regression of enhancing multifocal lesions that remained durable for >1.5 years. No treatment modifications or discontinuations due to toxicity were observed, including in those who underwent re-resection. Conclusions Weekly ONC201 is well tolerated, and meaningful intratumoral concentrations were achieved. ONC201 may be biologically active in a subset of adult patients with recurrent glioblastoma.

Purpose: NRG Oncology's RTOG 0933 demonstrated benefits to memory preservation after hippocampal avoidant whole-brain radiation therapy (HA-WBRT), the avoidance of radiation dose to the hippocampus (using intensity modulated radiation planning and delivery techniques) during WBRT, supporting the hypothesis of hippocampal radiosensitivity and associated memory specificity. However, some patients demonstrated cognitive decline, suggesting mechanisms outside hippocampal radiosensitivity play a role. White matter injury (WMI) has been implicated in radiation therapy–induced neurocognitive decline. This secondary analysis explored the relationship between pretreatment WMI and memory after HA-WBRT. Methods and Materials: Volumetric analysis of metastatic disease burden and disease-unrelated WMI was conducted on the pretreatment magnetic resonance image. Correlational analyses were performed examining the relationship between pretreatment WMI and Hopkins Verbal Learning Test-Revised (HVLT-R) outcomes at baseline and 4 months after HA-WBRT. Results: In the study, 113 patients received HA-WBRT. Of 113 patients, 33 underwent pretreatment and 4-month posttreatment HVLT testing and pretreatment postcontrast volumetric T1 and axial T2/fluid-attenuated inversion recovery magnetic resonance imaging. Correlation was found between larger volumes of pretreatment WMI and decline in HVLT-R recognition (r = 0.54, P

Highlights • Brain metastases in GI cancer patients are not uncommon. • Survival varies widely within this cohort. • New identified prognostic factors are incorporated in an updated prognostic index. • This index, the GI-GPA, will better estimate survival. • The GI-GPA is useful in treatment selection and stratification of clinical trials., Background Patients with gastrointestinal cancers and brain metastases (BM) represent a unique and heterogeneous population. Our group previously published the Diagnosis-Specific Graded Prognostic Assessment (DS-GPA) for patients with GI cancers (GI-GPA) (1985–2007, n = 209). The purpose of this study is to update the GI-GPA based on a larger contemporary database. Methods An IRB-approved consortium database analysis was performed using a multi-institutional (18), multi-national (3) cohort of 792 patients with gastrointestinal (GI) cancers, with newly-diagnosed BM diagnosed between 1/1/2006 and 12/31/2017. Survival was measured from date of first treatment for BM. Multiple Cox regression was used to select and weight prognostic factors in proportion to their hazard ratios. These factors were incorporated into the updated GI-GPA. Results Median survival (MS) varied widely by primary site and other prognostic factors. Four significant factors (KPS, age, extracranial metastases and number of BM) were used to formulate the updated GI-GPA. Overall MS for this cohort remains poor; 8 months. MS by GPA was 3, 7, 11 and 17 months for GPA 0–1, 1.5–2, 2.5–3.0 and 3.5–4.0, respectively. >30% present in the worst prognostic group (GI-GPA of ≤1.0). Conclusions Brain metastases are not uncommon in GI cancer patients and MS varies widely among them. This updated GI-GPA index improves our ability to estimate survival for these patients and will be useful for therapy selection, end-of-life decision-making and stratification for future clinical trials. A user-friendly, free, on-line app to calculate the GPA score and estimate survival for an individual patient is available at brainmetgpa.com.

BACKGROUND: H3 K27M-mutant diffuse midline glioma is a fatal malignancy with no proven medical therapies. The entity predominantly occurs in children and young adults. ONC201 is a small molecule selective antagonist of dopamine receptor D2/3 (DRD2/3) with an exceptional safety profile. Following up on a durable response in the first H3 K27M-mutant diffuse midline glioma patient who received ONC201 (NCT02525692), an expanded access program was initiated. METHODS: Patients with H3 K27M-mutant gliomas who received at least prior radiation were eligible. Patients with leptomeningeal spread were excluded. All patients received open-label ONC201 orally once every week. Safety, radiographic assessments, and overall survival were regularly assessed at least every 8 weeks by investigators. As of August 2018, a total of 18 patients with H3 K27M-mutant diffuse midline glioma or DIPG were enrolled to single patient expanded access ONC201 protocols. Among the 18 patients: seven adult (>20 years old) and seven pediatric (

RTOG 9802 identified a cohort of patients with age less than 40 years and undergoing gross total resection as having low-risk, low-grade glioma (LR-LGG). European Organization for Research and Treatment of Cancer studies have demonstrated additional prognostic features in this group. The aim of this study was to analyze clinical factors associated with overall survival (OS), identify a potentially higher risk group within LR-LGG, and investigate patterns of care for adjuvant therapy.Patients with LR-LGG diagnosed between 2010 to 2013 were identified in the National Cancer Database. Kaplan-Meier method was used to analyze OS. Propensity score matching and multivariate analysis were utilized to adjust for differences in cohorts.A total of 1,032 patients with LR-LGG were identified. Histological breakdown was 42.0% astrocytoma, 33.2% oligodendroglioma, and 25.8% mixed. Median follow-up was 3.9 years; median pre-operative tumor size was 4.0 cm. Overall, 834 (80.8%) underwent observation and 198 (19.2%) received adjuvant therapy. Tumor size5 cm predicted for receipt of adjuvant therapy on regression analyses (OR=2.02, p=0.001). On multivariate analysis, tumor size5 cm (hazard ratio=1.95) and non-oligodendroglioma histology (hazard ratio=2.50) were associated with inferior OS (both p0.05). For patients with both poor prognostic features (a subset we consider "intermediate-risk"), 5-year OS was 78.4%, compared to 94.1% for all other low-risk patients (p0.001). After propensity score matching, the intermediate-risk group continued to be associated with worse 5-year OS: 80.5% vs. 94.0%, p=0.004.Due to inferior OS for patients with LR-LGG with5 cm, non-oligodendroglioma tumors, we propose an 'intermediate-risk' clinical classification for this subset.

INTRODUCTION: NRG protocols for glioblastoma allow for clinical target volume (CTV) reductions at natural barriers; however, literature examining CTV contouring and the relevant white matter pathways is lacking. This study proposes consensus CTV guidelines, with a focus on areas of controversy while highlighting common errors in glioblastoma target delineation. METHODS: Ten academic radiation oncologists specializing in brain tumor treatment contoured CTVs on 4 glioblastoma cases. CTV expansions were based on NRG trial guidelines. Contour consensus was assessed and summarized by kappa statistics. A meeting was held to discuss the mathematically averaged contours and form consensus contours and recommendations. RESULTS: Contours of the cavity plus enhancement (mean kappa 0.69) and T2-FLAIR signal (mean kappa 0.74) showed moderate to substantial agreement. Experts were asked to trim off anatomic barriers while respecting pathways of spread to develop their CTVs. Submitted CTV_4600 (mean kappa 0.80) and CTV_6000 (mean kappa 0.81) contours showed substantial to near perfect agreement. Simultaneous Truth and Performance Level Estimation (STAPLE) contours were then reviewed and modified by group consensus. Anatomic trimming reduced the amount of total brain tissue planned for radiation targeting by a 13.6% (range 8.7% - 17.9%) mean proportional reduction. Areas for close scrutiny of target delineation were described, with accompanying recommendations. CONCLUSIONS: Consensus contouring guidelines were established based on expert contours. Careful delineation of anatomic pathways and barriers to spread can spare radiation to uninvolved tissue without compromising target coverage. Further study is necessary to accurately define optimal target volumes beyond isometric expansion techniques for individual patients.

We compared the clinical outcomes of BM treated with mask immobilization with zero-SM (i.e., zero-PTV) to standard zero-SM frame immobilization SRS. Consecutive patients with BM, 0.5–2.0 cm in maximal diameter, treated with single-fraction SRS (22–24 Gy) during March 2019–February 2021 were included. Univariable and multivariable analysis were performed using the Kaplan–Meier method and Cox proportional hazards regression. A total of 150 patients with 453 BM met inclusion criteria. A total of 129 (28.5%) lesions were treated with a zero-SM mask immobilization and 324 (71.5%) with zero-SM frame immobilization. Frame immobilization treatments were associated with a higher proportion of gastrointestinal and fewer breast-cancer metastases (p = 0.024), and a higher number of treated lesions per SRS course (median 7 vs. 3; p < 0.001). With a median follow up of 15 months, there was no difference in FFLF between the mask and frame immobilization groups on univariable (p = 0.29) or multivariable analysis (p = 0.518). Actuarial FFLF at 1 year was 90.5% for mask and 92% for frame immobilization (p = 0.272). Radiation necrosis rates at 1 year were 12.5% for mask and 4.1% for frame immobilization (p = 0.502). For BM 0.5–2.0 cm in maximal diameter treated with single-fraction SRS using 22–24 Gy, mask immobilization with zero SM produces comparable clinical outcomes to frame immobilization. The initial findings support omitting a SM when using mask immobilization with this treatment approach on a Gamma Knife® Icon™.