The use of master protocols for efficient trial design to evaluate radiotherapy interventions: a systematic review.

The aim of this review was to highlight why the use of master protocols trial design is particularly useful for radiotherapy intervention trials where complex-set up pathways (including quality assurance, user training, integrating multiple modalities of treatment) may hinder clinical advances. We carried out a systematic review according to PRISMA guidelines, reviewing the findings using a landscape analysis. Results were summarised descriptively, reporting on trial characteristics highlighting the benefits, limitations, and challenges of developing and implementing radiotherapy master protocols with three case studies selected to explore these issues in more detail. 12 studies were suitable for inclusion (4 platform trials, 3 umbrella trials, and 5 basket trials), evaluating a mix of solid tumour sites in both curative and palliative settings. The interventions were categorised into 1. Novel agent and radiotherapy combinations; 2. Radiotherapy dose personalisation; and 3. Device evaluation, with a case study provided for each intervention. Benefits of master protocol trials for radiotherapy intervention include: protocol efficiency for implementation of novel radiotherapy techniques; accelerating the evaluation of novel agent drug and radiotherapy combinations; and more efficient translational research opportunities, leading to cost savings and research efficiency to improve patient outcomes. Master protocols offer an innovative platform under which multiple clinical questions can be addressed within a single trial. Due to the complexity of radiotherapy trial set up, cost and research efficiency savings may be more apparent than in systemic treatment trials. Use of this research approach may be the change needed to push forward oncological innovation within radiation oncology.

Stereotactic Magnetic Resonance-guided Adaptive Radiation Therapy for Localized Kidney Cancer: Early Outcomes from a Prospective Phase 1 Trial and Supplemental Cohort.

Stereotactic magnetic resonance (MR)-guided adaptive radiotherapy (SMART) for renal cell carcinoma may result in more precise treatment delivery through the capabilities for improved image quality, daily adaptive planning, and accounting for respiratory motion during treatment with real-time MR tracking. In this study, we aimed to characterize the safety and feasibility of SMART for localized kidney cancer. Twenty patients with localized kidney cancer (ten treated in a prospective phase 1 trial and ten in the supplemental cohort) were treated to 40 Gy in five fractions on a 0.35 T MR-guided linear accelerator with daily adaptive planning and a cine MR-guided inspiratory breath hold technique. The median follow-up time was 17 mo (interquartile range: 13-20 months). A single patient developed local failure at 30 mo. No grade ≥3 adverse events were reported. The mean decrease in estimated glomerular filtration rate was -1.8 ml/min/1.73 m2 (95% confidence interval or CI [-6.6 to 3.1 ml/min/1.73 m2]), and the mean decrease in tumor diameter was -0.20 cm (95% CI [-0.6 to 0.2 cm]) at the last follow-up. Anterior location and overlap of the 25 or 28 Gy isodose line with gastrointestinal organs at risk were predictive of the benefit from online adaptive planning. Kidney SMART is feasible and, at the early time point evaluated in this study, was well tolerated with minimal decline in renal function. More studies are warranted to further evaluate the safety and efficacy of this technique. PATIENT SUMMARY: For patients with localized renal cell carcinoma who are not surgical candidates, stereotactic magnetic resonance--guided adaptive radiotherapy is a feasible and safe noninvasive treatment option that results in minimal impact on kidney function.

Widening the therapeutic window for central and ultra-central thoracic oligometastatic disease with stereotactic MR-guided adaptive radiation therapy (SMART).

BACKGROUND/PURPOSE: Central/ultra-central thoracic tumors are challenging to treat with stereotactic radiotherapy due potential high-grade toxicity. Stereotactic MR-guided adaptive radiation therapy (SMART) may improve the therapeutic window through motion control with breath-hold gating and real-time MR-imaging as well as the option for daily online adaptive replanning to account for changes in target and/or organ-at-risk (OAR) location. MATERIALS/METHODS: 26 central (19 ultra-central) thoracic oligoprogressive/oligometastatic tumors treated with isotoxic (OAR constraints-driven) 5-fraction SMART (median 50 Gy, range 35-60) between 10/2019-10/2022 were reviewed. Central tumor was defined as tumor within or touching 2 cm around proximal tracheobronchial tree (PBT) or adjacent to mediastinal/pericardial pleura. Ultra-central was defined as tumor abutting the PBT, esophagus, or great vessel. Hard OAR constraints observed were ≤ 0.03 cc for PBT V40, great vessel V52.5, and esophagus V35. Local failure was defined as tumor progression/recurrence within the planning target volume. RESULTS: Tumor abutted the PBT in 31 %, esophagus in 31 %, great vessel in 65 %, and heart in 42 % of cases. 96 % of fractions were treated with reoptimized plan, necessary to meet OAR constraints (80 %) and/or target coverage (20 %). Median follow-up was 19 months (27 months among surviving patients). Local control (LC) was 96 % at 1-year and 90 % at 2-years (total 2/26 local failure). 23 % had G2 acute toxicities (esophagitis, dysphagia, anorexia, nausea) and one (4 %) had G3 acute radiation dermatitis. There were no G4-5 acute toxicities. There was no symptomatic pneumonitis and no G2 + late toxicities. CONCLUSION: Isotoxic 5-fraction SMART resulted in high rates of LC and minimal toxicity. This approach may widen the therapeutic window for high-risk oligoprogressive/oligometastatic thoracic tumors.

Re-irradiation of recurrent IDH-wildtype glioblastoma in the bevacizumab and immunotherapy era: Target delineation, outcomes and patterns of recurrence.

Introduction and background: While recurrent glioblastoma patients are often treated with re-irradiation, there is limited data on the use of re-irradiation in the setting of bevacizumab (BEV), temozolomide (TMZ) re-challenge, or immune checkpoint inhibition (ICI). We describe target delineation in patients with prior anti-angiogenic therapy, assess safety and efficacy of re-irradiation, and evaluate patterns of recurrence. Materials and methods: Patients with a histologically confirmed diagnosis of glioblastoma treated at a single institution between 2013 and 2021 with re-irradiation were included. Tumor, treatment and clinical data were collected. Logistic and Cox regression analysis were used for statistical analysis. Results: One hundred and seventeen recurrent glioblastoma patients were identified, receiving 129 courses of re-irradiation. In 66 % (85/129) of cases, patients had prior BEV. In the 80 patients (62 %) with available re-irradiation plans, 20 (25 %) had all T2/FLAIR abnormality included in the gross tumor volume (GTV). Median overall survival (OS) for the cohort was 7.3 months, and median progression-free survival (PFS) was 3.6 months. Acute CTCAE grade ≥ 3 toxicity occurred in 8 % of cases. Concurrent use of TMZ or ICI was not associated with improved OS nor PFS. On multivariable analysis, higher KPS was significantly associated with longer OS (p < 0.01). On subgroup analysis, patients with prior BEV had significantly more marginal recurrences than those without (26 % vs. 13 %, p < 0.01). Conclusion: Re-irradiation can be safely employed in recurrent glioblastoma patients. Marginal recurrence was more frequent in patients with prior BEV, suggesting a need to consider more inclusive treatment volumes incorporating T2/FLAIR abnormality.

MR-guided prostate SBRT in prostate cancer patients with low-volume metastatic disease.

BACKGROUND: Recent data have found an overall survival benefit from prostate-directed radiotherapy in patients with low-volume metastatic prostate cancer. Prostate SBRT is an attractive treatment in this setting and may be optimised with MR-guided adaptive treatment. Here, we share our institutional experience delivering stereotactic MR-guided adaptive prostate SBRT (SMART) for patients with low-volume metastatic disease. METHODS: We reviewed patients with low-volume metastatic disease who received prostate SMART from October 2019 to December 2021 on a 0.35T MR-Linac. The cohort included 14 patients. Genitourinary (GU) and gastrointestinal (GI) toxicities were assessed using CTCAE v 5.0. Progression was defined as a change in systemic or hormonal therapy regimen as a result of PSA rise or disease progression. RESULTS: The median follow-up time was 29 months. Seven patients had hormone sensitive prostate cancer and 7 had castrate resistant prostate cancer (CRPC). 13 patients received 36.25 Gy in 5 fractions and one patient received 33 Gy in 5 fractions. At the time of last follow-up, 11 patients had not experienced progression and three patients, all with CRPC, had experienced progression. No patients developed local progression in the prostate after SMART. One patient experienced acute grade 2 urinary toxicity (7%) and no patients experienced acute grade 2 GI toxicity (0%). No grade 3 + acute toxicities were observed. CONCLUSIONS: Prostate SMART was found to be well tolerated and all patients had local control of disease within the prostate at the time of last follow-up. Prostate SMART may represent a low-risk and well-tolerated approach for delivering prostate-directed radiotherapy for patients with limited metastatic disease.

Inaugural Results of the Individualized Screening Trial of Innovative Glioblastoma Therapy: A Phase II Platform Trial for Newly Diagnosed Glioblastoma Using Bayesian Adaptive Randomization.

PURPOSE: The Individualized Screening Trial of Innovative Glioblastoma Therapy (INSIGhT) is a phase II platform trial that uses response adaptive randomization and genomic profiling to efficiently identify novel therapies for phase III testing. Three initial experimental arms (abemaciclib [a cyclin-dependent kinase [CDK]4/6 inhibitor], neratinib [an epidermal growth factor receptor [EGFR]/human epidermal growth factor receptor 2 inhibitor], and CC-115 [a deoxyribonucleic acid-dependent protein kinase/mammalian target of rapamycin inhibitor]) were simultaneously evaluated against a common control arm. We report the results for each arm and examine the feasibility and conduct of the adaptive platform design. PATIENTS AND METHODS: Patients with newly diagnosed O6-methylguanine-DNA methyltransferase-unmethylated glioblastoma were eligible if they had tumor genotyping to identify prespecified biomarker subpopulations of dominant glioblastoma signaling pathways (EGFR, phosphatidylinositol 3-kinase, and CDK). Initial random assignment was 1:1:1:1 between control (radiation therapy and temozolomide) and the experimental arms. Subsequent Bayesian adaptive randomization was incorporated on the basis of biomarker-specific progression-free survival (PFS) data. The primary end point was overall survival (OS), and one-sided P values are reported. The trial is registered with ClinicalTrials.gov (identifier: NCT02977780). RESULTS: Two hundred thirty-seven patients were treated (71 control; 73 abemaciclib; 81 neratinib; 12 CC-115) in years 2017-2021. Abemaciclib and neratinib were well tolerated, but CC-115 was associated with ≥ grade 3 treatment-related toxicity in 58% of patients. PFS was significantly longer with abemaciclib (hazard ratio [HR], 0.72; 95% CI, 0.49 to 1.06; one-sided P = .046) and neratinib (HR, 0.72; 95% CI, 0.50 to 1.02; one-sided P = .033) relative to the control arm but there was no PFS benefit with CC-115 (one-sided P = .523). None of the experimental therapies demonstrated a significant OS benefit (P > .05). CONCLUSION: The INSIGhT design enabled efficient simultaneous testing of three experimental agents using a shared control arm and adaptive randomization. Two investigational arms had superior PFS compared with the control arm, but none demonstrated an OS benefit. The INSIGhT design may promote improved and more efficient therapeutic discovery in glioblastoma. New arms have been added to the trial.

A genomic score to predict local control among patients with brain metastases managed with radiation.

BACKGROUND: Clinical predictors of local recurrence following radiation among patients with brain metastases (BrM) provide limited explanatory power. We developed a DNA-based signature of radiotherapeutic efficacy among patients with BrM to better characterize recurrence risk. METHODS: We identified 570 patients with 1487 BrM managed with whole-brain (WBRT) or stereotactic radiation therapy at Brigham and Women's Hospital/Dana-Farber Cancer Institute (2013-2020) for whom next-generation sequencing panel data (OncoPanel) were available. Fine/Gray's competing risks regression was utilized to compare local recurrence on a per-metastasis level among patients with versus without somatic alterations of likely biological significance across 84 genes. Genes with a q-value ≤ 0.10 were utilized to develop a "Brain-Radiation Prediction Score" ("Brain-RPS"). RESULTS: Genomic alterations in 11 (ATM, MYCL, PALB2, FAS, PRDM1, PAX5, CDKN1B, EZH2, NBN, DIS3, and MDM4) and 2 genes (FBXW7 and AURKA) were associated with decreased or increased risk of local recurrence, respectively (q-value ≤ 0.10). Weighted scores corresponding to the strength of association with local failure for each gene were summed to calculate a patient-level RPS. On multivariable Fine/Gray's competing risks regression, RPS [1.66 (1.44-1.91, P < .001)], metastasis-associated edema [1.60 (1.16-2.21), P = .004], baseline size [1.02 (1.01-1.03), P < .001] and receipt of WBRT without local therapy [4.04 (2.49-6.58), P < .001] were independent predictors of local failure. CONCLUSIONS: We developed a genomic score to quantify local recurrence risk following brain-directed radiation. To the best of our knowledge, this represents the first study to systematically correlate DNA-based alterations with radiotherapeutic outcomes in BrM. If validated, Brain-RPS has potential to facilitate clinical trials aimed at genome-based personalization of radiation in BrM.

Comparison of first-line radiosurgery for small-cell and non-small cell lung cancer brain metastases (CROSS-FIRE).

INTRODUCTION: Historical reservations regarding stereotactic radiosurgery (SRS) for small-cell lung cancer (SCLC) brain metastases include concerns for short-interval and diffuse central nervous system (CNS) progression, poor prognoses, and increased neurological mortality specific to SCLC histology. We compared SRS outcomes for SCLC and non-small cell lung cancer (NSCLC) where SRS is well established. METHODS: Multicenter first-line SRS outcomes for SCLC and NSCLC from 2000 to 2022 were retrospectively collected (n = 892 SCLC, n = 4785 NSCLC). Data from the prospective Japanese Leksell Gamma Knife Society (JLGK0901) clinical trial of first-line SRS were analyzed as a comparison cohort (n = 98 SCLC, n = 814 NSCLC). Overall survival (OS) and CNS progression were analyzed using Cox proportional hazard and Fine-Gray models, respectively, with multivariable adjustment for cofactors including age, sex, performance status, year, extracranial disease status, and brain metastasis number and volume. Mutation-stratified analyses were performed in propensity score-matched retrospective cohorts of epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) positive NSCLC, mutation-negative NSCLC, and SCLC. RESULTS: OS was superior for patients with NSCLC compared to SCLC in the retrospective dataset (median OS = 10.5 vs 8.6 months; P < .001) and in the JLGK0901 dataset. Hazard estimates for first CNS progression favoring NSCLC were similar in both datasets but reached statistical significance in the retrospective dataset only (multivariable hazard ratio = 0.82, 95% confidence interval = 0.73 to 0.92, P = .001). In the propensity score-matched cohorts, there were continued OS advantages for NSCLC patients (median OS = 23.7 [EGFR and ALK positive NSCLC] vs 13.6 [mutation-negative NSCLC] vs 10.4 months [SCLC], pairwise P values < 0.001), but no statistically significant differences in CNS progression were observed in the matched cohorts. Neurological mortality and number of lesions at CNS progression were similar for NSCLC and SCLC patients. Leptomeningeal progression was increased in patients with NSCLC compared to SCLC in the retrospective dataset only (multivariable hazard ratio = 1.61, 95% confidence interval = 1.14 to 2.26, P = .007). CONCLUSIONS: After SRS, SCLC histology was associated with shorter OS compared to NSCLC. CNS progression occurred earlier in SCLC patients overall but was similar in patients matched on baseline factors. SCLC was not associated with increased neurological mortality, number of lesions at CNS progression, or leptomeningeal progression compared to NSCLC. These findings may better inform clinical expectations and individualized decision making regarding SRS for SCLC patients.

Evaluation of Standard Response Assessment in Neuro-Oncology, Modified Response Assessment in Neuro-Oncology, and Immunotherapy Response Assessment in Neuro-Oncology in Newly Diagnosed and Recurrent Glioblastoma.

PURPOSE: The Response Assessment in Neuro-Oncology (RANO) criteria are widely used in high-grade glioma clinical trials. We compared the RANO criteria with updated modifications (modified RANO [mRANO] and immunotherapy RANO [iRANO] criteria) in patients with newly diagnosed glioblastoma (nGBM) and recurrent GBM (rGBM) to evaluate the performance of each set of criteria and inform the development of the planned RANO 2.0 update. MATERIALS AND METHODS: Evaluation of tumor measurements and fluid-attenuated inversion recovery (FLAIR) sequences were performed by blinded readers to determine disease progression using RANO, mRANO, iRANO, and other response assessment criteria. Spearman's correlations between progression-free survival (PFS) and overall survival (OS) were calculated. RESULTS: Five hundred twenty-six nGBM and 580 rGBM cases were included. Spearman's correlations were similar between RANO and mRANO (0.69 [95% CI, 0.62 to 0.75] v 0.67 [95% CI, 0.60 to 0.73]) in nGBM and rGBM (0.48 [95% CI, 0.40 to 0.55] v 0.50 [95% CI, 0.42 to 0.57]). In nGBM, requirement of a confirmation scan within 12 weeks of completion of radiotherapy to determine progression was associated with improved correlations. Use of the postradiation magnetic resonance imaging (MRI) as baseline scan was associated with improved correlation compared with use of the pre-radiation MRI (0.67 [95% CI, 0.60 to 0.73] v 0.53 [95% CI, 0.42 to 0.62]). Evaluation of FLAIR sequences did not improve the correlation. Among patients who received immunotherapy, Spearman's correlations were similar among RANO, mRANO, and iRANO. CONCLUSION: RANO and mRANO demonstrated similar correlations between PFS and OS. Confirmation scans were only beneficial in nGBM within 12 weeks of completion of radiotherapy, and there was a trend in favor of the use of postradiation MRI as the baseline scan in nGBM. Evaluation of FLAIR can be omitted. The iRANO criteria did not add significant benefit in patients who received immune checkpoint inhibitors.

Incidence proportion and prognosis of leptomeningeal disease among patients with breast vs. non-breast primaries.

BACKGROUND: Leptomeningeal disease (LMD) is a relatively uncommon manifestation of advanced cancer. Patients with LMD carry a poor prognosis and often decline rapidly, complicating inclusion in clinical trials. Identification of LMD subsets of greater incidence and more favorable prognosis might facilitate dedicated clinical trials in the future. We hypothesized that patients with breast cancer may represent such a population and sought to assess the relative incidence and prognosis of LMD secondary to breast vs. non-breast primaries. METHODS: We identified 2411 patients with intracranial metastases secondary to breast (N = 501) and non-breast (N = 1910) primaries at Brigham and Women's Hospital/Dana-Farber Cancer Institute between 1996 and 2020, of whom 112 presented with and an additional 161 subsequently developed LMD. A log-rank test and Cox modeling were used to compare outcomes in patients with breast vs. non-breast primaries. RESULTS: Among patients with newly diagnosed intracranial disease, the incidence proportion of concurrent LMD was 11.4% vs. 2.9% among patients with breast vs. non-breast primaries (P < .001). Development of LMD among initially LMD-naïve patients was also more common among patients with breast vs. non-breast primaries (HR = 1.49 [1.05-2.11], P = .03). Patients with LMD secondary to breast vs. non-breast primaries displayed lower all-cause mortality (HR 0.70 [0.52-0.93], P = .01; median survival: 5.2 vs. 2.4 months, respectively), with a greater numerical difference observed in patients with LMD at intracranial involvement (7.4 vs. 2.6 months, respectively). CONCLUSIONS: Patients with breast cancer and LMD may represent an ideal population for clinical trials given the higher incidence and potentially more favorable prognosis seen in this population.

Phase I study of a novel glioblastoma radiation therapy schedule exploiting cell-state plasticity.

BACKGROUND: Glioblastomas comprise heterogeneous cell populations with dynamic, bidirectional plasticity between treatment-resistant stem-like and treatment-sensitive differentiated states, with treatment influencing this process. However, current treatment protocols do not account for this plasticity. Previously, we generated a mathematical model based on preclinical experiments to describe this process and optimize a radiation therapy fractionation schedule that substantially increased survival relative to standard fractionation in a murine glioblastoma model. METHODS: We developed statistical models to predict the survival benefit of interventions to glioblastoma patients based on the corresponding survival benefit in the mouse model used in our preclinical study. We applied our mathematical model of glioblastoma radiation response to optimize a radiation therapy fractionation schedule for patients undergoing re-irradiation for glioblastoma and developed a first-in-human trial (NCT03557372) to assess the feasibility and safety of administering our schedule. RESULTS: Our statistical modeling predicted that the hazard ratio when comparing our novel radiation schedule with a standard schedule would be 0.74. Our mathematical modeling suggested that a practical, near-optimal schedule for re-irradiation of recurrent glioblastoma patients was 3.96 Gy × 7 (1 fraction/day) followed by 1.0 Gy × 9 (3 fractions/day). Our optimized schedule was successfully administered to 14/14 (100%) patients. CONCLUSIONS: A novel radiation therapy schedule based on mathematical modeling of cell-state plasticity is feasible and safe to administer to glioblastoma patients.

Less Time Is Less Motion: Analysis of Practical Efficiencies Gained With a Modified Workflow Integrating Planar kV Midimaging With CBCT for Spine Stereotactic Body Radiation Therapy.

Purpose: Our purpose was to optimize an image guided radiation therapy (IGRT) workflow to achieve practical setup accuracy in spine stereotactic body radiation therapy (SBRT). We assessed the time-saving efficiencies gained from incorporating planar kV midimaging as a surrogate for cone beam computed tomography (CBCT) for intrafraction motion monitoring. Methods and Materials: We selected 5 thoracic spine SBRT patients treated in 5 fractions and analyzed patient shifts captured by a modified IGRT workflow using planar kV midimaging integrated with CBCT to maintain a tolerance of 1 mm and 1°. We determined the frequency at which kV midimaging captured intrafraction motion as validated on repeat CBCT and assessed the potential time and dosimetric advantages of our modified IGRT workflow. Results: Patient motion, detected as out-of-tolerance shifts on planar kV midimaging, occurred during 6 of 25 fractions (24%) and were validated on repeat CBCT 100% of the time. Observed intrafraction absolute shifts (mean ± standard deviation) for the 25 fractions were 0.39 ± 0.21, 0.56 ± 0.22, and 0.45 ± 0.21 mm for lateral-longitude-vertical translations and 0.38 ± 0.12°, 0.32 ± 0.09°, and 0.47 ± 0.14° for pitch-roll-yaw rotation, which if uncorrected, could have significantly affected target coverage and increased spinal cord dose. The average times for pretreatment imaging, midtreatment verification, and total treatment time were 8.94, 2.81, and 16.21 minutes. Our modified IGRT workflow reduced the total number of CBCTs required from 120 to 35 (70%) and imaging dose from 126.2 to 43.4 cGy (65.6%) while maintaining high fidelity for our patient population. Conclusions: Accurate patient positioning was effectively achieved with use of multiple 2-dimensional-3-dimensional kV images and an average of 1 verification CBCT scan per fraction. Integration of planar kV midimaging can effectively reduce treatment time associated with spine SBRT delivery and minimize the potential dosimetric effect of intrafraction motion on target coverage and spinal cord dose.

Magnetic Resonance-Guided Prostate Stereotactic Body Radiation Therapy With Daily Online Plan Adaptation: Results of a Prospective Phase 1 Trial and Supplemental Cohort.

Purpose: Stereotactic magnetic resonance (MR)-guided adaptive radiation therapy (SMART) for prostate cancer allows for MR-based contouring, real-time MR motion management, and daily plan adaptation. The clinical and dosimetric benefits associated with prostate SMART remain largely unknown. Methods and Materials: A phase 1 trial of prostate SMART was conducted with primary endpoints of safety and feasibility. An additional cohort of patients similarly treated with prostate SMART were included in the analysis. SMART was delivered to 36.25 Gy in 5 fractions to the prostate ± seminal vesicles using the MRIdian linear accelerator system (ViewRay, Inc). Rates of urinary and gastrointestinal toxic effects and patient-reported outcome measures were assessed. Dosimetric analyses were conducted to evaluate the specific benefits of daily plan adaptation. Results: The cohort included 22 patients (n = 10 phase 1, n = 12 supplemental) treated in 110 fractions. Median follow-up was 7.9 months. Acute grade 2 urinary and gastrointestinal toxic effects were observed in 22.7% and 4.5%, respectively, and 4.5% and 0%, respectively, at last follow-up. No grade 3+ events were observed. Expanded Prostate Cancer Index-26 urinary obstructive scores decreased during SMART (mean, 9.3 points; P = .03) and returned to baseline by 3 months. No other significant changes in patient-reported outcome measures were observed. One-hundred percent of fractions required plan adaptation owing to exceeding organ-at-risk metrics (68%) or suboptimal target coverage (33%) resulting from anatomic changes. Minimum acceptable planning target volume, rectal, bladder, and urethra/bladder neck metrics were violated in 24%, 20%, 24%, and 33% of predicted plans, respectively; 0% of reoptimized plans violated metrics. Underlying causes for deficient dosimetry before reoptimization included changes in bladder filling, seminal vesicle position, prostate volume (median 4.7% increase by fraction 3; range, 0%-56%), and hotspots shifting into urethra/bladder neck. Conclusions: Prostate SMART results in low risk of acute toxic effects with improvements in target and organ-at-risk dosimetry. The clinical benefits resulting from daily plan adaptation, including urethra/bladder neck protection, warrant further investigation.

Stereotactic Magnetic Resonance-Guided Adaptive Radiation Therapy (SMART) for Abdominopelvic Oligometastases.

PURPOSE: Stereotactic body radiation therapy can be an effective treatment for oligometastases. However, safe delivery of ablative radiation is frequently limited by the proximity of mobile organs sensitive to high radiation doses. The goal of this study was to determine the feasibility, safety, and disease control outcomes of stereotactic magnetic resonance-guided adaptive radiation therapy (SMART) in patients with abdominopelvic oligometastases. METHODS AND MATERIALS: We identified 101 patients with abdominopelvic oligometastases, including 20 patients enrolled on phase 1 protocols, who were consecutively treated with SMART on a 0.35T magnetic resonance linear accelerator (MR linac) at a single institution from October 2019 to September 2021. Local control and overall survival were analyzed using the Kaplan-Meier method. RESULTS: Overall, 114 tumors were treated. The most common histology was prostate adenocarcinoma (60 tumors [53.5%]), and 65 sites (57.0%) were centered in the pelvis. Ninety-one sites (79.8%) were treated to 8 Gy × 5, and 49 (43.0%) were treated with breath-hold respiratory gating. Online adaptation resulted in a clinically significant improvement in coverage or organ sparing in 86.6% of delivered fractions. The median time required for adaptation was 24 minutes, and the median time in the treatment room was 58 minutes. With median follow-up of 11.4 months, the 12-month local control was 93% and was higher for prostate adenocarcinoma versus other histologies (100% vs 84%; P = .009). The 12-month overall survival was 96% and was higher for prostate adenocarcinoma versus other histologies (100% vs 91%; P = .046). Three patients (3.0%) developed grade 3 toxic effects (colonic hemorrhage at 3.4 months and urinary tract obstructions at 10.1 and 18.4 months, respectively). CONCLUSIONS: In this study, SMART was feasible, safe, and effective for delivering ablative radiation therapy to abdominopelvic metastases. Adaptive planning was necessary in the large majority of cases. The advantages of SMART warrant its further investigation as a standard option for the treatment of abdominopelvic oligometastases.

Frequency, etiologies, risk factors, and sequelae of falls among patients with brain metastases: A population- and institutional-level analysis.

Background: Falls in patients with cancer harbor potential for serious sequelae. Patients with brain metastases (BrM) may be especially susceptible to falls but supporting investigations are lacking. We assessed the frequency, etiologies, risk factors, and sequelae of falls in patients with BrM using 2 data sources. Methods: We identified 42 648 and 111 patients with BrM utilizing Surveillance, Epidemiology, and End Results (SEER)-Medicare data (2008-2016) and Brigham and Women's Hospital/Dana-Farber Cancer Institute (BWH/DFCI) institutional data (2015), respectively, and characterized falls in these populations. Results: Among SEER-Medicare patients, 10 267 (24.1%) experienced a fall that prompted medical evaluation, with cumulative incidences at 3, 6, and 12 months of 18.0%, 24.3%, and 34.1%, respectively. On multivariable Fine/Gray's regression, older age (≥81 or 76-80 vs 66-70 years, hazard ratio [HR] 1.18 [95% CI, 1.11-1.25], P < .001 and HR 1.10 [95% CI, 1.04-1.17], P < .001, respectively), Charlson comorbidity score of >2 vs 0-2 (HR 1.08 [95% CI, 1.03-1.13], P = .002) and urban residence (HR 1.08 [95% CI, 1.01-1.16], P = .03) were associated with falls. Married status (HR 0.94 [95% CI, 0.90-0.98], P = .004) and Asian vs white race (HR 0.90 [95% CI, 0.81-0.99], P = .03) were associated with reduced fall risk. Identified falls were more common among BWH/DFCI patients (N = 56, 50.4% of cohort), resulting in emergency department visits, hospitalizations, fractures, and intracranial hemorrhage in 33%, 23%, 11%, and 4% of patients, respectively. Conclusions: Falls are common among patients with BrM, especially older/sicker patients, and can have deleterious consequences. Risk-reduction measures, such as home safety checks, physical therapy, and medication optimization, should be considered in this population.

Graded Prognostic Assessment (GPA) for Patients With Lung Cancer and Brain Metastases: Initial Report of the Small Cell Lung Cancer GPA and Update of the Non-Small Cell Lung Cancer GPA Including the Effect of Programmed Death Ligand 1 and Other Prognostic Factors.

PURPOSE: 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. METHODS AND MATERIALS: 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. RESULTS: 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. CONCLUSIONS: 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.

Incidence and Predictors of Neurologic Death in Patients with Brain Metastases.

OBJECTIVE: Neurologic death is the most serious consequence of intracranial disease among patients with brain metastases. Identifying patients with brain metastases at increased risk of neurologic death can improve care and guide further research. We sought to delineate factors predictive of neurologic death among patients with brain metastases. METHODS: We identified 1218 patients with newly diagnosed brain metastases managed at Brigham and Women's Hospital/Dana-Farber Cancer Institute from 2008-2015. Factors predictive of neurologic death were assessed via univariable and multivariable Fine and Gray competing risks regression. RESULTS: On multivariable analysis, neurologic death was associated with number of brain metastases (hazard ratio [HR] 1.01 per 1 metastasis increase, 95% confidence interval [CI] 1.01-1.02, P < 0.001) and 3 primary tumor sites (reference=non-small cell lung cancer): melanoma (HR 4.67, 95% CI 3.27-6.68, P < 0.001), small cell lung cancer (HR 2.33, 95% CI 1.47-3.68, P < 0.001), and gastrointestinal cancer (HR 2.21, 95% CI 1.28-3.82, P = 0.005). Conversely, a reduction in neurologic death was found in patients with good Karnofsky performance status (90-100 vs. 30-80, HR 0.67, 95% CI 0.48-0.95, P = 0.03) and progressive extracranial metastases at diagnosis of intracranial disease (HR 0.50, 95% CI 0.38-0.67, P = 0.001). Among patients with breast primaries, HER2+ patients displayed increased neurologic death relative to the reference of HR+/HER2- (univariable analysis only: HR 2.41, 95% CI 1.00-5.84, P = 0.05). CONCLUSIONS: Patients with melanoma, small cell lung cancer, gastrointestinal cancer, and HER2+ breast cancer primaries, as well as greater intracranial versus extracranial disease burden, harbor significant risk of neurologic death. Future research investigating novel intracranial approaches should focus on these populations.

Patient specific distortion detection and mitigation in MR images used for stereotactic radiosurgery.

Objective.In MRI-based radiation therapy planning, mitigating patient-specific distortion with standard high bandwidth scans can result in unnecessary sacrifices of signal to noise ratio. This study investigates a technique for distortion detection and mitigation on a patient specific basis.Approach.Fast B0 mapping was performed using a previously developed technique for high-resolution, large dynamic range field mapping without the need for phase unwrapping algorithms. A phantom study was performed to validate the method. Distortion mitigation was validated by reducing geometric distortion with increased acquisition bandwidth and confirmed by both the B0 mapping technique and manual measurements. Images and contours from 25 brain stereotactic radiosurgery patients and 95 targets were analyzed to estimate the range of geometric distortions expected in the brain and to estimate bandwidth required to keep all treatment targets within the ±0.5 mm iso-distortion contour.Main Results.The phantom study showed, at 3 T, the technique can measure distortions with a mean absolute error of 0.12 mm (0.18 ppm), and a maximum error of 0.37 mm (0.6 ppm). For image acquisition at 3 T and 1.0 mm resolution, mean absolute distortion under 0.5 mm in patients required bandwidths from 109 to 200 Hz px-1for patients with the least and most distortion, respectively. Maximum absolute distortion under 0.5 mm required bandwidths from 120 to 390 Hz px-1.Significance.The method for B0 mapping was shown to be valid and may be applied to assess distortion clinically. Future work will adapt the readout bandwidth to prospectively mitigate distortion with the goal to improve radiosurgery treatment outcomes by reducing healthy tissue exposure.

Update on Radiation Therapy for Central Nervous System Tumors.

Radiation therapy has long been a critical modality of treatment of patients with central nervous system tumors, including primary brain tumors, brain metastases, and meningiomas. Advances in radiation technology and delivery have allowed for more precise treatment to optimize patient outcomes and minimize toxicities. Improved understanding of the molecular underpinnings of brain tumors and normal brain tissue response to radiation will allow for continued refinement of radiation treatment approaches to improve clinical outcomes for brain tumor patients. With continued advances in precision and delivery, radiation therapy will continue to be an important modality to achieve optimal outcomes of brain tumor patients.