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OBJECTIVE The authors’ objective was to examine the safety and efficacy of salvage intracranial cesium-131 brachytherapy in combination with resection of recurrent brain tumors. METHODS The authors conducted a retrospective chart review of consecutive patients treated with intraoperative intracranial cesium-131 brachytherapy at a single institution. Permanent suture-stranded cesium-131 seeds were implanted in the resection cavity after maximal safe tumor resection. The primary outcomes of interest were local, locoregional (within 1 cm), and intracranial control, as well as rates of overall survival (OS), neurological death, symptomatic adverse radiation effects (AREs), and surgical complication rate graded according to Common Terminology Criteria for Adverse Events version 5.0. RESULTS Between 2016 and 2020, 36 patients received 40 consecutive cesium-131 implants for 42 recurrent brain tumors and received imaging follow-up for a median (interquartile range [IQR]) of 17.0 (12.7–25.9) months. Twenty patients (55.6%) with 22 implants were treated for recurrent brain metastasis, 12 patients (33.3%) with 16 implants were treated for recurrent atypical (n = 7) or anaplastic (n = 5) meningioma, and 4 patients (11.1%) were treated for other recurrent primary brain neoplasms. All except 1 tumor (97.6%) had received prior radiotherapy, including 20 (47.6%) that underwent 2 or more prior radiotherapy treatments and 23 (54.8%) that underwent prior resection. The median (IQR) tumor size was 3.0 (2.3–3.7) cm, and 17 lesions (40.5%) had radiographic evidence of ARE prior to salvage therapy. Actuarial 1-year local/locoregional/intracranial control rates for the whole cohort and patients with metastases and meningiomas were 91.6%/83.4%/47.9%, 88.8%/84.4%/45.4%, and 100%/83.9%/46.4%, respectively. No cases of local recurrence of any histology (0 of 27) occurred after gross-total resection (p = 0.012, log-rank test). The 1-year OS rates for the whole cohort and patients with metastases and meningiomas were 82.7%, 79.1%, and 91.7%, respectively, and the median (IQR) survival of all patients was 26.7 (15.6–36.4) months. Seven patients (19.4%) experienced neurological death from progressive intracranial disease (7 of 14 total deaths [50%]), 5 (13.9%) of whom died of leptomeningeal disease. Symptomatic AREs were observed in 9.5% of resection cavities (n = 4), of which 1 (2.4%) was grade 3 in severity. The surgical complication rate was 16.7% (n = 7); 4 (9.5%) of these patients had grade 3 or higher complications, including 1 patient (2.4%) who died perioperatively. CONCLUSIONS Cesium-131 brachytherapy resulted in good local control and acceptable rates of symptomatic AREs and surgical complications in this heavily pretreated cohort, and it may be a reasonable salvage adjuvant treatment for this patient population.

Brain metastases occur frequently in advanced melanoma and traditionally require surgery and radiation therapy. New evidence demonstrates that systemic therapies are effective for controlling metastatic melanoma brain metastases. This study evaluated outcomes after resection of melanoma brain metastases treated with systemic therapy, with or without focal radiotherapy.All patients received immunotherapy or BRAF/MEK inhibitors preoperatively or in the immediate 3 months postoperatively. Resection cavity failure, distant central nervous system progression, and adverse radiation effects were reported in the presence and absence of focal radiotherapy using the Kaplan-Meier method.Between 2011 and 2020, 37 resection cavities in 29 patients met criteria for analysis. Of lesions, 22 (59%) were treated with focal radiotherapy, and 15 (41%) were treated with targeted therapy or immunotherapy alone. The 12- and 24-month freedom from local recurrence was 64.8% (95% confidence interval [CI] 42.1%-99.8%) and 46.3% (95% CI 24.5%-87.5%), respectively, for systemic therapy alone and 93.3% (95% CI 81.5%-100%) at both time points for focal radiotherapy (P = 0.01). On univariate analysis, focal radiotherapy was the only significant factor associated with reduction of local recurrence risk (hazard ratio 0.10, 95% CI 0.01-0.85; P = 0.04). There were no significant differences in central nervous system progression-free survival or overall survival between patients who received systemic therapy plus focal radiotherapy compared with systemic therapy alone. BRAF mutation status was reviewed for either the brain metastasis (n = 9 patients, 31%) or the primary site (n = 20 patients, 69%), and patients harboring BRAFFocal radiotherapy with systemic therapy for resected melanoma brain metastases significantly decreased resection cavity recurrence compared with systemic therapy alone. BRAF mutation status correlated with poorer outcomes.

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: Brain metastases are a common occurrence, with literature supporting the treatment of a limited number of brain metastases with stereotactic radiosurgery (SRS), as opposed to whole brain radiotherapy (WBRT). Less well understood is the role of SRS in patients with ≥10 brain metastases. METHODS: Patients treated with SRS to ≥10 brain metastases without concurrent WBRT between March 1999 and December 2016 were reviewed. Analysis was performed for overall survival, treated lesion freedom from progression (FFP), freedom from new metastases (FFNMs), and adverse radiation effect. Hippocampal volumes were retrospectively generated in patients treated with up-front SRS for evaluation of dose volume metrics. RESULTS: A total of 143 patients were identified with 75 patients having up-front SRS and 68 patients being treated as salvage therapy after prior WBRT. The median number of lesions per patient was 13 (interquartile range [IQR], 11–17). Median total volume of treatment was 4.1 cm(3) (IQR, 2.0–9.9 cm(3)). The median 12-month FFP for up-front and salvage treatment was 96.8% (95% confidence interval [CI], 95.5–98.1) and 83.6% (95% CI, 79.9–87.5), respectively (P < 0.001). Twelve-month FFNMs for up-front and salvage SRS was 18.8% (95% CI, 10.9–32.3) versus 19.2% (95% CI, 9.7–37.8), respectively (P = 0.90). The mean hippocampal dose was 150 cGy (IQR, 100–202 cGy). CONCLUSIONS: Excellent rates of local control can be achieved when treating patients with >10 intracranial metastases either in the up-front or salvage setting. Hippocampal sparing is readily achievable with expected high rates of new metastatic lesions in treated patients.

Understanding the molecular landscape and microenvironment of melanoma brain metastases is critical to devise improved treatments. Here, we perform bulk and single cell genomic analysis of melanoma brain metastases to identify molecular correlates of clinical outcome. 84 consecutive patients who underwent surgical resection at a single institution with a histo-pathologically confirmed diagnosis of melanoma brain metastasis were retrospectively identified. In 60 patients (71%) with sufficient brain metastasis tissue for targeted next generation sequencing, DNA mutations were assessed with a CLIA certified sequencing assay. Single nuclear RNA sequencing using the 10x platform was performed on n=6 samples from treatment naïve patients. Overall survival (OS) and CNS progression free survival (CNS PFS) from time of brain metastasis diagnosis were estimated using the Kaplan-Meier method. The median patient age was 62 years old (range: 25-78 years), and the median clinical follow up was 17 months. A total of 33 patients (39%) had BRAFV600E melanoma brain metastases. Multivariate analysis incorporating age, performance status, and extracranial disease revealed BRAF status was an independent prognostic factor for OS (p< 0.05). In patients undergoing targeted next generation sequencing, the most common pathogenic variant was TERT promoter mutation (n=44; 73%). With regard to TCGA molecular melanoma subgroups, NRAS mutant (n=22; 37%) brain metastases were most common followed by BRAF mutant (n=20; 33%), NF1 mutant (n=11; 18%), and triple wildtype (n=7; 12%). Evaluation of clinical outcomes in the context of next generation sequencing results revealed no differences by TERT status but demonstrated worse overall survival in the BRAF mutant molecular group (p< 0.01, log-rank test). Single nuclear sequencing of 36,115 nuclei across 6 samples revealed BRAF wildtype tumors exhibit greater infiltrating immune cell populations including microglia and T cell subtypes. Future work will require integration of these findings with different systemic therapy regimens and across larger, prospective, multi-institutional cohorts.

In response to the COVID-19 pandemic, many medical schools suspended clinical clerkships and implemented newly adapted curricula to facilitate continued educational progress. While the implementation of these new curricula has been described, an understanding of the impact on student learning outcomes is lacking. In 2020, the authors followed Kern's 6-step approach to curricular development to create and evaluate a novel COVID-19 curriculum for medical students at the University of California San Francisco School of Medicine and evaluate its learning outcomes. The primary goal of the curriculum was to provide third- and fourth-year medical students an opportunity for workplace learning in the absence of clinical clerkships, specifically for students to develop clerkship-level milestones in the competency domains of practice-based learning and improvement, professionalism, and systems-based practice. The curriculum was designed to match students with faculty-mentored projects occurring primarily in virtual formats. A total of 126 students enrolled in the curriculum and completed a survey about their learning outcomes (100% response rate). Of 35 possible clerkship-level milestones, there were 12 milestones for which over half of students reported development, in competency domains including practice-based learning and improvement, professionalism, and interpersonal and communication skills. Thematic analysis of students' qualitative survey responses demonstrated 2 central motivations for participating in the curriculum: identity as physicians-in-training, and patient engagement. Six central learning areas were developed during the curriculum: interprofessional teamwork, community resources, technology in medicine, skill-building, quality improvement, and specialty-specific learning. This analysis demonstrates that students can develop competencies and achieve rich workplace learning through project-based experiential learning, even in virtual clinical workplaces. Furthermore, knowledge of community resources, technology in medicine, and quality improvement were developed through the curriculum more readily than in traditional clerkships, and could be considered as integral learning objectives in future curricular design.

Quality improvement (QI) and patient safety (PS) are cornerstones of health care delivery. Accreditation organizations increasingly require that learners engage in QIPS. For many faculty, these are new domains. Additional faculty development is needed for them to teach and mentor trainees. Existing programs, such as the Association of American Medical Colleges Teaching for Quality (Te4Q) program, target individual faculty and thus accommodate only limited participants at a time, which is problematic for institutions that need to train many faculty to support their learners.The authors invited diverse stakeholders from across the University of California, San Francisco (UCSF) School of Medicine and related health systems to participate in a team-based adaptation of the Te4Q program. The teams completed 5 projects based on previously identified priority areas to increase local capacity for QIPS teaching: (1) online modules for faculty new to QIPS, (2) a tool kit for graduate medical education programs, (3) a module for medical school clerkship directors, (4) guidelines for faculty to integrate early learners into QI projects, and (5) a "Teach-for-UCSF" certificate program in teaching QIPS.Thirty-five faculty members participated in the initial Te4Q workshop in January 2015, and by fall 2016, all projects were implemented. These projects led to additional faculty development initiatives and a rapidly expanding number of faculty across campus with expertise in teaching QIPS.Further collaborations between faculty focused on QIPS in care delivery and those focused on QIPS education to promote QIPS teaching have resulted from these initial projects.

Purpose Previous studies suggest that within radiation oncology, medical physicists (MP) experience high workloads. Little is known about how MPs use social support (SS) in times of stress. Methods In collaboration with the Workgroup on Prevention of Medical Error, the American Association of Physicists in Medicine administered this Human Investigation Committee (HIC) approved email survey to 8566 members. Respondents were considered likely to seek SS if they answered (probably/definitely would) and unlikely to seek support if they answered (probably/definitely would not). Logistic regression was applied to determine associations between demographic factors and willingness to seek support as well as perception of barriers. Results One thousand two hundred and ninety‐seven members (15.1%) accessed and gave consent for the survey. One thousand and one (11.7%) respondents answered all relevant questions. Respondents were predominantly male (69.1%), MP in radiation oncology (81.8%), private practice (51.6%), with practice duration> 10 yr (60.2%). MPs were likely to seek SS for personal physical illness (78.63%), involvement in a medical error (73.94%) or adverse patient outcome (75.17%). MPs sought SS in the setting of personal fatigue (33.2%) or burnout (44.3%). Barriers to seeking SS were lack of time (80.3%), and uncertainty about whom to access (70.7%). MPs responded that they would be most likely to seek support from an equally experienced medical physicist colleague (81.0%). Most MPs (67.0%) identified as having experienced stressors, with serious family illness (35.2%), or burnout (32.8%) being most common. Factors associated with MPs unwillingness to seek SS for medical error included> 20 yr in practice (vs still in training — OR 0.30, P = 0.015), and male gender (OR 0.60, P = 0.003). Male gender was associated with the lowest willingness to seek support (OR 2.10, P = 0.0001), but also with fewer perceived barriers (OR 1.60, P = 0.0075). Conclusion Willingness to seek SS is demonstrated, and MPs want colleagues to provide support. Given these results, peer support could be considered among MPs.

Background Optimal techniques and patient selection for salvage reirradiation of high-grade glioma (HGG) are unclear. In this study, we identify prognostic factors for freedom from progression (FFP) and overall survival (OS) after reirradiation, risk factors for high-grade toxicity, and validate clinical prognostic scores. Methods A total of 116 patients evaluated between 2000 and 2018 received reirradiation for HGG (99 WHO grade IV, 17 WHO grade III). Median time to first progression after initial therapy was 10.6 months. Salvage therapies before reirradiation included surgery (31%) and systemic therapy (41%). Sixty-five patients (56%) received single-fraction stereotactic radiosurgery (SRS) as reirradiation. The median biologically effective dose (BED) was 47.25 Gy, and the median planning target volume (PTV) was 4.8 cc for SRS and 95.0 cc for non-SRS treatments. Systemic therapy was given concurrently to 52% and adjuvantly to 74% of patients. Results Median FFP was 4.9 months, and median OS was 11.0 months. Significant multivariable prognostic factors for FFP were performance status, time to initial progression, and BED; for OS they were age, time to initial progression, and PTV volume at recurrence. High-grade toxicity was correlated to PTV size at recurrence. Three-level prognostic scores were generated for FFP and OS, with cross-validated receiver operating characteristic area under the curve (AUC) of 0.640 and 0.687, respectively. Conclusions Clinical variables at the time of reirradiation for HGG can be used to prognosticate FFP and OS.

BACKGROUND Exercise has proven benefit in patients with cancer with most studies focused on patients with high functional and neurocognitive status. Patients with brain tumors, however, frequently have deficits in cognition, motor, balance, or other symptoms that are further exacerbated by surgery and adjuvant treatment. We sought to determine providers’ knowledge, attitudes, motivating factors and preferences for integrating exercise into the treatment of patients with brain tumors. METHODS We surveyed multidisciplinary providers in Neurosurgery, Radiation Oncology and Neuro-Oncology from a single, quaternary medical center. Questions assessed demographics, current practices, attitudes, knowledge, motivating factors and barriers for integrating exercise into treatment. Questions were extrapolated from existing published questionnaires and sent electronically. RESULTS Most providers (92%) reported that exercise was important for patients' lifestyle and 80% felt it should be integrated into the treatment of patients with primary brain tumors. Nighty-six percent felt that exercise improved quality of life, decreased fatigue (100%) and reduced treatment related side effects (92%) yet only 57% of providers initiated a conversation about exercise with patients. Top motivating factors for promoting exercise were perceived benefit to patients’ quality of life and disease outcomes. Barriers to provider/patient discussions about exercise included, lack of time or appropriate expertise to discuss exercise with patients, and concern that patients have competing priorities. Some providers (23%) were concerned about potential limitations/complications with patients exercising including inability to participate from side effects of treatment (38%), physical deficits (61%) and fatigue (42%). CONCLUSION Understanding barriers for providers to incorporate exercise into their patients’ treatment regimens is critical to strategizing best practices. Findings from this study help to expand our understanding of barriers and facilitators to incorporating exercise interventions into brain cancer treatment and will assist with the implementation of a structured exercise program to enhance physical health for our patients.

The present proof-of-principle study investigated radiobiological effects of redistributing central target dose hot spots across different treatment fractions during hypofractionated stereotactic radiosurgery (HSRS) of large intracranial tumors.Redistribution of central target dose hot spots during HSRS was simulated, and its effects were evaluated in eight cases of brain metastases. To assess dose variations in the target across N number of treatment fractions, a generalized biologically effective dose (gBED) was formulated. The gBED enhancement ratio was defined as the ratio of gBED in the tested treatment plan (with central target dose hot spot redistributions across fractions) to gBED in the conventional treatment plan (without central target dose hot spot redistributions).At a median α value of 0.3/Gy, the tested treatment plans resulted in average gBED increases of 15.6 ± 3.5% and 8.3 ± 1.8% for α/β ratios of 2 and 10 Gy, respectively. In comparison with conventional treatment plans, the differences in the Paddick conformity index and gradient index did not exceed 2%.Redistributing central target dose hot spots across different treatment fractions during HSRS may be considered promising for enhancing gBED in the target. It may be beneficial for management of large intracranial neoplasms; thus, it warrants further clinical testing.

The objective of the present study was evaluation of the interrelationships between changes in the skull size and variations in the normal brain radiation dose during Gamma Knife surgery (GKS).With use of systematic modeling within Leksell GammaPlanWith changes in the skull radius within ±3 cm, the maximum absolute deviation in the mean normal brain radiation dose was 0.8%. As the skull radius increased, the mean normal brain radiation dose also increased linearly (confidence level99%) with a positive slope of 0.2% per centimeter of radius length change. The maximum point dose deviations in all evaluated critical anatomical structures did not exceed 0.5%, with an overall trend toward a dose increase in parallel with an increase in the skull radius.The small skull size of pediatric patients may be associated with dosimetric advantages in terms of normal brain sparing during GKS.

BACKGROUND Safety of immunotherapy (IO) and targeted therapy (TT) with stereotactic radiosurgery (SRS) in melanoma brain metastases (MBM) treatment remains incompletely understood. We aim to identify whether timing of IO/TT in relation to SRS impacts rates of adverse radiation effect (ARE) in MBM. METHODS Retrospective review of patients with MBM treated with SRS and IO/TT within three months prior and one year after SRS, from 2011-2021 at a single institution with at least two months MRI follow-up, identified 108 patients with 939 unique MBM meeting criteria. ARE was confirmed on independent imaging review. Concurrent IO/TT was defined as receiving IO/TT within 4 weeks before or after SRS. Data analysis was performed with the univariate cox proportional hazard model and Kaplan-Meier method. RESULTS Median radiographic follow-up from time of SRS was 16months. IO/TT was initiated prior to SRS for 681 (72.5%) metastases and after SRS for 258 (27.5%) metastases. 837 (89.1%) metastases received concurrent IO/TT. Most common IO agents were ipilimumab (n=416), nivolumab (n=448), and pembrolizumab (n=203). Most common TT agents were dabrafenib (n=548), trametinib (n=540), and vemurafenib (n=81). 2-year local progression-free survival (PFS), distant intracranial PFS, and overall survival were 94.1%, 33.3%, and 55.2%, respectively. 55 (5.9%) metastases in 33 (30.6%) patients experienced ARE. Median time to ARE was 5mo (IQR 4-9mo). Of those who experienced ARE, 22 (66.7%) patients were symptomatic and treated with steroids; 12 (36.4%) patients underwent surgical intervention. ARE rates were not impacted by concurrent vs nonconcurrent IO/TT (5.5% vs 4.9%, p=0.34) nor IO/TT initiation pre vs post SRS (6.0% vs 5.4%, p=0.61). CONCLUSION IO/TT in conjunction with SRS resulted in low ARE rates as compared to historical controls in the pre-IO/TT era. Timing of IO/TT in relation to SRS may not significantly impact ARE rates in MBM treatment.

PURPOSE: The purpose of this study is to describe outcomes after pediatric radiosurgery for malignant CNS lesions. METHODS: Retrospective chart review was performed for 31 pediatric patients treated at a single institution with Gamma Knife stereotactic radiosurgery (SRS) for primary or metastatic CNS malignancies between 2000-2020. RESULTS: 25 patients were treated with SRS for focal recurrences of primary CNS malignancies, 1 patient was treated in the adjuvant setting after initial resection, and 5 patients were treated for brain metastases. Primary CNS histologies included ependymoma (n=14), glioma (n=4), medulloblastoma (n=2), and meningioma (n=2). 65% were WHO grade 3 or 4. 71% of patients had received a prior course of involved-field external beam radiation to the brain to a median dose of 59.4 Gy in 33 fractions. Median age at SRS was 14 years (range 4-21). Radiosurgery was predominantly performed in a single fraction to a median dose of 17 Gy to a total of 42 targets among 29 patients. Two patients underwent fractionated radiosurgery to 30 Gy in 5 fractions for larger lesions. Median follow up after SRS was 44 months. 7 patients (23%) had no evidence of disease after SRS at a median follow up of 39 months. 6 patients (19%) developed local recurrence at the site of their treated lesion at a median of 13 months after SRS. 20 patients (65%) developed recurrent disease in the CNS outside of the radiosurgery field at a median of 11 months after SRS. 4 patients developed toxicity from SRS related to radiation treatment effect, all of which occurred within 1 year of SRS. CONCLUSIONS: SRS for malignant CNS lesions in the pediatric population provides effective local control and is well-tolerated. However, there remains a substantial risk of distant CNS failures given the nature of recurrent or metastatic disease in these patients.

Purpose/objective(s) Management of progressive brain tumors following high dose radiotherapy is controversial. In select cases, surgical resection can provide rapid relief of regional mass effect and edema, and highly focal adjuvant re-irradiation can be administered in the form of brachytherapy. Permanent low-dose rate cesium-131 brachytherapy may offer dosimetric and radiobiologic advantages over other isotopes. The purpose of this study was to examine the safety and efficacy of intracranial cesium-131 brachytherapy after surgical resection in a heavily pre-treated patient cohort. Materials/methods A retrospective chart review was conducted of all patients treated with intraoperative intracranial cesium-131 brachytherapy from an institutional database. Treatment consisted of maximal safe resection followed by implantation of suture-stranded cesium-131 seeds, maintaining approximately 10mm spacing between seeds, with a planned target dose of 80 Gy to 5mm depth. Local failure was defined as recurrence in or contacting the resection cavity after salvage resection and brachytherapy. Regional failure was defined as recurrence within 10mm of the resection cavity. Recurrence was defined as a new lesion or growth of ≥25% in any axial dimension on interval MRI. Toxicity was collected based on CTCAE 4.0. Results A total of 35 patients with a median imaging follow up of 17.0 months (interquartile range [IQR] 9.7-25.9) underwent 41 consecutive cesium-131 implants between 2016 and 2020. 20 patients (59%; N = 22 implants) were treated for recurrent brain metastasis, 12 patients (34%; N = 16 implants) were treated for recurrent atypical (N = 8) or anaplastic meningioma (N = 4), and 3 patients (9%) were treated for recurrent glioma (N = 2) or hemangiopericytoma (N = 1). A majority of lesions had received prior surgery (N = 28, 66.7%, range 0-3 prior surgeries) and 34 patients had received prior high dose radiation. 34 of 41 (82.9%) tumors had received prior radiosurgery, and 12 (29.2%) had undergone prior external beam radiation (range 50-60 Gy). 17 of 41 lesions (41.5%) had radiologic evidence of adverse radiation/treatment effect (ARE) prior to salvage therapy. Median tumor size was 3.0cm (IQR 2.3-3.7). Overall actuarial local/loco-regional control at 1-year was 91.6%/84.7% (89.8%/88.9% for metastases and 100%/82.5% for meningiomas). Crude loco-regional control was 86.3% for metastases, 75% for meningiomas, and 66.7% for other lesions. Symptomatic ARE following treatment was observed in 9.8% (N = 4) resection cavities. The surgical complication rate was 14.6% (N = 6 total, N = 3 [7.3%] grade 3-5) including 1 peri-operative death. Conclusion Cesium-131 brachytherapy in this heavily pre-treated cohort resulted in good local control and an acceptable rate of symptomatic adverse radiation effect and toxicity and may be a reasonable treatment option for this select population. Author disclosure W.C. Chen: None. M. Lafreniere: None. C. Phuong: None. M. Lometti: None. O. Morin: None. B.P. Ziemer: None. H. Vasudevan: Research Grant; Children's Tumor Foundation. Patent/License Fees/Copyright; Genentech, Eli Lilly. S. Hervey-Jumper: None. P.V. Theodosopoulos: None. S. Magill: None. S.E. Fogh: Independent Contractor; Accuray. J.L. Nakamura: None. L. Boreta: None. P.K. Sneed: None. M.W. McDermott: Chair; Miami Baptist. D. Raleigh: None. S.E. Braunstein: Advisory Board; Radiation Oncology Questions, LLC.

PURPOSE/OBJECTIVE(S) Previous studies have characterized dose gradient patterns for various hypo-fractionated brain radiosurgery (hSRS) treatment platforms. The Gamma Knife Icon (GKI) has consistently exhibited either superior or non-inferior peripheral dose fall-off and normal brain sparing characteristics when compared to other Linac-based hSRS treatment platforms. Given the prevalence of Linac-based treatments, identifying planning techniques to optimize treatment parameters is desirable. In this study, we investigated a novel Linac-based treatment approach that aimed to create the sharpest dose fall-off for hSRS of large brain lesions. MATERIALS/METHODS A cohort of patient cases (n = 10) with single brain lesions (volume 27.6+/-8.1 mL, range 20.-42.1 mL) treated with GKI at our institution were selected as sample test cases for our study. A non-coplanar unconstrained VMAT (NCU-VMAT) treatment planning approach was developed, and its script was implemented on a commercial treatment planning system for clinical Linac treatment equipped with the latest high-definition multi-leaf collimators (MLCs). Treatment plans produced via the NCU-VMAT approach were then compared against further optimized treatment plans from GKI, as well as conventional coplanar and non-coplanar VMAT treatment planning approaches. The comparison was carried out using DVH-derived parameters including target volume coverage, target dose conformity, modified dose fall-off index defined as the volume of 50% prescribed target dose divided by the target volume (PIV50). RESULTS For each case studied, NCU-VMAT achieved practically identical target coverage (0.98 ± 0.01) and Paddick dose conformity index (0.87 ± 0.02) compared to optimized GKI treatments. The mean PIV50 values were 2.99 ± 0.14, 3.77 ± 0.22, and 3.36 ± 0.19 for optimized GKI, conventional coplanar, and non-coplanar VMAT treatment plans, respectively. These results were in excellent agreement with previously published studies. However, the NCU-VMAT technique yielded a mean PIV50 of 2.41 ± 0.07. This represents an improvement of approximately 40% (P < 0.001, paired two-tailed Student t-test) over all existing approaches including GKI. Further analyses revealed that PIV50 of NCU-VMAT approached the theoretical minimum for all the studied cases. CONCLUSION Our results demonstrate that in treatment of large brain tumors, a treatment planning approach using Bremsstrahlung x-ray based Linacs can achieve superior dose fall-off for intracranial hSRS compared to GKI. We dispel the myth that physical characteristics of Cobalt γ-rays are needed to create the sharpest dose fall-off. Given the prevalence of Linac-based treatments compared to GKI, we present a novel optimized planning technique that achieves a new benchmark of sharpest dose fall-off. AUTHOR DISCLOSURE T. Nano: None. O. Morin: None. B.P. Ziemer: None. D. Raleigh: None. L. Boreta: None. J.L. Nakamura: None. S.E. Fogh: Independent Contractor; Accuray. P.K. Sneed: None. S. Hervey-Jumper: None. P.V. Theodosopoulos: None. S.E. Braunstein: Advisory Board; Radiation Oncology Questions, LLC.L. Ma: Patent/License Fees/Copyright; University of California Regents.

Objective: The present proof-of-principle study investigated radiobiological effects of redistributing central target dose hot spots across different treatment fractions during hypofractionated stereotactic radiosurgery (HSRS) of large intracranial tumors.

Objective: The objective of the present study was evaluation of the interrelationships between changes in the skull size and variations in the normal brain radiation dose during Gamma Knife surgery (GKS).

After radical treatment, most high-grade gliomas (HGG) recur locally. Upon recurrence, no standard treatment exists. Options include re-resection, salvage systemic therapy and re-irradiation. This retrospective study evaluated patients who underwent re-irradiation for recurrent HGGs and assessed prognostic factors and their influence on management.Eighty-two patients who underwent re-irradiation for HGG from 2009 to 2014 were retrospectively identified. Re-irradiation consisted of either standard three-dimensional conformal, intensity-modulated radiotherapy or highly conformal stereotactic radiotherapy using mostly volumetric modulated arc therapy. Patient survival from re-irradiation was the primary end point. Survival was estimated via the Kaplan-Meier method with differences assessed using the Log-rank test; hazard ratios were estimated using Cox regression analysis.The median overall survival from re-irradiation was 9.5 months. Re-irradiation, to a median dose of 35 Gy in 10 fractions, was well tolerated: 4% developed grade 3 toxicity, no patients experienced grade ≥4 or radionecrosis. In the multivariate analysis, factors significantly associated with increased survival included: longer duration from initial radiotherapy, better performance status at re-irradiation of 0-1 versus ≥2, unifocal versus multifocal recurrence and higher total re-irradiation dose (≥35 Gy versus35 Gy). Re-resection, salvage systemic therapy and age were unrelated to survival.Patients with recurrent HGG tolerated re-irradiation well with minimal toxicity. Those patients in good prognostic groups, including good performance status can achieve durable control, suggesting managing patients with regular magnetic resonance imaging surveillance post-radical treatment, identifying early radiological progression and instituting salvage therapy when performance status is best.

PURPOSE/OBJECTIVE(S) Patients with large brain metastases may receive fractionated stereotactic radiosurgery (FSRS) if they are not surgical candidates yet still pursuing cancer-directed therapy. FSRS with limited margins can allow for optimal sparing of uninvolved regional brain tissue. However, due to required treatment planning process, there is often elapsed time between MRI brain and treatment start which may contribute to marginal misses. Growth rates of large brain metastases and implications for optimal margin to account for growth rate and time interval between planning MRI and FSRS are incompletely characterized. MATERIALS/METHODS Patients treated at a single institution from 2018-2020 who received frameless FSRS on a Cobalt-60 treatment unit for large (> 2cm diameter) brain metastases were identified. Patients with a prior diagnostic brain MRI scan with technically similar parameters to a second MRI obtained for treatment planning were included. Resection cavities and lesions undergoing re-treatment after prior SRS were excluded. Brain metastasis volumes were obtained by contouring on both diagnostic and planning MRIs. Patient characteristics and treatment details were also collected. Analysis was conducted using paired Student's t test and Pearson's R and growth rate was determined using a linear model. RESULTS Thirty-six patients with 54 brain metastases met inclusion criteria. The most common primary cancer sites were lung (36%), colorectal (14%), and skin (14%), and most common histologies were adenocarcinoma (53%) and melanoma (17%). Nearly half (47%) of patients were on systemic therapy at the time of FSRS and the majority (85%) received steroids prior to starting FSRS. Treatment dose ranged from 24-32.5 Gy in 3-5 fractions, with median of 30 Gy in 5 fractions with zero margin. Median time from diagnostic to planning MRI was 15 days (IQR: 11-21) and planning MRI to FSRS was 1 day (IQR 1-3). The median size of included brain metastases on planning MRI was 7.38cc (IQR: 5.09-11.55) compared to 6.03cc (IQR: 3.87-8.95) on prior diagnostic MRI (P 90% of lesions over 3, 7, 10, and 14 days between planning and treatment, respectively. CONCLUSION In the absence of expedited planning, FSRT for intact large brain metastases with limited margins may result in geometric under treatment. An adaptive margin strategy based upon initial tumor size, and time between planning imaging and treatment delivery may be afforded to maintain ideal conformity, properly targeting a growing target lesion while maximally sparing uninvolved regional brain. AUTHOR DISCLOSURE J. Chew: None. S. Sinha: None. S.J. Liu: None. S.E. Fogh: Independent Contractor; Accuray. L. Boreta: None. D. Raleigh: None. L. Ma: Patent/License Fees/Copyright; University of California Regents. S.E. Braunstein: Advisory Board; Radiation Oncology Questions, LLC.

A challenge in precision medicine is the identification of actionable driver mutations. Alterations can be identified within the tumor tissue, by small biopsy or fine‐needle aspirates, or by noninvasive methods, such as circulating tumor cells or circulating tumor DNA. This article presents a case of atypical neuroendocrine tumor metastatic to the bone and brain for which circulating tumor DNA analysis found an ALK translocation., A challenge in precision medicine requires identification of actionable driver mutations. Critical to such effort is the deployment of sensitive and well‐validated assays for mutation detection. Although identification of such alterations within the tumor tissue remains the gold standard, many advanced non‐small cell lung cancer cases have only limited tissue samples, derived from small biopsies or fine‐needle aspirates, available for testing. More recently, noninvasive methods using either circulating tumor cells or tumor DNA (ctDNA) have become an alternative method for identifying molecular biomarkers and screening patients eligible for targeted therapies. In this article, we present a case of a 52‐year‐old never‐smoking male who presented with widely metastatic atypical neuroendocrine tumor to the bones and the brain. Molecular genotyping using DNA harvested from a bone metastasis was unsuccessful due to limited material. Subsequent ctDNA analysis revealed an ALK translocation. The clinical significance of the mutation in this particular cancer type and therapeutic strategies are discussed. Key Points. To our knowledge, this index case represents the first reported ALK translocation identified in an atypical carcinoid tumor.Liquid biopsy such as circulating tumor DNA is a feasible alternative platform for identifying sensitizing genomic alterations.Second‐generation ALK inhibitors represent a new paradigm for treating ALK‐positive patients with brain metastases.

Purpose Randomized trials have shown that honey is effective for the prevention of radiation-induced mucositis in head and neck cancer patients. Because there is no efficacious preventative for radiation esophagitis in lung cancer patients, this trial compared liquid honey, honey lozenges, and standard supportive care for radiation esophagitis. Methods The patients were stratified by percentage of esophagus receiving specific radiation dose (V60 Gy esophagus Results 53 patients were randomized to supportive care, 54 were randomized to liquid honey, and 56 were randomized to lozenge honey. There was no significant difference in the primary endpoint of change in the NRPS at 4 weeks between arms. There were no differences in any of the secondary endpoints except for opioid use at 4 weeks during treatment between the supportive care and liquid honey arms, which was found to be significant ( P =.03), with more patients on the supportive care arm taking opioids. Conclusion Honey as prescribed within this protocol was not superior to best supportive care in preventing radiation esophagitis. Further testing of other types of honey and research into the mechanisms of action are needed.

Radiotherapy-induced second malignant neoplasms (SMNs) are a severe late complication in pediatric cancer survivors. Germline mutations in tumor suppressor genes contribute to SMNs; however, the most relevant germline variants mediating susceptibility are not fully defined. The authors performed matched whole-exome sequencing analyses of germline and tumor DNA from 4 pediatric solid tumor survivors who subsequently developed radiation-associated SMNs. Pathogenic and predicted deleterious germline variants were identified for each patient and validated with Sanger sequencing. These germline variants were compared with germline variants in a cohort of 59 pediatric patients diagnosed with primary sarcomas. Pathway analysis was performed to test for similarities in the germline variant profiles between individuals diagnosed with SMNs or primary sarcomas. One index patient was found to have a pathogenic germline monoallelic mutation in the MUTYH gene, which encodes the base excision repair enzyme adenine DNA glycosylase. This specific germline mutation is associated with a form of familial adenomatous polyposis, a new diagnosis in the patient. Germline-level genetic similarity exists between SMN-developing patients and patients developing primary sarcomas, with relevant genes involved in signal transduction and DNA repair mechanisms. The authors identify a germline MUTYH mutation in a pediatric cancer survivor developing an SMN. Germline mutations involving specific pathways such as base excision repair may identify individuals at risk for developing SMNs. The composition of germline variants in individual patients may enable estimates of patient-specific risk for developing SMNs. The authors anticipate that further analyses of germline genomes and epigenomes will reveal diverse genes and mechanisms influencing cancer risk.

PURPOSE: Although continued tobacco use in patients who are treated with radiation therapy is associated with inferior outcomes and increased treatment-related toxicity, multiple studies have shown that current tobacco cessation efforts in oncology are insufficient. A quality improvement (QI) initiative was developed with the goal of improving tobacco cessation efforts in radiation oncology. METHODS: Using iterative plan-do-study-act cycles, barriers to tobacco cessation were identified and then addressed with a single-institutional QI initiative designed to improve physician assessment of patient readiness to quit tobacco by 50% or more. Residents assessed readiness to quit tobacco during new patient consultations and recorded this assessment in prespecified fields within the electronic health record. Feedback on assessment efforts was provided to our department via an automated search of the electronic health record. RESULTS: From December 2014 to February 2015, before the initiation of the QI initiative, 4% of patients were assessed for their readiness to quit tobacco. After implementing the initiative, 67% of patients were assessed for their readiness to quit. CONCLUSION: After instituting a QI initiative at our institution, significantly more patients were assessed for readiness to quit tobacco before treatment with radiation therapy. Ongoing efforts in our department are aimed at improving the efficacy of this intervention.

Palliative radiotherapy (RT) is frequently an effective treatment option for patients with advanced cancer; however, a substantial proportion will receive RT at the end of life.1 Prognostic tools, including the TEACHH (Type of cancer, ECOG [Eastern Cooperative Oncology Group] performance status, Age, prior palliative Chemotherapy, prior Hospitalizations, and Hepatic metastases),2 the model developed by Chow et al,3 and NEAT (Number of active tumors, ECOG performance status, Albumin, primary Tumor)4 models, can help guide decision-making to better align treatment intensity and prognosis. However, these may not generalize to all clinical scenarios, particularly for patients at imminent risk of death.5 Given this important unmet clinical need, we sought to identify prognostic criteria for 30-day mortality among patients with metastatic cancer undergoing palliative RT at our institution.

Brain metastases are the most common intracranial neoplasm yet clinical outcomes remain poor. The purpose of this study was to evaluate the efficacy of multimodal therapy comprising surgery followed by focal radiation, and/or systemic therapy and elucidate clinically significant biomarkers for resected melanoma brain metastases. Forty consecutive patients with newly diagnosed melanoma brain metastases who underwent surgical resection and targeted mutational analysis at UCSF between 2011 and 2020 were identified. Demographic, clinical, and outcome data were extracted from the medical record and institutional cancer registry. Surgical cavity local recurrence free survival (LRFS), intracranial progression free survival (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method. The median age of patients in this cohort was 58 years (range: 27-75 years) with median MRI follow up of 13.15 months. Twenty patients (50%) were treated with concurrent stereotactic radiation (1-5 fractions) and systemic therapy while 16 patients (40%) were treated with systemic therapy only. Mutational testing demonstrated the most common pathogenic variant was BRAF V600E, found in 16 patients (40%), while the remaining 24 patients (60%) did not harbor this mutation. Microsatellite instability (MSI) estimation was available for 8 patients (20%), all of which were found to be MSI low ( Citation Format: Harish N. Vasudevan, Matthew S. Susko, Lijun Ma, Jean L. Nakamura, David R. Raleigh, Lauren Boreta, Shannon Fogh, Philip V. Theodosopoulos, Michael W. McDermott, Katy K. Tsai, Penny K. Sneed, Steve E. Braunstein. Mutational status and clinical outcomes following systemic therapy and focal radiation for melanoma brain metastases [abstract]. In: Proceedings of the AACR Virtual Special Conference on Radiation Science and Medicine; 2021 Mar 2-3. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(8_Suppl):Abstract nr PO-073.

BackgroundThe role of stereotactic radiosurgery (SRS) for recurrent glioblastoma and the radionecrosis risk in this setting remain unclear.ObjectiveTo perform a large retrospective study to help inform proper indications, efficacy, and anticipated complications of SRS for recurrent glioblastoma.MethodsWe retrospectively analyzed patients who underwent Gamma Knife SRS between 1991 and 2013. We used the partitioning deletion/substitution/addition algorithm to identify potential predictor covariate cut points and Kaplan-Meier and proportional hazards modeling to identify factors associated with post-SRS and postdiagnosis survival.ResultsOne hundred seventy-four glioblastoma patients (median age, 54.1years) underwent SRS a median of 8.7months after initial diagnosis. Seventy-five percent had 1 treatment target (range, 1-6), and median target volume and prescriptions were 7.0cm 3 (range, 0.3-39.0cm 3 ) and 16.0Gy (range, 10-22Gy), respectively. Median overall survival was 10.6months after SRS and 19.1months after diagnosis. Kaplan-Meier and multivariable modeling revealed that younger age at SRS, higher prescription dose, and longer interval between original surgery and SRS are significantly associated with improved post-SRS survival. Forty-six patients (26%) underwent salvage craniotomy after SRS, with 63% showing radionecrosis or mixed tumor/necrosis vs 35% showing purely recurrent tumor. The necrosis/mixed group had lower mean isodose prescription compared with the tumor group (16.2 vs 17.8Gy; P = .003) and larger mean treatment volume (10.0 vs 5.4cm 3 ; P = .009).ConclusionGamma Knife may benefit a subset of focally recurrent patients, particularly those who are younger with smaller recurrences. Higher prescriptions are associated with improved post-SRS survival and do not seem to have greater risk of symptomatic treatment effect.

OBJECTIVEHigh-resolution double-dose gadolinium-enhanced Gamma Knife (GK) radiosurgery-planning MRI (GK MRI) on the day of GK treatment can detect additional brain metastases undiagnosed on the prior diagnostic MRI scan (dMRI), revealing increased intracranial disease burden on the day of radiosurgery, and potentially necessitating a reevaluation of appropriate management. The authors identified factors associated with detecting additional metastases on GK MRI and investigated the relationship between detection of additional metastases and postradiosurgery patient outcomes.METHODSThe authors identified 326 patients who received GK radiosurgery at their institution from 2010 through 2013 and had a prior dMRI available for comparison of numbers of brain metastases. Factors predictive of additional brain metastases on GK MRI were investigated using logistic regression analysis. Overall survival was estimated by Kaplan-Meier method, and postradiosurgery distant intracranial failure was estimated by cumulative incidence measures. Multivariable Cox proportional hazards model and Fine-Gray regression modeling assessed potential risk factors of overall survival and distant intracranial failure, respectively.RESULTSThe mean numbers of brain metastases (SD) on dMRI and GK MRI were 3.4 (4.2) and 5.8 (7.7), respectively, and additional brain metastases were found on GK MRI in 48.9% of patients. Frequencies of detecting additional metastases for patients with 1, 2, 3–4, and more than 4 brain metastases on dMRI were 29.5%, 47.9%, 55.9%, and 79.4%, respectively (p < 0.001). An index brain metastasis with a diameter greater than 1 cm on dMRI was inversely associated with detecting additional brain metastases, with an adjusted odds ratio of 0.57 (95% CI 0.4–0.9, p = 0.02). The median time between dMRI and GK MRI was 22 days (range 1–88 days), and time between scans was not associated with detecting additional metastases. Patients with additional brain metastases did not have larger total radiosurgery target volumes, and they rarely had an immediate change in management (abortion of radiosurgery or addition of whole-brain radiation therapy) due to detection of additional metastases. Patients with additional metastases had a higher incidence of distant intracranial failure than those without additional metastases (p = 0.004), with an adjusted subdistribution hazard ratio of 1.4 (95% CI 1.0–2.0, p = 0.04). Significantly worse overall survival was not detected for patients with additional brain metastases on GK MRI (log-rank p = 0.07), with the relative adjusted hazard ratio of 1.07, (95% CI 0.81–1.41, p = 0.65).CONCLUSIONSDetecting additional brain metastases on GK MRI is strongly associated with the number of brain metastases on dMRI and inversely associated with the size of the index brain metastasis. The discovery of additional brain metastases at time of GK radiosurgery is very unlikely to lead to aborting radiosurgery but is associated with a higher incidence of distant intracranial failure. However, there is not a significant difference in survival.▪ CLASSIFICATION OF EVIDENCE Type of question: prognostic; study design: retrospective cohort trial; evidence: Class IV.

OBJECTIVEStereotactic radiosurgery (SRS) with or without whole-brain radiotherapy can be used to achieve local control (> 90%) for small brain metastases after resection. However, many brain metastases are unsuitable for SRS because of their size or previous treatment, and whole-brain radiotherapy is associated with significant neurocognitive morbidity. The purpose of this study was to investigate the efficacy and toxicity of surgery and iodine-125 (125I) brachytherapy for brain metastases.METHODSA total of 95 consecutive patients treated for 105 brain metastases at a single institution between September 1997 and July 2013 were identified for this analysis retrospectively. Each patient underwent MRI followed by craniotomy with resection of metastasis and placement of 125I sources as permanent implants. The patients were followed with serial surveillance MRIs. The relationships among local control, overall survival, and necrosis were estimated by using the Kaplan-Meier method and compared with results of log-rank tests and multivariate regression models.RESULTSThe median age at surgery was 59 years (range 29.9–81.6 years), 53% of the lesions had been treated previously, and the median preoperative metastasis volume was 13.5 cm3 (range 0.21–76.2 cm3). Gross-total resection was achieved in 81% of the cases. The median number of 125I sources implanted per cavity was 28 (range 4–93), and the median activity was 0.73 mCi (range 0.34–1.3 mCi) per source. A total of 476 brain MRIs were analyzed (median MRIs per patient 3; range 0–22). Metastasis size was the strongest predictor of cavity volume and shrinkage (p < 0.0001). Multivariable regression modeling failed to predict the likelihood of local progression or necrosis according to metastasis volume, cavity volume, or the rate of cavity remodeling regardless of source activity or previous SRS. The median clinical follow-up time in living patients was 14.4 months (range 0.02–13.6 years), and crude local control was 90%. Median overall survival extended from 2.1 months in the shortest quartile to 62.3 months in the longest quartile (p < 0.0001). The overall risk of necrosis was 15% and increased significantly for lesions with a history of previous SRS (p < 0.05).CONCLUSIONSTherapeutic options for patients with large or recurrent brain metastases are limited. Data from this study suggest that resection with permanent 125I brachytherapy is an effective strategy for achieving local control of brain metastasis. Although metastasis volume significantly influences resection cavity size and remodeling, volumetric parameters do not seem to influence local control or necrosis. With careful patient selection, this treatment regimen is associated with minimal toxicity and can result in long-term survival for some patients.▪ CLASSIFICATION OF EVIDENCE Type of question: therapeutic; study design: retrospective case series; evidence: Class IV.

OBJECTIVES Brain metastases are a common sequelae of advanced melanoma, and can lead to significant morbidity and mortality. Systemic therapy, inclusive of BRAF/MEK inhibitors and immunotherapy, are increasingly being utilized for metastatic melanoma brain metastases. This study sought to evaluate the clinical outcomes of resected melanoma brain metastases treated with systemic therapy, with or without focal radiotherapy. METHODS Patients at a single institution who underwent resection of a melanoma brain metastasis were retrospectively identified and reviewed. Patients were required to have received immunotherapy or BRAF/MEK inhibitors in the 3-month perioperative time period. This cohort was then analyzed by receipt of focal radiotherapy, including SRS and brachytherapy, for resection cavity failure, distant CNS progression, and adverse radiation effect, using the Kaplan Meier method. RESULTS From 2011-2020, 43 resections for melanoma brain metastases were performed, of which 29 patients and 37 resection cavities met criteria for analysis. Median MRI follow up was 15 months (IQR: 6-38). Twenty-two (59%) lesions were treated with focal radiotherapy and systemic therapy, and 15 (41%) were treated with systemic therapy alone. 12-month freedom from local recurrence was 64.8% (95% CI: 42.1-99.8%) for systemic therapy alone, and 93.3% (95% CI: 81.5-100%) for focal radiotherapy with systemic therapy (p=0.01). 12-month CNS progression free survival was 35.7% (95% CI: 17.7-72.1%) for systemic therapy alone, and 31.8% (95% CI: 17.3-58.7%) for focal radiotherapy (p=0.51). UVA demonstrated focal radiotherapy (HR: 0.10; 95% CI: 0.01-0.85; p=0.04) was the only significant factor associated with reduction of risk for surgical cavity recurrence. CONCLUSIONS Use of focal radiotherapy with systemic therapy for resected melanoma brain metastases significantly reduced surgical cavity recurrence compared to systemic therapy alone. Focal radiotherapy did not delay initiation of systemic therapy and should be the preferred treatment option for optimal local control of the surgical cavity in melanoma brain metastases.

Purpose The incidence of brain metastases is increasing as a result of more routine diagnostic imaging and improved extracranial systemic treatment strategies. As noted in recent consensus guidelines, postoperative stereotactic radiosurgery (SRS) to the resection cavity has lower rates of local control than whole brain radiation therapy but improved cognitive outcomes. Further analyses are needed to improve local control and minimize toxicity. Methods and materials Patients receiving SRS to a resection cavity between 2006 and 2016 were retrospectively analyzed. Presurgical variables, including tumor location, diameter, dural/meningeal contact, and histology, were collected, as were SRS treatment parameters. Patients had routine follow-up with magnetic resonance imaging, and those noted to have local failure were further assessed for the recurrence location, distance from the target volume, and dosimetric characteristics. Results Overall, 82 patients and 85 resection cavities underwent postoperative SRS during the study period. Of these, 58 patients with 60 resection cavities with available follow-up magnetic resonance imaging scans were included in this analysis. With a median follow-up of 19.8 months, local recurrence occurred in 12 of the resection cavities for a 15% 1-year and 18% 2-year local recurrence rate. Pretreatment tumor volume contacted the dura/meninges in 100% of cavities with recurrence versus 67% of controlled cavities (P = .025). A total of 5 infield, 5 marginal, and 4 out-of-field recurrences were found, with a median distance to the centroid from the target volume of 3 mm. The addition of a 10-mm dural margin increased the target volume overlap with the recurrence contours for 10 of the 14 recurrences. Conclusions Dural contact was associated with an increased rate of recurrence for patients who received SRS to a surgical cavity, and the median distance of marginal recurrences from the target volume was 3 mm. These results provide evidence in support of recent consensus guidelines suggesting that additional dural margin on SRS volumes may benefit local control.

Meningioma is by far the most common primary intracranial tumor in adults. Treatment of meningioma is complex due to a tremendous amount of variability in tumor behavior. Many patients are incidentally found to have tumors that will remain asymptomatic throughout their lives. It is important to identify these patients so that they can be spared from potentially morbid interventions. On the other end of the spectrum, high-grade meningiomas can behave very aggressively. When treatment is necessary, surgical resection is the cornerstone of meningioma therapy. Studies spanning decades have demonstrated that extent of resection correlates with prognosis. Radiation therapy, either in the form of external beam radiation therapy or stereotactic radiosurgery, represents another important therapeutic tool that can be used in place of or as a supplement to surgery. There are no chemotherapeutic agents of proven efficacy against meningioma, and chemotherapy treatment is generally reserved for patients who have exhausted surgical and radiotherapy options. Ongoing and future studies will help to answer unresolved questions such as the optimum use of radiation in resected WHO grade II meningiomas and the efficacy of additional chemotherapy agents.

For over 30 years, the International Statistical Classification of Diseases and Related Health Problems, 9th edition (ICD9) has provided a framework for medical coding in the United States (1). Beginning October 1, 2015, physicians in the United States are required to begin using the updated, more complex version of this framework for the coding of morbidity: International Statistical Classification of Diseases and Related Health Problems, 10th edition (ICD-10). This much-anticipated transition has already occurred in many countries, and as the implementation date has now arrived in the United States, we summarize the changes specific to radiation oncology, highlight implications for future practice and research, and suggest useful references for radiation oncologists. The World Health Organization has been updating the ICD since 1948 (2). ICD-10 represents the 10th edition of this infrastructure. In the United States, ICD-10 was adopted for mortality coding in 1999 (3), but ICD-9 has continued to provide a framework for morbidity coding. The United States adopted 2 versions of ICD-10 on October 1, 2015: ICD-10 Clinical Modification (ICD-10CM), a set of inpatient and outpatient diagnostic codes, replacing ICD-9-CM Volumes 1 and 2, and ICD-10 Procedure Coding System (ICD-10-PCS), a set of inpatient procedure codes, replacing ICD-9-CM Volume 3. The Current Procedural Terminology (CPT) codes assigned to outpatient procedures are not a part of this transition (4). Collectively, ICD-10-CM and ICD-10-PCS will have an impact on diagnostic and procedural coding for all

One clinical teaching challenge is the engagement of learners at different levels. Faculty development offerings mostly address general strategies applicable to all learners. This study examined how clinical faculty members develop the skills to work with different level learners.We conducted semi-structured interviews with medical school faculty members identified as excellent clinical teachers teaching multiple levels of learners. They discussed how they developed their approach to teaching different level learners and how their teaching evolved over time. We performed thematic analysis of the interview transcripts using open and axial coding.We interviewed 19 faculty members and identified three themes related to development of teaching practices: teacher agency and work-based learning of teaching strategies, developmental trajectory of clinical teachers, and interplay between clinical confidence and teaching skills. Faculty members were proactive in using on-the-job experiences to develop their teaching practices. Their teaching practices followed a developmental trajectory towards learner centeredness, and this evolution was associated with the development of clinical skills and confidence.Learning skills to teach multi-level learners requires workplace learning. Faculty development should include workplace learning opportunities and use a developmental approach that accounts for the trajectory of teaching as well as clinical skills attainment.

A technique for delivering high-precision volume-staged stereotactic radiosurgery has been developed with Leksell Gamma Knife Perfexion for treating large arteriorvenous malformations (AVMs). The technique employs a hybrid method of combining landmark registration and voxel-based 3D image registration to enable multiple staged partial-volume treatments that accommodate repeated stereotactic frame placements. The technique was clinically implemented at our institution and the results were analyzed for a series (n=14) of large AVM cases treated since 2007. Overall, an averaged 0.34±0.09 mm in matching procedural accuracy versus standard single-fraction radiosurgery was found for these treatments. Such a result is a factor of 3-4 times lower than those previously reported, and it approaches the physical accuracy of the latest Leksell Gamma Knife Perfexion system. In conclusion, volume-staged radiosurgery has been demonstrated to be deliverable with the same level of accuracy as standard single-fraction radiosurgery.

Purpose Accurate International Classification of Diseases (ICD) diagnosis coding is critical for patient care, billing purposes, and research endeavors. In this single-institution study, we evaluated our baseline ICD-9 (9th revision) diagnosis coding accuracy, identified the most common errors contributing to inaccurate coding, and implemented a multimodality strategy to improve radiation oncology coding. Methods and materials We prospectively studied ICD-9 coding accuracy in our radiation therapy--specific electronic medical record system. Baseline ICD-9 coding accuracy was obtained from chart review targeting ICD-9 coding accuracy of all patients treated at our institution between March and June of 2010. To improve performance an educational session highlighted common coding errors, and a user-friendly software tool, RadOnc ICD Search, version 1.0, for coding radiation oncology specific diagnoses was implemented. We then prospectively analyzed ICD-9 coding accuracy for all patients treated from July 2010 to June 2011, with the goal of maintaining 80% or higher coding accuracy. Data on coding accuracy were analyzed and fed back monthly to individual providers. Results Baseline coding accuracy for physicians was 463 of 661 (70%) cases. Only 46% of physicians had coding accuracy above 80%. The most common errors involved metastatic cases, whereby primary or secondary site ICD-9 codes were either incorrect or missing, and special procedures such as stereotactic radiosurgery cases. After implementing our project, overall coding accuracy rose to 92% (range, 86%-96%). The median accuracy for all physicians was 93% (range, 77%‐100%) with only 1 attending having accuracy below 80%. Incorrect primary and secondary ICD-9 codes in metastatic cases showed the most significant improvement (10% vs 2% after intervention). Conclusions Identifying common coding errors and implementing both education and systems changes led to significantly improved coding accuracy. This quality assurance project highlights the potential problem of ICD-9 coding accuracy by physicians and offers an approach to effectively address this shortcoming.

TPS8578 Background: Multiple clinical trials have shown that prophylactic cranial irradiation (PCI) prevents brain metastases and may prolong survival in small cell lung cancer (SCLC). However,prophylactic cranial irradiation can lead to decline in cognitive function. Preclinical evidence suggests that the pathogenesis of this toxicity includes inflammatory injury to proliferating neuronal progenitor cells in the peri-hippocampal stem cell niches. We hypothesized that conformal avoidance of the hippocampal neural stem cell compartment during brain irradiation using intensity-modulated radiotherapy (IMRT) would decrease the likelihood and/or severity of this toxicity. This hypothesis was recently validated by positive results from NRG Oncology CC001, a phase III trial of hippocampal avoidance during whole-brain radiotherapy for patients with brain metastases. NRG Oncology CC003 is an ongoing randomized phase II/III trial of hippocampal avoidance during prophylactic cranial irradiation (HA-PCI) for small cell lung cancer, conducted in parallel with NRG Oncology CC001. Methods: The primary endpoints of the phase IIR and III components are 12-month intracranial relapse rate and 6-month deterioration in Hopkins Verbal Learning Test-Revised (HVLT-R) Delayed Recall, respectively. This is a seamless phase IIR/III trial, with the phase IIR designed to demonstrate non-inferiority. If the non-inferiority margin of the phase IIR component is not exceeded, then the trial would transition to the phase III component. Following accrual of 182 of planned 172 patients on the phase IIR component, the trial closed to accrual on 10/13/17 to assess the phase IIR primary endpoint. The DSMB evaluated the IIR outcomes, and on 1/9/19, the trial was reactivated to accrue an additional 122 patients to the phase III component. Eligibility criteria include: 1) small cell lung cancer with at least partial response to chemotherapy; 2) contrast-enhanced thin-slice volumetric MRI scan; and, 3) Zubrod performance status 0-2. Supported by grant UG1CA189867 (NCORP) from the National Cancer Institute. Clinical trial information: NCT02635009.

Background Male breast cancer (MBC) accounts for approximately 1% of all breast cancers. Given the rarity of this disease, treatment of MBC generally follows the same principles as treatment of female breast cancer. However, the traditional surgical approach for MBC is modified radical mastectomy (MRM) or total simple mastectomy (TSM) instead of breast conservation surgery (BCS). The purpose of this study was to examine the feasibility of BCS as an alternative to mastectomy for MBC with respect to musculoskeletal functionality and treatment outcome. Patients and Methods A retrospective analysis was undertaken of all male patients with breast cancer who presented to Massachusetts General Hospital or Boston Medical Center for localized therapy from 1990 to 2003. Musculoskeletal functionality (tissue fibrosis, arm edema, and range of motion) and treatment outcome (local-regional control, disease-free survival, and overall survival) were evaluated. Functional/cosmetic outcomes were assessed by multidisciplinary review of patient follow-up visits and were scored as either “good-excellent” or “fair-poor” to account for subjectivity between different clinicians. Results Forty-two patients in total were identified to undergo localized treatment. Thirty patients (71%) received MRM, 4 (10%) had TSM, and 8 (19%) underwent BCS. Actuarial overall 1-year fair-poor documented tissue fibrosis, arm edema, and decreased range of motion rates were 13%, 23%, and 27% for patients receiving MRM; 25%, 0%, and 50% for patients who underwent TSM; and 13%, 0%, and 0% for those undergoing BCS, respectively. Overall survival and disease-free survival were not statistically different between the groups. Conclusions These data suggest that breast conservation therapy may be considered a reasonable local treatment option for male patients presenting with breast cancer because it may offer functional advantages over mastectomy with comparable rates of local control and disease-free survival and overall survival.

Stereotactic radiosurgery (SRS) refers to a high dose of radiation delivered to a focal region of interest while maximizing the steep dose gradient to minimize dose to the surrounding normal tissues. Multiple factors can influence the dose fall-off, and the relative importance of such factors have not yet been characterized for non-isocentric Cyberknife SRS. Our aim was to investigate whether the composite dose fall-off near a target may be enhanced via sharpening the lateral beam profile (or penumbra) of each individual beam. Cyberknife beam profiles were fitted and parameterized to obtain a characteristic penumbra function for each collimator size. Simulated beam profiles with progressively sharper penumbras were then generated, and used to perform simulated treatment planning on seven pediatric intracranial arteriovenous malformations (AVMs) cases. Penumbra size was found to significantly influence the peripheral dose fall-off. Peripheral dose volumes were reduced by 5 to 10% with reductions in penumbra size ranging from 40 to 80%. Dose conformality and homogeneity were not significantly changed with decreasing penumbra size. Therefore, individual beam sharpening provides a straightforward way of improving the composite dose fall-off for non-isocentric Cyberknife SRS.

Purpose To assess the feasibility of measuring symptomatic adverse events (AEs) in a multicenter clinical trial using the National Cancer Institute's Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE). Methods and Materials Patients enrolled in NRG Oncology's RTOG 1012 (Prophylactic Manuka Honey for Reduction of Chemoradiation Induced Esophagitis-Related Pain during Treatment of Lung Cancer) were asked to self-report 53 PRO-CTCAE items representing 30 symptomatic AEs at 6 time points (baseline; weekly ×4 during treatment; 12 weeks after treatment). Reporting was conducted via wireless tablet computers in clinic waiting areas. Compliance was defined as the proportion of visits when an expected PRO-CTCAE assessment was completed. Results Among 226 study sites participating in RTOG 1012, 100% completed 35-minute PRO-CTCAE training for clinical research associates (CRAs); 80 sites enrolled patients, of which 34 (43%) required tablet computers to be provided. All 152 patients in RTOG 1012 agreed to self-report using the PRO-CTCAE (median age 66 years; 47% female; 84% white). Median time for CRAs to learn the system was 60 minutes (range, 30-240 minutes), and median time for CRAs to teach a patient to self-report was 10 minutes (range, 2-60 minutes). Compliance was high, particularly during active treatment, when patients self-reported at 86% of expected time points, although compliance was lower after treatment (72%). Common reasons for noncompliance were institutional errors, such as forgetting to provide computers to participants; patients missing clinic visits; Internet connectivity; and patients feeling “too sick.” Conclusions Most patients enrolled in a multicenter chemoradiotherapy trial were willing and able to self-report symptomatic AEs at visits using tablet computers. Minimal effort was required by local site staff to support this system. The observed causes of missing data may be obviated by allowing patients to self-report electronically between visits, and by using central compliance monitoring. These approaches are being incorporated into ongoing studies.

A clinical workflow was developed for urgent palliative radiotherapy treatments that integrates patient simulation, planning, quality assurance, and treatment in one 30-minute session. This has been successfully tested and implemented clinically on a linac with MV CBCT capabilities. To make this approach available to all clinics equipped with common imaging systems, dose calculation accuracy based on treatment sites was assessed for other imaging units. We evaluated the feasibility of palliative treatment planning using on-board imaging with respect to image quality and technical challenges. The purpose was to test multiple systems using their commercial setup, disregarding any additional in-house development. kV CT, kV CBCT, MV CBCT, and MV CT images of water and anthropomorphic phantoms were acquired on five different imaging units (Philips MX8000 CT Scanner, and Varian TrueBeam, Elekta VersaHD, Siemens Artiste, and Accuray Tomotherapy linacs). Image quality (noise, contrast, uniformity, spatial resolution) was evaluated and compared across all machines. Using individual image value to density calibrations, dose calculation accuracies for simple treatment plans were assessed for the same phantom images. Finally, image artifacts on clinical patient images were evaluated and compared among the machines. Image contrast to visualize bony anatomy was sufficient on all machines. Despite a high noise level and low contrast, MV CT images provided the most accurate treatment plans relative to kV CT-based planning. Spatial resolution was poorest for MV CBCT, but did not limit the visualization of small anatomical structures. A comparison of treatment plans showed that monitor units calculated based on a prescription point were within 5% difference relative to kV CT-based plans for all machines and all studied treatment sites (brain, neck, and pelvis). Local dose differences >5% were found near the phantom edges. The gamma index for 3%/3 mm criteria was ≥95% in most cases. Best dose calculation results were obtained when the treatment isocenter was near the image isocenter for all machines. A large field of view and immediate image export to the treatment planning system were essential for a smooth workflow and were not provided on all devices. Based on this phantom study, image quality of the studied kV CBCT, MV CBCT, and MV CT on-board imaging devices was sufficient for treatment planning in all tested cases. Treatment plans provided dose calculation accuracies within an acceptable range for simple, urgently planned palliative treatments. However, dose calculation accuracy was compromised towards the edges of an image. Feasibility for clinical implementation should be assessed separately and may be complicated by machine specific features. Image artifacts in patient images and the effect on dose calculation accuracy should be assessed in a separate, machine-specific study. PACS number(s): 87.55.D-, 87.57.C-, 87.57.Q.

Object The goal of this study was to develop a technique for performing submillimeter high-precision volume-staged Gamma Knife surgery and investigate its potential benefits in comparison with hypofractionated stereotactic radiotherapy (SRT) for treating large arteriovenous malformations (AVMs). Methods The authors analyzed 7 pediatric AVM cases treated with volume-staged stereotactic radiosurgery (SRS) using the Gamma Knife Perfexion at the University of California, San Francisco. The target and normal tissue contours from each case were exported for hypofractionated treatment planning based on the Gamma Knife Extend system or the CyberKnife SRT. Both the Gamma Knife Extend and CyberKnife treatment plans were matched to yield the same level of target coverage (95%–98%) and conformity indices (1.24–1.46). Finally, hypofractionated treatment plans were compared with volume-staged treatment plans for sparing normal brain by using biologically equivalent 12-Gy normal brain volumes. Results Hypofractionated Gamma Knife Extend and CyberKnife treatment plans exhibited practically identical sparing of normal brain for the studied cases. However, when matching such values with volume-staged treatments for the biological effective dose, only conservative dose fractionation schemes, such as 27.3 Gy in 5 fractions and 25 Gy in 4 fractions, were found to be comparable to the volume-staged treatments. On average, this represents a mean 18.7% ± 7.3% reduction in the single-fraction biologically equivalent dose for hypofractionated treatments versus the reference volume-staged treatments (p < 0.001). Conclusions Volume staging remains advantageous over hypofractionation in delivering a higher dose to the target and for better sparing of normal brain tissue in the treatment of large AVMs. More clinical data are needed, however, to justify the clinical superiority of this increased dose when compared with a hypofractionated treatment regimen.

OBJECTIVES The role of positron emission tomography (PET) scans in the staging of head and neck cancer (HNC) is unclear. The National Comprehensive Cancer Network guidelines do not recommend routine metastatic workup beyond physical examination, chest x-ray, and laboratory tests. The purpose of this report is to examine the accuracy of staging PET scans for detecting distant metastatic disease in patients with HNC. METHODS Retrospective review of 182 consecutive newly diagnosed HNC patients who had a staging PET scan at Thomas Jefferson University Hospital between 2003 and 2007. RESULTS The overall incidence of confirmed distant metastatic disease in this population was 5.0%. About 26 of the staging PET scans had areas suspicious for a metastatic lesion(s). Of total, 23 patients were further evaluated with imaging and/or biopsy, revealing 9 (39%) true positives, and 14 (60%) false positives. Of the 156 negative PET scans, there was 1 false negative and 155 true negatives. Thus, the sensitivity of PET was 90% and specificity was 92%. Positive predictive value was 39% and negative predictive value was 99.4%. No patients with pre-PET clinical stage I or II cancer had confirmed distant metastases. The only statistically significant predictor for metastatic disease was clinical stage IV versus all other stages (P=0.03). CONCLUSIONS Given the marked differences in the treatment of locally advanced/nonmetastatic HNC versus metastatic HNC, we recommend PET for clinical stage IV disease. Although the sensitivity, specificity, and negative predictive value rates were acceptable, the positive predictive value was suboptimal. Patients found to have a PET scan "positive" for metastatic disease require confirmatory imaging or ideally biopsy.

Purpose Advanced head-and-neck cancer (HNC) remains a difficult disease to cure. Proteasome inhibitors such as bortezomib have the potential to improve survival over chemoradiotherapy alone. This Phase I dose-escalation study examined the potential of bortezomib in combination with cisplatin chemotherapy and concurrent radiation in the treatment of locally advanced and recurrent HNC. Methods and Materials Eligible patients received cisplatin once weekly at 30 mg/m 2 per week and bortezomib along with concurrent radiation. Bortezomib was given on Days 1, 4, 8, and 11 every 3 weeks, with an initial starting dose of 0.7 mg/m 2 and escalation levels of 1.0 and 1.3 mg/m 2 . Dose escalation was performed only after assessment to rule out any dose-limiting toxicity. Results We enrolled 27 patients with HNC, including 17 patients with recurrent disease who had received prior irradiation. Patients received bortezomib dose levels of 0.7 mg/m 2 (7 patients), 1.0 mg/m 2 (10 patients), and 1.3 mg/m 2 (10 patients). No Grade 5 toxicities, 3 Grade 4 toxicities (all hematologic and considered dose-limiting toxicities), and 39 Grade 3 toxicities (in 20 patients) were observed. With a median follow-up of 7.4 months, the overall median survival was 24.7 months (48.4 months for advanced HNC patients and 15.4 months for recurrent HNC patients). Conclusion Bortezomib in combination with radiation therapy and cisplatin chemotherapy is safe in the treatment of HNC with a bortezomib maximum tolerated dose of 1.0 mg/m 2 in patients previously treated for HNC and 1.3 mg/m 2 in radiation-naive patients.