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Background Glioblastoma (GBM) poses therapeutic challenges due to its aggressive nature, particularly for patients with poor functional status and/or advanced disease. Hypofractionated radiotherapy (RT) regimens have demonstrated comparable disease outcomes for this population while allowing treatment to be completed more quickly. Here, we report our institutional outcomes of patients treated with 2 hypofractionated RT regimens: 40 Gy/15fx (3w-RT) and 50 Gy/20fx (4w-RT). Methods A single-institution retrospective analysis was conducted of 127 GBM patients who underwent 3w-RT or 4w-RT. Patient characteristics, treatment regimens, and outcomes were analyzed. Univariate and multivariable Cox regression models were used to estimate progression-free survival (PFS) and overall survival (OS). The impact of chemotherapy and RT schedule was explored through subgroup analyses. Results Median OS for the entire cohort was 7.7 months. There were no significant differences in PFS or OS between 3w-RT and 4w-RT groups overall. Receipt and timing of temozolomide (TMZ) emerged as the variable most strongly associated with survival, with patients receiving adjuvant-only or concurrent and adjuvant TMZ having significantly improved PFS and OS (P <.001). In a subgroup analysis of patients that did not receive TMZ, patients in the 4w-RT group demonstrated a trend toward improved OS as compared to the 3w-RT group (P =.12). Conclusions This study demonstrates comparable survival outcomes between 3w-RT and 4w-RT regimens in GBM patients. Receipt and timing of TMZ were strongly associated with survival outcomes. The potential benefit of dose-escalated hypofractionation for patients not receiving chemotherapy warrants further investigation and emphasizes the importance of personalized treatment approaches. [ABSTRACT FROM AUTHOR]

Simple Summary: Myxopapillary ependymoma (MPE) is a rare tumor that typically grows in the lower spine. It is usually not aggressive and is most effectively treated with surgery. We studied data from over a thousand patients with spinal MPE from 2000 to 2020. Surgery was the main treatment for almost all patients. We found that younger age and having surgery were linked to better survival. Surprisingly, being male was associated with worse survival, and they tended to be diagnosed at a younger age than females. Our study, the largest of its kind, provides important information for treating spinal MPE. (1) Background: Myxopapillary ependymoma (MPE) is a rare tumor of the spine, typically slow-growing and low-grade. Optimal management strategies remain unclear due to limited evidence given the low incidence of the disease. (2) Methods: We analyzed data from 1197 patients with spinal MPE from the Surveillance, Epidemiology, and End Results (SEER) database (2000–2020). Patient demographics, treatment modalities, and survival outcomes were examined using statistical analyses. (3) Results: Most patients were White (89.9%) with a median age at diagnosis of 42 years. Surgical resection was performed in 95% of cases. The estimated 10-year overall survival was 91.4%. Younger age (hazard ratio (HR) = 1.09, p < 0.001) and receipt of surgery (HR = 0.43, p = 0.007) were associated with improved survival. Surprisingly, male sex was associated with worse survival (HR = 1.86, p = 0.008) and a younger age at diagnosis compared to females. (4) Conclusions: This study, the largest of its kind, underscores the importance of surgical resection in managing spinal MPE. The unexpected association between male sex and worse survival warrants further investigation into potential sex-specific pathophysiological factors influencing prognosis. Despite limitations, our findings contribute valuable insights for guiding clinical management strategies for spinal MPE. [ABSTRACT FROM AUTHOR]

Purpose: The purpose of this study is to investigate inter‐planner plan quality variability using a manual forward planning (MFP)‐ or fast inverse planning (FIP, Lightning)‐approach for single brain lesions treated with the Gamma Knife® (GK) Icon™. Methods: Thirty patients who were previously treated with GK stereotactic radiosurgery or radiotherapy were selected and divided into three groups (post‐operative resection cavity, intact brain metastasis, and vestibular schwannoma [10 patients per group]). Clinical plans for the 30 patients were generated by multiple planners using FIP only (1), a combination of FIP and MFP (12), and MFP only (17). Three planners (Senior, Junior, and Novice) with varying experience levels re‐planned the 30 patients using MFP and FIP (two plans per patient) with planning time limit of 60 min. Statistical analysis was performed to compare plan quality metrics (Paddick conformity index, gradient index, number of shots, prescription isodose line, target coverage, beam‐on‐time (BOT), and organs‐at‐risk doses) of MFP or FIP plans among three planners and to compare plan quality metrics between each planner's MFP/FIP plans and clinical plans. Variability in FIP parameter settings (BOT, low dose, and target max dose) and in planning time among the planners was also evaluated. Results: Variations in plan quality metrics of FIP plans among three planners were smaller than those of MFP plans for all three groups. Junior's MFP plans were the most comparable to the clinical plans, whereas Senior's and Novice's MFP plans were superior and inferior, respectively. All three planners' FIP plans were comparable or superior to the clinical plans. Differences in FIP parameter settings among the planners were observed. Planning time was shorter and variations in planning time among the planners were smaller for FIP plans in all three groups. Conclusions: The FIP approach is less planner dependent and more time‐honored than the MFP approach. [ABSTRACT FROM AUTHOR]

Purpose: Distinguishing radiation necrosis from tumor progression among patients with brain metastases previously treated with stereotactic radiosurgery represents a common diagnostic challenge. We performed a prospective pilot study to determine whether PET/CT with 18F-fluciclovine, a widely available amino acid PET radiotracer, repurposed intracranially, can accurately diagnose equivocal lesions. Methods: Adults with brain metastases previously treated with radiosurgery presenting with a follow-up tumor-protocol MRI brain equivocal for radiation necrosis versus tumor progression underwent an 18F-fluciclovine PET/CT of the brain within 30 days. The reference standard for final diagnosis consisted of clinical follow-up until multidisciplinary consensus or tissue confirmation. Results: Of 16 patients imaged from 7/2019 to 11/2020, 15 subjects were evaluable with 20 lesions (radiation necrosis, n = 16; tumor progression, n = 4). Higher SUVmax statistically significantly predicted tumor progression (AUC = 0.875; p = 0.011). Lesion SUVmean (AUC = 0.875; p = 0.018), SUVpeak (AUC = 0.813; p = 0.007), and SUVpeak-to-normal-brain (AUC = 0.859; p = 0.002) also predicted tumor progression, whereas SUVmax-to-normal-brain (p = 0.1) and SUVmean-to-normal-brain (p = 0.5) did not. Qualitative visual scores were significant predictors for readers 1 (AUC = 0.750; p < 0.001) and 3 (AUC = 0.781; p = 0.045), but not for reader 2 (p = 0.3). Visual interpretations were significant predictors for reader 1 (AUC = 0.898; p = 0.012) but not for reader 2 (p = 0.3) or 3 (p = 0.2). Conclusions: In this prospective pilot study of patients with brain metastases previously treated with radiosurgery presenting with a contemporary MRI brain with a lesion equivocal for radiation necrosis versus tumor progression, 18F-fluciclovine PET/CT repurposed intracranially demonstrated encouraging diagnostic accuracy, supporting the pursuit of larger clinical trials which will be necessary to establish diagnostic criteria and performance. [ABSTRACT FROM AUTHOR]

Objectives: The objective of this study is to evaluate the user‐defined optimization settings in the Fast Inverse Planning (FIP) optimizer in Leksell GammaPlan® and determine the parameters that result in the best stereotactic radiosurgery (SRS) plan quality for brain metastases, benign tumors, and arteriovenous malformations (AVMs). Methods: Thirty patients with metastases and 30 with benign lesions—vestibular schwannoma, AVMs, pituitary adenoma, and meningioma‐treated with SRS were evaluated. Each target was planned by varying the low dose (LD) and beam‐on‐time (BOT) penalties in increments of 0.1, from 0 to 1. The following plan quality metrics were recorded for each plan: Paddick conformity index (PCI), gradient index (GI), BOT, and maximum organ‐at‐risk (OAR) doses. A novel objective score matrix was calculated for each target using a linearly weighted combination of the aforementioned metrics. A histogram of optimal solutions containing the five best scores was extracted. Results: A total of 7260 plans were analyzed with 121 plans per patient for the range of LD/BOT penalties. The ranges of PCI, GI, and BOT across all metastatic lesions were 0.58–0.97, 2.1–3.8, and 8.8–238 min, respectively, and were 0.13–0.97, 2.1–3.8, and 8.8–238 min, respectively, for benign lesions. The objective score matrix showed unique optimal solutions for metastatic lesions and benign lesions. Additionally, the plan metrics of the optimal solutions were significantly improved compared to the clinical plans for metastatic lesions with equivalent metrics for all other cases. Conclusion: In this study, FIP optimizer was evaluated to determine the optimal solution space to maximize PCI and minimize GI, BOT and OAR doses simultaneously for single metastatic/benign/non‐neoplastic targets. The optimal solution chart was determined using a novel objective score which provides novice and expert planners a roadmap to generate the most optimal plans efficiently using FIP. [ABSTRACT FROM AUTHOR]

Simple Summary: There is an increasing incidence of patients diagnosed with multiple brain metastasis (MBM) in the modern era. Although stereotactic radiosurgery (SRS) has been shown to result in similar survival with less neurocognitive deterioration for patients with MBM, the intracranial disease extent, both in quantity and volume, able to be treated with modern dedicated SRS platforms has yet to be empirically demonstrated. In this study, we evaluate the effect of the number and volume of lesions treated on mean brain dose using two dedicated intracranial SRS delivery technologies. We found that mean brain dose linearly increased with the number of lesions and total gross tumor volume (GTV), while selected metrics associated with radiation necrosis risk (i.e., V8 Gy, V10 Gy, and V12 Gy) had quadratic correlations to the number of lesions and the total GTV. This study shows that it is dosimetrically feasible to treat MBMs with SRS. We evaluated the effect of lesion number and volume for brain metastasis treated with SRS using GammaKnife® ICON™ (GK) and CyberKnife® M6™ (CK). Four sets of lesion sizes (<5 mm, 5–10 mm, >10–15 mm, and >15 mm) were contoured and prescribed a dose of 20 Gy/1 fraction. The number of lesions was increased until a threshold mean brain dose of 8 Gy was reached; then individually optimized to achieve maximum conformity. Across GK plans, mean brain dose was linearly proportional to the number of lesions and total GTV for all sizes. The numbers of lesions needed to reach this threshold for GK were 177, 57, 29, and 10 for each size group, respectively; corresponding total GTVs were 3.62 cc, 20.37 cc, 30.25 cc, and 57.96 cc, respectively. For CK, the threshold numbers of lesions were 135, 35, 18, and 8, with corresponding total GTVs of 2.32 cc, 12.09 cc, 18.24 cc, and 41.52 cc respectively. Mean brain dose increased linearly with number of lesions and total GTV while V8 Gy, V10 Gy, and V12 Gy showed quadratic correlations to the number of lesions and total GTV. Modern dedicated intracranial SRS systems allow for treatment of numerous brain metastases especially for ≤10 mm; clinical evidence to support this practice is critical to expansion in the clinic. [ABSTRACT FROM AUTHOR]

Purpose: Cerebral radiation necrosis is a complication of radiation therapy that can be seen months to years following radiation treatment. Differentiating radiation necrosis from tumor progression on standard magnetic resonance imaging (MRI) is often difficult and advanced imaging techniques may be needed to make an accurate diagnosis. The purpose of this article is to review the imaging modalities used in differentiating radiation necrosis from tumor progression following radiation therapy for brain metastases. Methods: We performed a review of the literature addressing the radiographic modalities used in the diagnosis of radiation necrosis. Results: Differentiating radiation necrosis from tumor progression remains a diagnostic challenge and advanced imaging modalities are often required to make a definitive diagnosis. If diagnostic uncertainty remains following conventional imaging, a multi-modality diagnostic approach with perfusion MRI, magnetic resonance spectroscopy (MRS), positron emission tomography (PET), single photon emission spectroscopy (SPECT), and radiomics may be used to improve diagnosis. Conclusion: Several imaging modalities exist to aid in the diagnosis of radiation necrosis. Future studies developing advanced imaging techniques are needed. [ABSTRACT FROM AUTHOR]

Simple Summary: The Gamma Knife® Icon™ allows for mask immobilization for stereotactic radiosurgery (SRS) as an alternative to frame immobilization. However, standardized recommendations for setup margins (SM) to create the planning target volume (PTV) with the mask immobilization do not exist and, therefore, practice patterns vary. Adding a SM might be the correct approach, if the possibility of significant intrafraction motion exists; on the other hand, it may be unnecessary as it increases the risk of radiation necrosis. This study, comprising 150 patients with 453 brain metastases (BM) treated for a median of 15 months of follow up, demonstrates that zero-SM mask immobilization had comparable clinical outcomes compared to a control group of similar patients undergoing frame immobilization SRS. There was no difference in freedom from local failure (FFLF) between the mask and frame immobilization groups on univariable or multivariable analysis. The initial findings support omitting a SM when using mask immobilization with this treatment approach on a GK Icon™. We compared the clinical outcomes of BM treated with mask immobilization with zero-SM (i.e., zero-PTV) to standard zero-SM frame immobilization SRS. Consecutive patients with BM, 0.5–2.0 cm in maximal diameter, treated with single-fraction SRS (22–24 Gy) during March 2019–February 2021 were included. Univariable and multivariable analysis were performed using the Kaplan–Meier method and Cox proportional hazards regression. A total of 150 patients with 453 BM met inclusion criteria. A total of 129 (28.5%) lesions were treated with a zero-SM mask immobilization and 324 (71.5%) with zero-SM frame immobilization. Frame immobilization treatments were associated with a higher proportion of gastrointestinal and fewer breast-cancer metastases (p = 0.024), and a higher number of treated lesions per SRS course (median 7 vs. 3; p < 0.001). With a median follow up of 15 months, there was no difference in FFLF between the mask and frame immobilization groups on univariable (p = 0.29) or multivariable analysis (p = 0.518). Actuarial FFLF at 1 year was 90.5% for mask and 92% for frame immobilization (p = 0.272). Radiation necrosis rates at 1 year were 12.5% for mask and 4.1% for frame immobilization (p = 0.502). For BM 0.5–2.0 cm in maximal diameter treated with single-fraction SRS using 22–24 Gy, mask immobilization with zero SM produces comparable clinical outcomes to frame immobilization. The initial findings support omitting a SM when using mask immobilization with this treatment approach on a Gamma Knife® Icon™. [ABSTRACT FROM AUTHOR]

Simple Summary: Pulsed-reduced dose rate (PRDR) is a technique used to safely deliver re-irradiation by targeting dividing neoplastic cells while permitting intra-therapy sublethal damage repair in previously irradiated normal tissues. However, treatment-related toxicities are not uniformly reported in previous PRDR studies; thus, it is unclear whether the cumulative thresholds (EQD2) for CNS organs-at-risk (OARs) can be designated in a "safe" category. In this study, we evaluated dosimetric data for patients treated with PRDR IMRT for recurrent primary CNS malignancies, generated accumulated equivalent uniform doses with rigid registration of all intracranial treatments, and investigated toxicity as a function of cumulative EQD2. We found that PRDR IMRT re-irradiation is a safe and feasible strategy for appropriately selected recurrent primary CNS tumor patients after exhausting other options. The clinical outcomes were favorable given the unique population treated with this approach (ineligible for other salvage treatments or enrollment onto clinical trials), and the toxicities observed were mild to moderate. Purpose: The objective was to describe PRDR outcomes and report EQD2 OAR toxicity thresholds. Methods: Eighteen patients with recurrent primary CNS tumors treated with PRDR at a single institution between April 2017 and September 2021 were evaluated. The radiotherapy details, cumulative OAR doses, progression-free survival (PFS), overall survival (OS), and toxicities were collected. Results: The median PRDR dose was 45 Gy (range: 36–59.4 Gy); the median cumulative EQD2 prescription dose was 102.7 Gy (range: 93.8–120.4 Gy). The median cumulative EQD2 D0.03cc for the brain was 111.4 Gy (range: 82.4–175.2 Gy). Symptomatic radiation necrosis occurred in three patients, for which the median EQD2 brain D0.03cc was 115.9 Gy (110.4–156.7 Gy). The median PFS and OS after PRDR were 6.3 months (95%CI: 0.9–11.6 months) and 8.6 months (95%CI: 4.9–12.3 months), respectively. The systematic review identified five peer-reviewed studies with a median cumulative EQD2 prescription dose of 110.3 Gy. At a median follow-up of 8.7 months, the median PFS and OS were 5.7 months (95%CI: 2.1–15.4 months) and 6.7 months (95%CI: 3.2–14.2 months), respectively. Conclusion: PRDR re-irradiation is a relatively safe and feasible treatment for recurrent primary CNS tumors. Despite high cumulative dose to OARs, the risk of high-grade, treatment-related toxicity within the first year of follow-up remains acceptable. [ABSTRACT FROM AUTHOR]

• Postoperative management of lower grade gliomas (grade 2 and 3) is heterogeneous. • The ARS brain panel systematically reviewed the literature to develop guidelines. • These recommendations provide an evidence-based framework for lower grade gliomas. Postoperative management of lower grade gliomas (grade 2 and 3) is heterogeneous. The American Radium Society's brain malignancies panel systematically reviewed and evaluated the literature to develop consensus guidelines addressing timing of postoperative therapy, monotherapy versus combined modality therapy, type of chemotherapy used with radiotherapy, and radiotherapy dose. Thirty-six studies were included. Using consensus methodology (modified Delphi), the panel voted upon representative case variants using a 9-point appropriateness scale to address key questions. Voting results were collated to develop summarized recommendations. Following gross-total surgical resection, close surveillance is appropriate for well-selected grade 2, IDH-mutant oligodendrogliomas or astrocytomas with low-risk features. For grade 2 gliomas with high-risk features or any grade 3 glioma, immediate adjuvant therapy is recommended. When postoperative therapy is administered, radiation and planned chemotherapy is strongly recommended over monotherapy. For grade 2 and 3 IDH-mutant oligodendrogliomas and astrocytomas, either adjunctive PCV (procarbazine, lomustine, vincristine) or temozolomide is appropriate. For grade 3 IDH-mutant astrocytomas, radiotherapy followed by temozolomide is strongly recommended. The recommended radiotherapy dose for grade 2 gliomas is 45–54 Gy/1.8–2.0 Gy, and for grade 3 gliomas is 59.4–60 Gy/1.8–2.0 Gy. While multiple appropriate treatment options exist, these consensus recommendations provide an evidence-based framework to approach postoperative management of lower grade gliomas. [ABSTRACT FROM AUTHOR]

To determine if patients with unfavorable intermediate-risk (UIR), high-risk (HR), or very high-risk (VHR) prostate cancer (PCa) treated with 125I interstitial brachytherapy benefit from androgen deprivation therapy (ADT). We reviewed our institutional database of patients with UIR, HR, or VHR PCa, per 2018 NCCN risk classification, treated with definitive 125I interstitial brachytherapy with or without ADT from 1998−2017. Outcomes including biochemical failure (bF), distant metastases (DM), and overall survival (OS) were analyzed with the Kaplan-Meier method and Cox proportional hazards regression. PCa-specific mortality (PCSM) was analyzed with Fine-Gray competing-risk regression. Of 1033 patients, 262 (25%) received ADT and 771 (75%) did not. Median ADT duration was 6 months. By risk group, 764 (74%) patients were UIR, 219 (21%) HR, and 50 (5%) VHR. ADT was more frequently given to HR (50%) and VHR (56%) patients compared to UIR (16%; p <0.001), to older patients (p <0.001), corresponding with increasing PSA (p <0.001) and Grade Group (p <0.001). Median follow-up was 4.9 years (0.3−17.6 years). On multivariable analysis accounting for risk group, age, and year of treatment, ADT was not associated with bF, DM, PCSM, or OS (p ≥0.05 each). Among patients with UIR, HR, and VHR PCa, the addition of ADT to 125I interstitial brachytherapy was not associated with improved outcomes, and no subgroup demonstrated benefit. Our findings do not support the use of ADT in combination with 125I interstitial brachytherapy. Prospective studies are required to elucidate the role of ADT for patients with UIR, HR, and VHR PCa treated with prostate brachytherapy. [ABSTRACT FROM AUTHOR]

Background The objective of this study was to evaluate the impact of the time interval between planning imaging and stereotactic radiosurgery (SRS) delivery on tumor volumes and spatial anatomic displacements of brain metastases (BM). Methods Consecutive patients diagnosed with BM treated with SRS over a 3-year period were evaluated. Only patients who underwent an institutionally standardized diagnostic MRI (MRI-1) and a treatment planning MRI (MRI-2) were included. The impact of histology, inter-scan time interval, lesion location, tumor volume, and diameter were evaluated on final lesion diameter, volume, anatomic displacement, and ultimate need for change in management (ie, expanding margins, rescanning). Results 101 patients (531 lesions) with a median inter-scan time interval of 8 days (range: 1-42 days) met the inclusion criteria. The median percentage increase in BM diameter and volume were 9.5% (IQR: 2.25%-24.0%) and 20% (IQR: 0.7%-66.7%). Overall, 147 lesions (27.7%) in 57 patients (56.4%) required a change in management. There was a statistically significant relationship between initial tumor diameter (cm) and change in management (OR: 2.69, 95% CI: 1.93-3.75; P <.001). Each day between MRI-1 and MRI-2 was associated with a change in management with an OR of 1.05 (95% CI: 1.03-1.07; P <.001). Conclusions Changes in tumor diameter, volume, and spatial position occur as a function of time. Planning imaging for SRS is recommended to occur in close temporal proximity to treatment; for those with delays, a larger setup margin may need to be used to ensure tumor coverage and account for positional changes. [ABSTRACT FROM AUTHOR]

Adjuvant radiation therapy has been associated with improved local control following breast‐conserving surgery. Traditionally, treatment has been delivered with whole breast irradiation over 3‐6 weeks or partial breast irradiation over 1‐3 weeks. However, intraoperative radiation therapy (IORT) has emerged as a technique that delivers a single dose of radiotherapy at the time of surgery for early‐stage breast cancers. We report initial outcomes and acute toxicities with intraoperative radiation from a single institution. Patients with DCIS or Stage I‐II breast cancer who underwent lumpectomy and sentinel lymph node biopsy (nodal sampling excluded in some cases) were included. All patients in this analysis were treated with IORT as at the time of surgery, 20 Gy in 1 fraction with 50 kV x‐ray. Patients were treated at a single institution between 2011 and 2019. Follow‐up was per standard institutional protocol. Two hundred and one patients were included in the analysis, with a median follow‐up of 23 months (range: 0‐73 months). Median age was 71 years old. Overall, 4 (2.0%) patients had DCIS, 186 (92.5%) patients had Stage 1 disease, and 11 patients had (5.5%) Stage 2 disease. All patients were estrogen receptor‐positive, 175 (87.9%) progesterone receptor‐positive, and 1 (0.5%) HER2 amplified. The crude rate of local recurrence was 2.0% (n = 4) and distant metastasis rate was 0.5% (n = 1). The rate of arm lymphedema was 0.5% (n = 1) and chronic telangiectasia rate was 1.1% (n = 2). Intraoperative radiation therapy, in a cohort of low‐risk patients, demonstrated low rates of recurrence and reproducibility in a multi‐disciplinary setting. Further follow‐up, analysis of patient satisfaction and cosmesis, and comparison to whole breast irradiation and partial breast techniques is necessary in order to further validate these findings. [ABSTRACT FROM AUTHOR]

Patients were treated at a single institution to a dose of 30 Gy in five fractions delivered every other day using image‐guided intensity modulated radiation therapy (IMRT) partial breast irradiation. A total of 34 patients were treated with a median follow‐up of 4.6 months. The rate of acute Grade 1 dermatitis was 23.5% (n = 8), and Grade 1 fatigue was 17.6% (n = 6), with no Grade 2 or higher acute toxicities. The rate of chronic Grade 1 dermatitis was 25.0% (n = 6), Grade 1 fat necrosis 4.2% (n=1), with no patients demonstrating other chronic toxicities. Image‐guided APBI delivered with IMRT is associated with low rates of acute and chronic toxicity though additional follow‐up is warranted. [ABSTRACT FROM AUTHOR]

PURPOSE: To determine which factors influence cost in head and neck cancer (HNC) to inform the development of a bundled payment model (BPM). METHODS: Patients with stages 0 to IVB (by American Joint Commission on Cancer, 7th edition) HNC of various sites and histology treated definitively at a single tertiary care center during 2013 were included. Clinical variables and direct cost data were obtained, and their associations were investigated using χ2, t , Wilcoxon rank sum, and analysis of variance testing. Results were used to develop a BPM. RESULTS: One hundred fifty patients were included; 87% were white, 74% were men, 48% had oropharyngeal cancer, and 58% had stage IVA disease. Treatment consisted of surgery alone (17%), radiation alone (11%), surgery plus radiation (14%), chemoradiation (45%), and surgery plus chemoradiation (13%). On multivariable analysis, both increasing group stage and number of treatment modalities used were significantly associated with higher cost. Given that stage often dictates treatment, we developed three cost tiers that were based on overall treatment modality. Tier A, the least costly, consisted of single-modality therapy with either surgery alone or radiation alone (median cost divided by the median overall cost of treatment, 0.54; 25th to 75th percentile range, 0.29 to 1.02), followed by tier B, which consisted of bimodality therapy with either chemoradiation or surgery plus radiation (1.03; range, 0.81 to 1.35), followed by tier C, which consisted of trimodality therapy with surgery plus chemoradiation (1.43; range, 1.10 to 1.96). CONCLUSION: The number of treatment modalities required is the primary driver of cost in HNC. These data can simplify development of a comprehensive HNC BPM. [ABSTRACT FROM AUTHOR]

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

Simple Summary: Malignant pleural mesothelioma (MPM) is a rare cancer with an aggressive disease course. For patients who are medically inoperable or surgically unresectable, multi-agent systemic therapy remains an accepted standard-of-care around the world. Given the rare incidence of MPM and the disease's aggressive nature, novel clinical trial designs are required. The purpose of this meta-analysis is to provide baseline summative survival estimates as well as evaluate the influence of prognostic variables to provide comparative estimates for future trial designs. In this study, a nomogram model was created to estimate survival with treatment with platinum-pemetrexed using covariates known to be associated with survival, including median age, gender, ECOG performance status, tumor stage, and tumor pathology subtype. Collaborative efforts can drive the change in the right direction, and appreciable progress has to be facilitated and newer trial designs may need to pave the way for future innovations in this rare disease. (1) Purpose: Malignant pleural mesothelioma (MPM) is a rare cancer with an aggressive course. For patients who are medically inoperable or surgically unresectable, multi-agent systemic chemotherapy remains an accepted standard-of-care. The purpose of this meta-analysis is to provide baseline summative survival estimates as well as evaluate the influence of prognostic variables to provide comparative estimates for future trial designs. (2) Methods: Using PRISMA guidelines, a systematic review and meta-analysis was performed of MPM studies published from 2002–2019 obtained from the Medline database evaluating systemic therapy combinations for locally advanced or metastatic disease. Weighted random effects models were used to calculate survival estimates. The influence of proportions of known prognostic factors on overall survival (OS) were evaluated in the creation of a prognostic nomogram to estimate survival. The performance of this model was evaluated against data generated from one positive phase II study and two positive randomized trials. (3) Results: Twenty-four phase II studies and five phase III trials met the eligibility criteria; 2534 patients were treated on the included clinical studies. Ten trials included a platinum-pemetrexed-based treatment regimen, resulting in a pooled estimate of progression-free survival (PFS) of 6.7 months (95% CI: 6.2–7.2 months) and OS of 14.2 months (95% CI: 12.7–15.9 months). Fifteen experimental chemotherapy regimens have been tested in phase II or III studies, with a pooled median survival estimate of 13.5 months (95% CI: 12.6–14.6 months). Meta-regression analysis was used to estimate OS with platinum-pemetrexed using a variety of features, such as pathology (biphasic vs. epithelioid), disease extent (locally advanced vs. metastatic), ECOG performance status, age, and gender. The nomogram-predicted estimates and corresponding 95% CIs performed well when applied to recent randomized studies. (4) Conclusions: Given the rarity of MPM and the aggressive nature of the disease, innovative clinical trial designs with significantly greater randomization to experimental regimens can be performed using robust survival estimates from prior studies. This study provides baseline comparative values and also allows for accounting for differing proportions of known prognostic variables. [ABSTRACT FROM AUTHOR]

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