Purpose Hippocampal neural stem-cell injury during whole-brain radiotherapy (WBRT) may play a role in memory decline. Intensity-modulated radiotherapy can be used to avoid conformally the hippocampal neural stem-cell compartment during WBRT (HA-WBRT). RTOG 0933 was a single-arm phase II study of HA-WBRT for brain metastases with prespecified comparison with a historical control of patients treated with WBRT without hippocampal avoidance. Patients and Methods Eligible adult patients with brain metastases received HA-WBRT to 30 Gy in 10 fractions. Standardized cognitive function and quality-of-life (QOL) assessments were performed at baseline and 2, 4, and 6 months. The primary end point was the Hopkins Verbal Learning Test–Revised Delayed Recall (HVLT-R DR) at 4 months. The historical control demonstrated a 30% mean relative decline in HVLT-R DR from baseline to 4 months. To detect a mean relative decline ≤ 15% in HVLT-R DR after HA-WBRT, 51 analyzable patients were required to ensure 80% statistical power with α = 0.05. Results Of 113 patients accrued from March 2011 through November 2012, 42 patients were analyzable at 4 months. Mean relative decline in HVLT-R DR from baseline to 4 months was 7.0% (95% CI, −4.7% to 18.7%), significantly lower in comparison with the historical control (P < .001). No decline in QOL scores was observed. Two grade 3 toxicities and no grade 4 to 5 toxicities were reported. Median survival was 6.8 months. Conclusion Conformal avoidance of the hippocampus during WBRT is associated with preservation of memory and QOL as compared with historical series.

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

Retrospective data suggests that low serum glucose levels during the treatment of glioblastoma multiforme (GBM) may improve clinical outcomes. As such, many patients are implementing a ketogenic diet (KD) in order to decrease serum glucose flux while simultaneously elevating circulating ketones during radiation therapy and chemotherapy for the treatment of GBM. With IRB approval, a retrospective review of patients with high-grade glioma treated with concurrent chemoradiotherapy and adjuvant chemotherapy was carried out from August 2010 to April 2013. Serum glucose and ketone levels, dexamethasone dose, and toxicity of patients undergoing a KD during treatment were also assessed. Blood glucose levels were compared between patients on an unspecified/standard diet and a KD. Toxicity was assessed by Common Terminology Criteria for Adverse Events version 4. In total, 53 patients were analyzed. Six underwent a KD during treatment. The diet was well tolerated with no grade III toxicity and one episode of grade II fatigue. No episodes of symptomatic hypoglycemia were experienced. Four patients are alive at a median follow-up of 14 months. The mean blood glucose of patients on a standard diet was 122 versus 84 mg/dl for those on a KD. Based on this retrospective study, a KD appears safe and well tolerated during the standard treatment of GBM. Dietary restriction of carbohydrates through a KD reduces serum glucose levels significantly, even in conjunction with high dose steroids, which may affect the response to standard treatment and prognosis. Larger prospective trials to confirm this relationship are warranted.

Glioblastoma, the most common and most rapidly progressing primary malignant tumor of the central nervous system, continues to portend a dismal prognosis, despite improvements in diagnostic and therapeutic strategies over the last 20 years. The standard of care radiographic characterization of glioblastoma is magnetic resonance imaging (MRI), which is a widely utilized examination in the diagnosis and post-treatment management of patients with glioblastoma. Basic MRI modalities available from any clinical scanner, including native T1-weighted (T1w) and contrast-enhanced (T1CE), T2-weighted (T2w), and T2-fluid-attenuated inversion recovery (T2-FLAIR) sequences, provide critical clinical information about various processes in the tumor environment. In the last decade, advanced MRI modalities are increasingly utilized to further characterize glioblastomas more comprehensively. These include multi-parametric MRI sequences, such as dynamic susceptibility contrast (DSC), dynamic contrast enhancement (DCE), higher order diffusion techniques such as diffusion tensor imaging (DTI), and MR spectroscopy (MRS). Significant efforts are ongoing to implement these advanced imaging modalities into improved clinical workflows and personalized therapy approaches. Functional MRI (fMRI) and tractography are increasingly being used to identify eloquent cortices and important tracts to minimize postsurgical neuro-deficits. A contemporary review of the application of standard and advanced MRI in clinical neuro-oncologic practice is presented here.

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ObjectivesThis study compares the dosimetry and efficiency of two modern radiosurgery [stereotactic radiosurgery (SRS)] modalities for multiple brain metastases [Gamma Knife (GK) and LINAC-based RapidArc/volumetric modulated arc therapy], with a special focus on the comparison of low-dose spread.MethodsSix patients with three or four small brain metastases were used in this study. The size of targets varied from 0.1 to 10.5 cc. SRS doses were prescribed according to the size of lesions. SRS plans were made using both Gamma Knife® Perfexion and a single-isocenter, multiple non-coplanar RapidArc®. Dosimetric parameters analyzed included RTOG conformity index (CI), gradient index (GI), 12 Gy isodose volume (V12Gy) for each target, and the dose “spread” (Dspread) for each plan. Dspread reflects SRS plan’s capability of confining radiation to within the local vicinity of the lesion and to not spread out to the surrounding normal brain tissues. Each plan has a dose (Dspread), such that once dose decreases below Dspread (on total tissue dose–volume histogram), isodose volume starts increasing dramatically. Dspread is defined as that dose when volume increase first exceeds 20 cc/0.1 Gy dose decrease.ResultsRapidArc SRS has smaller CI (1.19 ± 0.14 vs. 1.50 ± 0.16, p < 0.001) and larger GI (4.77 ± 1.49 vs. 3.65 ± 0.98, p < 0.01). V12Gy results were comparable (2.73 ± 1.38 vs. 3.06 ± 2.20 cc, p = 0.58). Moderate to lower dose spread, V6, V4.5, and V3, were also equivalent. GK plans achieved better very low-dose spread (≤3 Gy) and also had slightly smaller Dspread, 1.9 vs. 2.5 Gy. Total treatment time for GK is estimated between 60 and 100 min. GK treatments are between 3 and 5 times longer compared to RapidArc treatment techniques.ConclusionDosimetric parameters reflecting prescription dose conformality (CI), dose fall off (GI), radiation necrosis indicator (V12Gy), and dose spread (Dspread) were compared between GK SRS and RapidArc SRS for multi-mets. RapidArc plans have smaller CI but larger GI. V12Gy are comparable. GK appears better at reducing only very low-dose spread (<3 Gy). The treatment time of RapidArc SRS is significantly reduced compared to GK SRS.

IMPORTANCEFor brain metastases, the combination of neurosurgical resection and postoperative hypofractionated stereotactic radiotherapy (HSRT) is an emerging therapeutic approach preferred to the prior practice of postoperative whole-brain radiotherapy. However, mature large-scale outcome data are lacking.OBJECTIVE To evaluate outcomes and prognostic factors after HSRT to the resection cavity in patients with brain metastases.DESIGN, SETTING, AND PARTICIPANTS An international, multi-institutional cohort study was performed in 558 patients with resected brain metastases and postoperative HSRT treated between December 1, 2003, and October 31, 2019, in 1 of 6 participating centers. Exclusion criteria were prior cranial radiotherapy (including whole-brain radiotherapy) and early termination of treatment.EXPOSURES A median total dose of 30 Gy (range, 18-35 Gy) and a dose per fraction of 6 Gy (range, 5-10.7 Gy) were applied. MAIN OUTCOMES AND MEASURESThe primary end points were overall survival, local control (LC), and the analysis of prognostic factors associated with overall survival and LC. Secondary end points included distant intracranial failure, distant progression, and the incidence of neurologic toxicity.RESULTS A total of 558 patients (mean [SD] age, 61 [0.50] years; 301 [53.9%] female) with 581 resected cavities were analyzed. The median follow-up was 12.3 months (interquartile range, 5.0-25.3 months). Overall survival was 65% at 1 year, 46% at 2 years, and 33% at 3 years, whereas LC was 84% at 1 year, 75% at 2 years, and 71% at 3 years. Radiation necrosis was present in 48 patients (8.6%) and leptomeningeal disease in 73 patients (13.1%). Neurologic toxic events according to the Common Terminology Criteria for Adverse Events grade 3 or higher occurred in 16 patients (2.8%) less than 6 months and 24 patients (4.1%) greater than 6 months after treatment. Multivariate analysis identified a Karnofsky Performance Status score of 80% or greater (hazard ratio [HR], 0.61; 95% CI, 0.46-0.82; P < .001), 22 to 33 days between resection and radiotherapy (HR, 1.50; 95% CI, 1.07-2.10; P = .02), and a controlled primary tumor (HR, 0.69; 95% CI, 0.52-0.90; P = .007) as prognostic factors associated with overall survival. For LC, a single brain metastasis (HR, 0.57; 95% CI, 0.35-0.93; P = .03) and a controlled primary tumor (HR, 0.59; 95% CI, 0.39-0.92; P = .02) were significant in the multivariate analysis. CONCLUSIONS AND RELEVANCETo date, this cohort study includes one of the largest series of patients with brain metastases and postoperative HSRT and appears to confirm an excellent risk-benefit profile of local HSRT to the resection cavity. Additional studies will help determine radiation dose-volume parameters and provide a better understanding of synergistic effects with systemic and immunotherapies.

Purpose/Objectives: There are several popular treatment options currently available for stereotactic radiosurgery (SRS) of multiple brain metastases: 60 Co sources and cone collimators around a spherical geometry (GammaKnife), multi-aperture dynamic conformal arcs on a linac (BrainLab Elements™ v1.5), and volumetric arc therapy on a linac (VMAT) calculated with either the conventional optimizer or with the Varian HyperArc™ solution. This study aimed to dosimetrically compare and evaluate the differences among these treatment options in terms of dose conformity to the tumor as well as dose sparing to the surrounding normal tissues. Methods and Materials: Sixteen patients and a total of 112 metastases were analyzed. Five plans were generated per patient: GammaKnife, Elements, HyperArc-VMAT, and two Manual-VMAT plans to evaluate different treatment planning styles. Manual-VMAT plans were generated by different institutions according to their own clinical planning standards. The following dosimetric parameters were extracted: RTOG and Paddick conformity indices, gradient index, total volume of brain receiving 12Gy, 6Gy, and 3Gy, and maximum doses to surrounding organs. The Wilcoxon signed rank test was applied to evaluate statistically significant differences ( p < 0.05). Results: For targets ≤ 1 cm, GammaKnife, HyperArc-VMAT and both Manual-VMAT plans achieved comparable conformity indices, all superior to Elements. However, GammaKnife resulted in the lowest gradient indices at these target sizes. HyperArc-VMAT performed similarly to GammaKnife for V 12Gy parameters. For targets ≥ 1 cm, HyperArc-VMAT and Manual-VMAT plans resulted in superior conformity vs. GammaKnife and Elements. All SRS plans achieved clinically acceptable organs-at-risk dose constraints. Beam-on times were significantly longer for GammaKnife. Manual-VMAT A and Elements resulted in shorter delivery times relative to Manual-VMAT B and HyperArc-VMAT. Conclusion: The study revealed that Manual-VMAT and HyperArc-VMAT are capable of achieving similar low dose brain spillage and conformity as GammaKnife, while significantly minimizing beam-on time. For targets smaller than 1 cm in diameter, GammaKnife still resulted in superior gradient indices. The quality of the two sets of Manual-VMAT plans varied greatly based on planner and optimization constraint settings, whereas HyperArc-VMAT performed dosimetrically superior to the two Manual-VMAT plans.