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Radiotherapy (RT) is a feasible adjuvant therapeutic option for managing intracranial pathologies. One of the late complications of RT that frequently develops within months following RT is radiation necrosis (RN). Corticosteroids are the first-line therapeutic option for RNs; however, in case of unfavorable outcomes or intolerability, several other options, including bevacizumab, laser interstitial thermal therapy, surgery, and hyperbaric oxygen therapy (HBOT). Our goal was to investigate the feasibility and efficacy of the application of HBOT in RNs following RT and help physicians make decisions based on the latest data in the literature. We provide a comprehensive review of the literature on the current issues of utilization of HBOT in RNs. We included 11 studies with a total of 46 patients who underwent HBOT. Most of the cases were diagnosed with brain tumors or arteriovenous malformations. Improvement was achieved in most of the cases. HBOT is a noninvasive therapeutic intervention that can play a role in adjuvant therapy concurrent with RT and chemotherapy and treating RNs. HBOT resolves the RN through 3 mechanisms, including angiogenesis, anti-inflammatory modulation, and cellular repair. Previous studies demonstrated that HBOT is a feasible and well-tolerated therapeutic option that has shown promising results in improving clinical and radiological outcomes in intracranial RNs. Complications of HBOT are usually mild and reversible. HBOT is a feasible and effective therapeutic option in steroid-refractory RNs and is associated with favorable outcomes and a low rate of side effects. [Display omitted] [ABSTRACT FROM AUTHOR]

Imaging changes after stereotactic radiosurgery (SRS) can occur for years after treatment, although the available data on the incidence of tumor progression and adverse radiation effects (ARE) are generally limited to the first 2 years after treatment. A single-institution retrospective review was conducted of patients who had >18 months of imaging follow-up available. Patients who had ≥1 metastatic brain lesions treated with Gamma Knife SRS were assessed for the time to radiographic progression. Those with progression ≥18 months after the initial treatment were included in the present study. The lesions that progressed were characterized as either ARE or tumor progression based on the tissue diagnosis or imaging characteristics over time. The cumulative incidence of delayed imaging radiographic progression was 35% at 5 years after the initial SRS. The cumulative incidence curves of the time to radiographic progression for lesions determined to be ARE and lesions determined to be tumor progression were not significantly different statistically. The cumulative incidence of delayed ARE and delayed tumor progression was 17% and 16% at 5 years, respectively. Multivariate analysis indicated that the number of metastatic brain lesions present at the initial SRS was the only factor associated with late radiographic progression. The timing of late radiographic progression does not differ between ARE and tumor progression. The number of metastatic brain lesions at the initial SRS is a risk factor for late radiographic progression. [ABSTRACT FROM AUTHOR]

Radiation necrosis (RN) is a long-term side effect of Gamma Knife stereotactic radiosurgery that may require surgical intervention. Pentoxifylline and vitamin E have previously been shown to be effective in the treatment of RN in the published literature, but there are no data on the prophylactic use of these molecules or, more importantly, whether prophylaxis is required. The iatrogenic RN model included 50 Sprague–Dawley rats of both sexes. There were 7 treatment subgroups established. Gamma–Plan 8.32 was used to plan after magnetic resonance scans were performed in a specially designed frame. The injection doses used in the treatment groups were vitamin E (30 mg/kg/day in a single dose) and pentoxifylline (50 mg/kg/day in 2 doses). Control magnetic resonance scans were performed at the end of a 16-week treatment, and the subjects were decapitated for pathological evaluations. The intensity of hypoxia - inducible factor 1α immunoreactivity is statistically significantly lower in the therapeutic vitamin E, prophylactic pentoxifylline and vitamin E, and therapeutic pentoxifylline and vitamin E groups than in the other groups. Similarly, the intensity of vascular endothelial growth factor immunoreactivity was reduced in the therapeutic vitamin E and prophylactic pentoxifylline and vitamin E treatment modality groups. When compared with other groups, the therapeutic pentoxifylline group had significantly fewer vascular endothelial growth factor-immunoreactive cells in the perinecrotic area, with an accompanying decreased contrast enhancement pattern. Both vitamin E and pentoxifylline are effective for the treatment and/or restriction of RN, either alone or in combination. The use of these molecules as a preventive measure did not outperform the therapeutic treatment. [ABSTRACT FROM AUTHOR]

Radiographic worsening in patients with glioblastoma undergoing treatment may be due to tumor recurrence or treatment effect. The overall prognosis of these patients based on histologic findings at the time of repeat resection is not well established. Patients with glioblastoma at our institution were identified. Patients who only had 1 surgery were excluded. Demographic and clinical data were recorded. The histologic diagnosis at the time of repeat surgery was recorded as either tumor recurrence or pseudoprogression. For this study, pseudoprogression was defined as absence of tumor histologic features and could show coagulative necrosis, reactive gliosis, and/or inflammatory infiltration. A total of 115 patients were identified, 106 with tumor recurrence and 9 with pseudoprogression. The pseudoprogression group had a greater percentage of patients with O 6 -methylguanine DNA-methyltransferase (MGMT) methylation (37.7% vs. 66.7%), but these results did not reach statistical significance. The overall median survival was 23.1 months. The overall median survival was 22.0 months in the tumor recurrence group and 33.3 months in the pseudoprogression group (P = 0.0814). The overall median survival from the time of repeat surgery was 8.4 months for the entire cohort, 8.3 months for the tumor recurrence group and 18.4 months for the pseudoprogression group (P = 0.0063). In multivariable analysis, presence of tumor features was predictive of worse overall survival from the time of second surgery (hazards ratio 3.96, 95% confidence interval: 1.30-12.06, P = 0.0156). In patients with worsening imaging, the absence of tumor on histologic diagnosis is associated with improved survival from the time of second surgery. [ABSTRACT FROM AUTHOR]

Clinical and/or neuroimaging changes after whole-brain radiation therapy (WBRT) or stereotactic radiosurgery (SRS) for metastatic brain tumor(s) present the clinical dilemma of differentiating tumor recurrence from radiation necrosis. Several imaging modalities attempt to answer this clinical question, including magnetic resonance spectroscopy (MRS) and positron emission tomography (PET) computed tomography (CT). We evaluated our experience regarding the ability of MRS and PET CT to differentiate tumor recurrence from radiation necrosis in patients who have received WBRT or SRS. We retrospectively reviewed records of 242 patients with previous WBRT or SRS to identify those who had MRS and/or PET CT to differentiate tumor recurrence from radiation necrosis. Patients were sorted into true-positive, false-positive, false-negative, and true-negative groups on the basis of imaging interpretation and clinical course combined with surgical pathology results or reaction to nonsurgical treatments including SRS, dexamethasone, or observation. Sensitivity, specificity, positive predictive value, negative predictive value, and accuracy were then calculated. Of 25 patients presenting such diagnostic questions, 19 were evaluated with MRS and 13 with PET CT. MRS sensitivity was 100%, specificity was 50%, and accuracy was 81.8%, whereas PET CT sensitivity was 36.4%, specificity was 66.7%, and accuracy was 42.9%. MRS has better accuracy than PET CT and a high negative predictive value, therefore making it more useful in distinguishing recurrent tumor from radiation necrosis. We encourage correlation with symptoms at imaging to aid in clinical decision making. [ABSTRACT FROM AUTHOR]

Bevacizumab, an anti-vascular endothelial growth factor (VEGF) antibody, is a new treatment approach for radionecrosis. In our study, we compared the prophylactic and therapeutic usage of a promising agent, ramipril (an angiotensin-converting enzyme inhibitor), with that of bevacizumab for reducing radiation-induced brain injury after high-dose stereotactic radiosurgery (SRS). A total of 60 Wistar rats were used. The rats were irradiated with a single dose of 50 Gy using a Leksell Gamma Knife device. Bevacizumab and ramipril were administered in the prophylactic protocol (starting the first day of SRS) and in the therapeutic protocol (starting the fourth week of SRS). Their usage was continued until 12 weeks, and the right frontal lobes of the rats were examined histologically (hematoxylin and eosin stain) and immunohistochemically (hypoxia-inducible factor [HIF]-1α, VEGF, and CD31 antibody expression). The expression of VEGF, HIF-1α, and CD31 had significantly increased at 12 weeks after SRS compared with the control group. The addition of bevacizumab or ramipril to SRS significantly mitigated the histological severity of radiation injury and the expression of VEGF, HIF-1α, and CD31. However, the prophylactic use of bevacizumab and ramipril seemed to be more effective than therapeutic administration. Our results also revealed that the greatest benefit was achieved with the use of prophylactic administration of bevacizumab compared with other treatment protocols. Ramipril might be a promising agent for patients with radionecrosis. Clinical studies are required to investigate the effective and safe doses of ramipril, which is an inexpensive, well-tolerated drug that can cross the blood–brain barrier. [ABSTRACT FROM AUTHOR]

The use of targeted therapies and immune checkpoint inhibitors has drastically changed the management of patients with melanoma and brain metastases. Specifically, combination therapy with ipilimumab, a cytotoxic T-lymphocyte antigen 4 inhibitor, and nivolumab, a programmed cell death protein 1 inhibitor, has become a preferred systemic therapy option for patients with melanoma and asymptomatic brain metastases. However, the efficacy and toxicity profile of these agents in combination with brain-directed radiation therapy is not well described. In this case series, we highlight a series of patients with melanoma demonstrating severe radiation necrosis immediately refractory to surgical resection following brain-directed stereotactic radiation therapy with concurrent ipilimumab and nivolumab. Three patients described in this series each received stereotactic radiation therapy to a dose of 30 Gy in 5 fractions to a melanoma brain metastasis. These areas developed radiographic evidence of necrosis, which was managed surgically and progressed immediately and rapidly after resection. Re-resection, bevacizumab, steroids, and/or discontinuation of nivolumab was used to mitigate further necrosis with varying efficacy. Patients with metastatic melanoma receiving brain-directed radiation therapy with concurrent ipilimumab and nivolumab are at risk for developing severe, surgically refractory radiation necrosis and should be closely followed clinically and with imaging. The exact mechanism for such severe necrosis is unknown, and future studies are needed to better understand this pathophysiology and identify optimal treatment strategies. [ABSTRACT FROM AUTHOR]

There is a lack of consensus regarding diagnosis, timing, and method of intervention for progressive enhancement on surveillance imaging after stereotactic radiosurgery (SRS) treatment of brain metastases. We sought to characterize current practices among neurosurgeons in identifying and treating infield tumor recurrence (TR) or radiation necrosis (RN) after SRS for brain metastases. A voluntary survey was distributed electronically to preidentified neurosurgeons. Results were analyzed using descriptive statistics and χ2 analysis. A total of 120 participants completed the survey from 72 U.S. and 17 international centers. Most (69.2%) agreed that growth over ≥2 surveillance scans spaced ≥90 days apart identified irreversible progression after SRS for brain metastases. Respondents were evenly divided on the need for tissue biopsy to distinguish between TR and RN. Preferred treatment modality and time frame to initiate treatment of suspected RN differed among neurosurgeons based on SRS case volume for brain metastases (P = 0.002 and P = 0.02, respectively). Neurosurgeons who used magnetic resonance–guided laser interstitial thermal therapy (LITT) for brain metastases were more likely to prefer LITT for suspected RN, whereas those with minimal LITT experience preferred steroids (P < 0.0001). Neurosurgeons in the United States were more likely to prefer LITT for RN (37.3%) compared with international counterparts (0%). Our survey of practicing neurosurgeons highlights areas of controversy in distinguishing between TR and RN and preferred management of suspected RN. [ABSTRACT FROM AUTHOR]

Laser interstitial thermal therapy (LITT) is a novel, minimally invasive alternative to craniotomy, and as with any new technology, comes with a learning curve. We present our experience detailing the evolution of this technology in our practice in one of the largest patient cohorts to date regarding LITT in neuro-oncology. We reviewed 238 consecutive patients with brain tumor treated with LITT at our institution. Data on patient, surgery and tumor characteristics, and follow-up were collected. Patients were categorized into 2 cohorts: early (<2014, 100 patients) and recent (>2015, 138 patients). Median follow-up for the entire cohort was 8.4 months. The indications for LITT included gliomas (70.2%), radiation necrosis (21.0%), and metastasis (8.8%). Patient demographics stayed consistent between the 2 cohorts, with the exception of age (early, 54.3; recent, 58.4; P = 0.04). Operative time (6.6 vs. 3.5; P < 0.001) and number of trajectories (53.1% vs. 77.9% with 1 trajectory; P < 0.001) also decreased in the recent cohort. There was a significant decrease in permanent motor deficits over time (15.5 vs. 4.4%; P = 0.005) and 30-day mortality (4.1% vs. 1.5%) also decreased (not statistically significant) in the recent cohort. In terms of clinical outcomes, poor preoperative Karnofsky Performance Status (≤70) were significantly correlated with increased permanent deficits (P = 0.001) and decreased overall survival (P < 0.001 for all time points). We observed improvement in operative efficiency and permanent deficits over time and also patients with poor preoperative Karnofsky Performance Status achieved suboptimal outcomes with LITT. As many other treatment modalities, patient selection is important in this procedure. [ABSTRACT FROM AUTHOR]

Symptomatic peritumoral edema (PTE) is a known complication after radiosurgical treatment of meningiomas. Although the edema in most patients can be successfully managed conservatively with corticosteroid therapy or bevacizumab, some medically refractory cases may require surgical resection of the underlying lesion when feasible. Laser interstitial thermotherapy (LITT) continues to gain traction as an effective therapeutic modality for the treatment of radiation necrosis where its biggest impact is through the control of peritumoral edema. A 56-year-old woman with neurofibromatosis 2 presented with a symptomatic, regrowing left frontotemporal lesion that had previously been radiated, then resected with confirmed recurrence of grade I meningioma, and subsequently radiated again for lesion recurrence. Given her history of 2 prior same-side craniotomies, including a complication of wound infection, she was not a candidate for further open surgical resection. Having failed conservative management, she underwent LITT with intraoperative biopsy demonstrating viable grade I meningioma. Postoperatively, she demonstrated radiographic marked, serial reduction of PTE and experienced resolution of her symptoms. This case demonstrates that LITT may be a viable alternative treatment for patients with meningioma with symptomatic PTE who have failed medical therapy and require surgical intervention. [ABSTRACT FROM AUTHOR]

Treatment for surgically inaccessible medically refractory cerebral radiation necrosis (RN) has remained limited. Recently, laser interstitial thermal therapy (LITT) has gained traction as an effective means of treating these lesions but limited data are available regarding the effect of ablation size on patient outcome. Therefore, this study analyzed various outcome measures as a function of ablation volume/diameter for a series of 20 patients with surgically inaccessible biopsy-proven RN. Twenty patients with biopsy-proven RN treated with LITT from 2013 to 2018 at our institution were retrospectively reviewed. Local progression-free survival (PFS), overall survival, and steroid dependence were analyzed with Kaplan-Meier and Cox regression analysis for ablation volume/diameter. Comparison of preoperative and postoperative Karnofsky Performance Status was conducted with a matched paired t test. Patients with subtotal ablation (<100% increase in pre-LITT lesion volume or <0 mm increase in pre-LITT lesion diameter) had higher risk of local disease progression (hazard ratio, 12.4; P = 0.004) compared with patients with total ablations. Patients who received radical ablations (>200% increase in pre-LITT lesion volume or >2 mm increase in pre-LITT lesion diameter) showed the most favorable PFS (P < 0.0458 and P < 0.0378, respectively). There was no difference in post-LITT Karnofsky Performance Status and time to steroid freedom between ablation groups. Overall survival increased with radical diametric ablation (P = 0.0401). Although LITT has proved to be an effective salvage therapy for patients with RN, detailed volumetric studies have not been explored. Our results suggest that radical ablations have the potential to increase PFS. [ABSTRACT FROM AUTHOR]

Posterior fossa tumors are rare in adults and pose a challenge to treat due to the bony contour of the posterior fossa, complex anatomical structures including deep venous sinuses, and the proximity of the fourth ventricle and brain stem. We describe our experience with laser interstitial thermal therapy (LITT) for the management of brain metastases and radiation necrosis of the posterior fossa. We retrospectively analyzed 13 patients with metastases and radiation necrosis of the posterior fossa managed with LITT. Thirteen patients with histopathologically confirmed radiation necrosis (n = 5) and metastases (n = 8) of the posterior fossa underwent LITT. The median preoperative tumor was 4.66 cm3, and median postoperative ablation cavity volume was 6.29 cm3. The median volume of the ablation cavity was decreased to 2.90 cm3 at a 9-month follow-up. The median volume of peritumoral edema was 12.25 cm3, which fell to a median of 5.77 cm3 at 1-month follow-up. The median progression-free survival was 7 months (range, 3–14 months) and the mean overall survival was 40 months (range, 2–49 months) after LITT. There were no intraoperative complications. One patient experienced palsy of the seventh and eighth cranial nerves on follow-up, attributable to LITT. Lesions of the posterior fossa are challenging to treat given their proximity to the dura and venous sinuses. Our findings demonstrate that LITT ablation may be a safe and feasible option for metastases and radiation necrosis of the posterior fossa. Larger studies are needed to confirm the efficacy of this approach. [ABSTRACT FROM AUTHOR]

The current treatment for patients with relapsed malignant glioma (MG) remains unsatisfactory. Use of hypofractionated stereotactic radiotherapy (HFSRT) for recurrent MG has shown some encouraging results and may be a viable option. We performed a systematic review and meta-analysis of articles that investigated the use of HFSRT for recurrent MG. Relevant studies were obtained through searching PubMed, Embase, and the Cochrane Library. Data about treatment regimens, median overall survival, and radiation necrosis (RN), as well as other major neurologic complications were extracted. We performed a descriptive analysis of the median overall survival and meta-analysis of the reported rates of RN and other major neurologic complications (MNCs). A total of 26 studies were included in our study, comprising 861 patients. Median overall survival ranged from 8.6 to 18 months. A total of 19 studies were included to perform a meta-analysis of the RN rate and the pooled RN rate was 5% (3%–7%). The pooled rate of other MNCs was 2% (1%–4%), calculated from 20 studies. The present evidence suggests that HFSRT is an efficacious and safe treatment approach to treat patients with recurrent MG. However, the retrospective and observational nature of the studies included in our systematic review and meta-analysis restricted formation of more solid conclusions. Thus, well-designed prospective controlled trials are warranted to further define the therapeutic role of HFSRT for recurrent MG. [ABSTRACT FROM AUTHOR]

Introduction Radiation necrosis (RN) and pseudoprogression are known as postradiation treatment effects and may simulate tumor progression. The disease course of glioblastoma patients who had developed RN and the impact of resecting RN on survival have not been evaluated. This study examines the clinical course of patients considered candidates for repeat surgery for a recurring brain mass proven to be RN and compared these with patients who had true tumor recurrence at surgery. Methods Of 159 patients with glioblastoma who were reoperated on because of a presumed recurrent tumor requiring repeat surgery, 18 had RN as the major component of the resected mass. The characteristics and outcome of these 18 patients were retrospectively analyzed and compared with patients in whom active and bulky tumor was found during surgery. Results Radiation necrosis occurred significantly earlier than true tumor recurrence. Patients with RN harbored larger lesions and were significantly more symptomatic before the second surgery. Most patients with RN who underwent GTR of the lesion in the second operation experienced faster resolution of the surrounding edema compared with patients who underwent STR or biopsy only. There was no significant difference in survival between the 2 groups. Conclusions These data provide an opportunity to examine the clinical course of a selected group of patients with histologically verified RN. Although RN is associated with more severe neurologic symptoms that improve after surgery, its occurrence or surgical removal carries no survival advantage compared with patients who undergo a repeat operation for true tumor recurrence. [ABSTRACT FROM AUTHOR]

Radiation therapy represents a mainstay of treatment for patients with brain metastases. Recently, the widespread adoption of immune checkpoint blockade has led to keen interest in treating cancers with checkpoint inhibitors in place of, or as an adjunct to, traditional chemotherapy. However, with the exception of melanoma, immune checkpoint blockade in solid tumors has failed to achieve significant brain control in patients with brain metastases. The possibility of combining immune checkpoint blockade with radiation for the treatment of brain and other metastases represents an exciting new strategy that is in its early stages of investigation. Success with this combinatorial strategy has the potential to result in enhanced rates of brain control, less brain exposure to radiation, and improved cognitive outcomes. In this review, we discuss the mechanisms behind this synergy, describe its limitations, and suggest ways to move the field forward., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background Distinguishing radiation necrosis from brain tumor recurrence remains challenging. We performed a meta-analysis to assess the diagnostic accuracy of 2 different amino acid tracers used in positron emission tomography/computed tomography scans: 18 F-FDOPA (6-[18F]-fluoro-L-3,4-dihydroxyphenylalanine) and 18 F-FET (O-(2-18F-fluoroethyl)-L-tyrosine). Methods We searched for studies in 3 databases: PubMed, Embase, and Chinese Biomedical databases. The data were extracted from eligible studies and then processed with heterogeneity test, threshold effect test, and calculations of sensitivity, specificity, and area under the summary receiver operating characteristic curve. Meta-regression and subgroup analyses were performed to explore the source of heterogeneity. Results A total of 48 studies ( 18 F-FDOPA, n = 21; 18 F-FET, n = 27) were included. Quantitative synthesis determined pooled weight values in the 18 F-FDOPA and 18 F-FET groups: sensitivity, 0.85 versus 0.82; specificity, 0.77 versus 0.80; diagnostic odds ratio, 21.7 versus 23.03; area under the curve (AUC) values, 0.8771 versus 0.8976 ( P = 0.46). Moreover, the type of tumor was identified as the possible source of the significant heterogeneity ( I 2 = 52%; P = 0.003) found in the 18 F-FDOPA group. In meta-regression and subgroup analyses, 18 F-FDOPA showed better diagnostic accuracy in patients with glioma compared with patients with brain metastases (AUC values, 0.9691 vs. 0.837; P < 0.01). 18 F-FDOPA also showed a significant advantage in the diagnosis of glioma recurrence compared with 18 F-FET (AUC values, 0.9691 vs. 0.9124; P = 0.015). Conclusions Both 18 F-FDOPA and 18 F-FET exhibit moderate overall accuracy in diagnosing brain tumor recurrence from radiation necrosis. However, 18 F-FDOPA is more adept at diagnosing glioma recurrence compared with brain metastases, and it is more effective than 18 F-FET in diagnosing glioma recurrence. [ABSTRACT FROM AUTHOR]

Background Radiation therapy is an effective treatment for primary brain tumors and intracranial metastases but can occasionally precede new enhancing lesions on imaging studies that are difficult to discern between tumor recurrence (TR) and radiation necrosis (RN). The aim of this study was to identify clinical presentation and imaging patterns of RN compared with TR that may obviate the need for invasive definitive biopsy. Methods Patients who received radiation therapy and subsequently presented with a new intracranial lesion were reviewed from 2001 to 2016; 27 patients were identified with adequate records and confirmed pathology to have RN present or TR only. Patient and lesion characteristics were assessed using univariate and multivariate logistic regression analyses. Sensitivity and specificities were calculated for imaging features and quantitatively segmented lesion and edema volumes for identifying RN. Results Karnofsky performance scale score at presentation significantly predicted pathologic diagnosis on univariate analysis ( P = 0.044). Radiation dosage and time from radiation therapy to lesion onset did not differ among pathologic diagnosis groups. No differences existed between RN and TR on quantitative imaging analyses. Multivariate logistic regression found higher Karnofsky performance scale score to be an independent factor associated with TR relative to RN (odds ratio 1.26, 95% confidence interval 1.02–1.56, P = 0.030). Conclusions Diagnostic imaging can often be inaccurate in detecting RN alone, even with quantitative volume assessment. Functional status on repeat presentation may increase the likelihood of accurate diagnosis before definitive biopsy when neuroimaging remains unclear. [ABSTRACT FROM AUTHOR]