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Background: Prognostic markers for meningioma are needed to risk-stratify patients and guide postoperative surveillance and adjuvant therapy., Objective: To identify a prognostic gene signature for meningioma recurrence and mortality after resection using targeted gene-expression analysis., Methods: Targeted gene-expression analysis was used to interrogate a discovery cohort of 96 meningiomas and an independent validation cohort of 56 meningiomas with comprehensive clinical follow-up data from separate institutions. Bioinformatic analysis was used to identify prognostic genes and generate a gene-signature risk score between 0 and 1 for local recurrence., Results: We identified a 36-gene signature of meningioma recurrence after resection that achieved an area under the curve of 0.86 in identifying tumors at risk for adverse clinical outcomes. The gene-signature risk score compared favorably to World Health Organization (WHO) grade in stratifying cases by local freedom from recurrence (LFFR, P < .001 vs .09, log-rank test), shorter time to failure (TTF, F-test, P < .0001), and overall survival (OS, P < .0001 vs .07) and was independently associated with worse LFFR (relative risk [RR] 1.56, 95% CI 1.30-1.90) and OS (RR 1.32, 95% CI 1.07-1.64), after adjusting for clinical covariates. When tested on an independent validation cohort, the gene-signature risk score remained associated with shorter TTF (F-test, P = .002), compared favorably to WHO grade in stratifying cases by OS (P = .003 vs P = .10), and was significantly associated with worse OS (RR 1.86, 95% CI 1.19-2.88) on multivariate analysis., Conclusion: The prognostic meningioma gene-expression signature and risk score presented may be useful for identifying patients at risk for recurrence., (Copyright © 2020 by the Congress of Neurological Surgeons.)

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., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Introduction: Recurrent intracranial epidermoid cysts may be difficult to address surgically given their proximity to critical neurovascular structures of the skull base. There are emerging reports of using radiotherapy (RT) for the treatment of recurrent epidermoid cysts. Here, we report a case series of adjuvant fractionated external beam RT for recurrent intracranial epidermoid cysts., Methods: A single-institution review of all recurrent epidermoid cysts treated with adjuvant therapy between 2000 and 2017 was performed., Results: Eight patients with recurrent epidermoid cysts who underwent adjuvant external beam RT were identified. Average age at initial diagnosis was 42.2 years, and median clinical follow-up after initial diagnosis and RT was 16.4 and 2.9 years, respectively. The median number of surgical resections prior to RT was 3 (range 2-5). Rationale for RT included multiple recurrent disease, rapid recurrence following prior resection, increased risk of further surgical morbidity, and patient preference. Median dose was 50.4 delivered in 1.8 Gy fractions (median 28 fractions). By the date of last follow-up, no patient has demonstrated progression, and there have been no cases of malignant degeneration., Conclusion: Adjuvant RT should be considered in the context of recurrent epidermoid cysts to decrease the likelihood of further recurrences.

Background: The role of stereotactic radiosurgery (SRS) for recurrent glioblastoma and the radionecrosis risk in this setting remain unclear., Objective: To perform a large retrospective study to help inform proper indications, efficacy, and anticipated complications of SRS for recurrent glioblastoma., Methods: We 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., Results: One hundred seventy-four glioblastoma patients (median age, 54.1 years) underwent SRS a median of 8.7 months after initial diagnosis. Seventy-five percent had 1 treatment target (range, 1-6), and median target volume and prescriptions were 7.0 cm 3 (range, 0.3-39.0 cm 3 ) and 16.0 Gy (range, 10-22 Gy), respectively. Median overall survival was 10.6 months after SRS and 19.1 months 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 17.8 Gy; P = .003) and larger mean treatment volume (10.0 vs 5.4 cm 3 ; P = .009)., Conclusion: Gamma 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., (Copyright © 2016 by the Congress of Neurological Surgeons)

Purpose: To evaluate prognostic factors for survival after stereotactic radiosurgery (SRS) for new, progressive, or recurrent brain metastases (BM) after prior whole brain radiotherapy (WBRT)., Methods and Materials: Patients treated between 1991 and 2007 with Gamma Knife SRS for BM after prior WBRT were retrospectively reviewed. Potential prognostic factors were analyzed overall and by primary site using univariate and stepwise multivariate analyses and recursive partitioning analysis, including age, Karnofsky performance status (KPS), primary tumor control, extracranial metastases, number of BM treated, total SRS target volume, and interval from WBRT to SRS., Results: A total of 310 patients were analyzed, including 90 breast, 113 non-small-cell lung, 31 small-cell lung, 42 melanoma, and 34 miscellaneous patients. The median age was 56, KPS 80, number of BM treated 3, and interval from WBRT to SRS 8.1 months; 76% had controlled primary tumor and 60% had extracranial metastases. The median survival was 8.4 months overall and 12.0 vs. 7.9 months for single vs. multiple BM treated (p = 0.001). There was no relationship between number of BM and survival after excluding single-BM patients. On multivariate analysis, favorable prognostic factors included age <50, smaller total target volume, and longer interval from WBRT to SRS in breast cancer patients; smaller number of BM, KPS >60, and controlled primary in non-small-cell lung cancer patients; and smaller total target volume in melanoma patients., Conclusions: Among patients treated with salvage SRS for BM after prior WBRT, prognostic factors appeared to vary by primary site. Although survival time was significantly longer for patients with a single BM, the median survival time of 7.9 months for patients with multiple BM seems sufficiently long for salvage SRS to appear to be worthwhile, and no evidence was found to support the use of a cutoff for number of BM appropriate for salvage SRS., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Background and Purpose: MR image-guided gamma knife radiosurgery is often used to treat intra-axial metastatic neoplasms. Following treatment, it is often difficult to determine whether a progressively enhancing lesion is due to metastatic tumor recurrence or radiation necrosis. The purpose of our study was to determine whether relative cerebral blood volume (rCBV), relative peak height (rPH), and percentage of signal-intensity recovery (PSR) derived from dynamic susceptibility-weighted contrast-enhanced perfusion MR imaging can distinguish recurrent metastatic tumor from radiation necrosis., Materials and Methods: Twenty-seven patients with systemic cancer underwent gamma knife radiosurgery for metastatic lesions of the brain and subsequently developed enlarging regions of enhancement within the radiation field. Subsequent surgical resection or clinicoradiologic follow-up established a diagnosis of recurrent metastatic tumor or radiation necrosis. Perfusion MR imaging datasets were retrospectively reprocessed, and regions of interest were drawn around the entire contrast-enhancing region. The resulting T2* signal-intensity time curves produced rCBV, rPH, and PSR values for each examination. A Welch t test was used to compare imaging values between groups., Results: The mean, minimum, and maximum PSR values were significantly lower (P < .01) in cases of recurrent metastatic tumor. The mean and maximum rCBV and rPH values were significantly higher (P < .02) in the recurrent metastatic tumor group., Conclusions: The findings of our study suggest that perfusion MR imaging may be used to differentiate recurrent intra-axial metastatic tumor from gamma knife-induced radiation necrosis.

Glioblastoma multiforme (GBM) tumors almost invariably recur despite initial treatments. Correct diagnosis using a variety of imaging techniques and the involvement of a multidisciplinary tumor board are critical for evaluating each stage of a patient's progression and determining optimal management. Standard therapies for recurrence generally include repeated resection, radiation therapy, chemotherapy, and supportive care; however, salvage therapy must be highly individualized, and not all patients are eligible for every type of standard therapy. Factors such as the size and location of the tumor, previous treatment, and general health of the patient must be taken into consideration. Although standard therapies can prolong a patient's duration of survival, the median survival time for patients with recurrent GBM is usually less than 1 year. Experimental targeted drug therapies have been developed to inhibit aberrant cell-signaling pathways involved in tumorigenesis, and enrolling patients in clinical trials using these therapies is another option for treatment of recurrent GBM. The use of these novel therapies is often confined to large research institutions, but the severe limitations of standard treatment options make it important to highlight the potential of experimental therapies. In this paper the authors outline standard therapies and review the emerging role of targeted drug therapy in the treatment of recurrent GBM.

High-grade gliomas represent a significant source of cancer-related death, and usually recur despite treatment. In this analysis of current brain tumor medicine, we review diagnosis, standard treatment, and emerging therapies for recurrent astrocytomas. Difficulties in interpreting radiographic evidence, especially with regard to differentiating between tumor and necrosis, present a formidable challenge. The most accurate diagnoses come from tissue confirmation of recurrent tumor, but a combination of imaging techniques, such as magnetic resonance spectroscopy imaging, may also be relevant for diagnosis. Repeat resection can prolong life, but repeat irradiation of the brain poses serious risks and results in necrosis of healthy brain tissue; therefore, reirradiation is usually not offered to patients with recurrent tumors. We describe the use of conventional radiotherapy, intensity-modulated radiotherapy, brachytherapy, radiosurgery, and photodynamic therapy for recurrent high-grade glioma. The use of chemotherapy is limited by drug distribution and toxicity, but the development of new drug-delivery techniques such as convection-enhanced delivery, which delivers therapeutic molecules at an effective concentration directly to the brain, may provide a way to reduce systemic exposure to cytotoxic agents. We also discuss targeted therapies designed to inhibit aberrant cell-signaling pathways, as well as new experimental therapies such as immunotherapy. The treatment of this devastating disease has so far been met with limited success, but emerging knowledge of neuroscience and the development of novel therapeutic agents will likely give patients new options and require the neuro-oncology community to redefine clinical trial design and strategy continually.

The prognostic significance of the histologic type and grade of gliomas at initial surgery is well established, but the value of histologic findings in resections after radiotherapy is unclear. Despite this uncertainty, pathologic interpretation of specimens after radiotherapy influences immediate treatment decisions. It is important to determine if, and to what extent, treatment decisions should be based on this information. We aimed to determine the prognostic value of pathologic evaluation in postradiation specimens from 54 patients with similar clinical features who underwent a second surgery for the treatment of radiologic worsening after external beam radiotherapy. We categorized the specimens from the second surgery as either recurrent tumor (category 1) or radionecrosis (category 2). Patients in category 1 had actively proliferating neoplasms with classical features of glioblastoma, whereas patients in category 2 had no evidence of tumor in their surgical specimens. Cases in which a clear-cut definition could not be made were labeled indeterminate (category 3). Despite the morphological evidence of tumor, there were no significant differences between categories 1 and 2 in any of the survival parameters tested. The only difference between groups was higher frequency of iodine 125 (125I) placement at second surgery in category 1 patients (P <.028). Patients in category 1 with or without 125I treatment had similar survival characteristics. We conclude that histopathologic evaluation of postradiotherapy specimens was not helpful in predicting outcome or dictating further management. A comprehensive prospective study with advanced radiologic, pathologic, and molecular analyses may be more useful to determine prognostically valuable parameters.

This study reports the initial experience at the University of California San Francisco (UCSF) with tumor resection and permanent, low-activity iodine 125 (125I) brachytherapy in patients with progressive or recurrent glioblastoma multiforme (GM) and compares these results to those of similar patients treated previously at UCSF with temporary brachytherapy without tumor resection. Thirty-eight patients with progressive or recurrent GM were treated at UCSF with repeat craniotomy, tumor resection, and permanent, low-activity 125I brachytherapy between June 1997 and May 1998. Selection criteria were Karnofsky performance score > or =60, unifocal, contrast-enhancing, well-circumscribed progressive or recurrent GM that was judged to be completely resectable, and no evidence of leptomeningeal or subependymal spread. The median brachytherapy dose 5 mm exterior to the resection cavity was 300 Gy (range, 150-500 Gy). One patient was excluded from analysis. Median survival was 52 weeks from the date of brachytherapy. Age, Karnofsky performance score, and preimplant tumor volume were all statistically significant on univariate analyses. Multivariate analysis for survival showed only age to be significant. Median time to progression was 16 weeks. Both univariate and multivariate analysis of freedom from progression showed only preoperative tumor volume to be significant. Comparison to temporary brachytherapy patients showed no apparent difference in survival time. Chronic steroid requirements were low in patients with minimal postoperative residual tumor. We conclude that permanent 125I brachytherapy for recurrent or progressive GM is well tolerated. Survival time was comparable to that of a similar group of patients treated with temporary brachytherapy.

Objective: Recurrent atypical and malignant meningiomas are difficult to treat successfully. Chemotherapy to date has been unsuccessful, and radiosurgery is limited to smaller tumors. Reoperation alone provides limited tumor control and limited prolonged survival. The addition of brachytherapy at the time of operation is an option. Here, we report the results of our series of patients with recurrent malignant meningioma treated with resection and brachytherapy with permanent low-dose (125)I., Methods: The charts of patients in our database with recurrent atypical and malignant meningiomas treated by surgical resection and permanent (125)I brachytherapy at the University of California, San Francisco, between 1988 and 2002 were selected for this study. Calculations of disease-free survival and overall survival curves were made by the Kaplan-Meier actuarial method. Univariate analysis between Kaplan-Meier curves was based on the log-rank statistic, with a significance level set at a value of P

Background: The management of skull base recurrence of salivary gland tumors is challenging, because complete surgical resection and fractionated reirradiation are seldom possible. Experience is being gained with radiosurgery for this indication., Methods: From 1994-2000, eight patients with 16 skull base recurrences of salivary gland tumors underwent Gamma Knife radiosurgery at the University of California San Francisco. Local freedom from progression (FFP), regional FFP, locoregional FFP, and survival times were measured from the date of radiosurgery and estimated using the Kaplan-Meier method., Results: All patients experienced symptomatic response, usually pain resolution. The median local FFP, regional FFP, locoregional FFP, and survival times were 15.4, 12.0, 10.0, and 21.2 months, respectively. The 1-year local FFP probabilities are 93% and 59%, respectively. Local FFP, allowing for salvage radiosurgery, was 100% at 1 year and 75% at 2 years. Five of seven patients with locoregional failure underwent repeat radiosurgery, successfully achieving control for an additional 4.4 to 13.4 months in four patients. One patient had radiation necrosis develop., Conclusion: Radiosurgery provided good local control and symptomatic relief in patients with recurrent salivary gland malignancies involving the base of skull. In patients with good performance status, radiosurgery should be considered as salvage treatment., (Copyright 2003 Wiley Periodicals, Inc. Head Neck 25: 210-216, 2003)

Objective: The goal of this study was to investigate the use of proton magnetic resonance spectroscopic imaging as a prognostic indicator in gamma knife radiosurgery of recurrent gliomas., Methods: Thirty-six patients with recurrent gliomas were studied with proton magnetic resonance spectroscopic imaging at the time of radiosurgery, and with conventional magnetic resonance imaging examinations at regular time intervals until the initiation of a new treatment strategy. Patients were categorized on the basis of their initial spectroscopic results, and their performance was assessed in terms of change in contrast-enhancing volume, time to further treatment, and survival., Results: The trends in the overall population were toward more extensive increase in the percent contrast-enhancing volume, a decreased time to further treatment, and a reduced survival time for patients with more extensive initial metabolic abnormalities. Statistical analysis of the subpopulation of patients with glioblastoma multiforme found a significant increase in relative contrast-enhancing volume (P < 0.01, Wilcoxon signed-rank test), a decrease in time to further treatment (P < 0.01, log-rank test), and a reduction in survival time (P < 0.01, log-rank test) for patients with regions containing tumor-suggestive spectra outside the gamma knife target, compared with patients exhibiting spectral abnormalities restricted to the gamma knife target. Further studies are needed to establish statistical significance for patients with lower-grade lesions and to confirm the results observed in this study., Conclusion: The pretreatment spectroscopic results provided information that was predictive of outcome for this patient pool, both in local control (change in contrast-enhancing volume) and global outcome (time to further treatment and survival). This modality may have an important role in improving the selection, planning, and treatment process for glioma patients.

Promising results have been obtained using brachytherapy in the treatment of brain tumors. Very low-dose rate brachytherapy (60-100 Gy given at 0.05-0.10 Gy/h) has been used for low-grade gliomas, resulting in 5- and 10-year survival probabilities of 85% and 83% for pilocytic astrocytomas and 61% and 51% for grade II astrocytomas. Only 2.6% of patients had symptomatic radiation necrosis. For faster-growing high-grade gliomas, temporary implants delivering about 60 Gy at 0.40-0.60 Gy/h are generally used. The largest series have reported median survival times of 12-13 months after brachytherapy for recurrent malignant gliomas and 18-19 months after diagnosis of primary glioblastomas treated with external beam radiotherapy and brachytherapy boost. A recent prospective, randomized trial demonstrated significantly improved survival for high-grade glioma patients who had brachytherapy boost. However, over 50% of patients who undergo brachytherapy for malignant gliomas require reoperation for tumor progression and/or radiation necrosis. Strategies are under development to improve local control without increasing radiation toxicity.

Purpose: To study patterns of recurrence in patients with focal primary glioblastoma treated on Northern California Oncology Group protocol 6G-82-2 including surgery, focal external beam radiotherapy (59.4-60 Gy) with oral hydroxyurea followed by temporary brain implant with high-activity iodine-125 sources (50 Gy), and six cycles of chemotherapy with procarbazine, lomustine, and vincristine., Methods and Materials: Serial brain imaging scans were available for review in 25 of 34 patients with glioblastoma who underwent brain implant boost. Of 381 scans performed between the date of diagnosis and the date of death or last follow-up, 362 (95%) were re-reviewed. Disease progression was scored as local (within 2 cm of the implant site), separate within the brain parenchyma (> or = 2 cm from the implant site), subependymal, or systemic. Both initial and subsequent failures were scored., Results: Three patients are 5-year survivors, without evidence of disease, at 267, 292, and 308 weeks. Of the 22 initial sites of failure, 17 (77%) were local, three (14%) were separate brain lesions (one of which was due in retrospect to multicentric disease at diagnosis), one (5%) subependymal, and one (5%) systemic. Five patients with local failure later had other sites of failure, including a separate brain lesion in 1, subependymal spread in 3, and both in 1. One patient with separate brain failure later had local progression and then subependymal spread., Conclusion: Although there was a significant risk of separate brain lesions or subependymal spread over time, local tumor progression was the predominant pattern of failure.

In an attempt to improve local control and survival over those achieved with brain implant alone, a Phase I/II study of interstitial thermoradiotherapy was undertaken for recurrent malignant gliomas and recurrent solitary brain metastases. Between June 1987 and September 1990, 49 tumors in 48 patients were treated with thermoradiotherapy, including 26 glioblastoma multiforme (GM), 16 anaplastic astrocytomas (AA), 4 adenocarcinomas, and 3 melanomas. Patient age ranged from 18 to 71 years and Karnofsky Performance Status from 40 to 90. Stereotactically implanted catheters were used for both hyperthermia and brachytherapy. Hyperthermia was administered immediately before and after brachytherapy, heating as much of the tumor as possible to 42.5 degrees C for 30 min using helical coil microwave antennas. High-activity iodine-125 sources delivered tumor doses of 32.6 to 63.3 Gy. Complications included reversible neurologic changes in 13 patients, 9 seizures, 4 infections, 1 deep venous thrombosis with pulmonary embolus, and 1 scalp burn. Eighteen patients underwent reoperation for tumor and/or necrosis. Follow-up ranged from 9 to 166+ weeks. The median follow-up for living patients with GM and AA was 37 weeks and 92 weeks, respectively. Actuarial median survival was 47 weeks for patients with GM. For patients with AA, actuarial survival was 65% at 18 months and median survival has not yet been reached. Multivariate analysis showed a strong correlation between freedom from local tumor progression and "T90" temperature or minimum tumor temperature. Interstitial brain thermoradiotherapy is now being evaluated in a randomized Phase II trial for previously untreated GM.

Between June 1987 and June 1989, 29 recurrent malignant gliomas or recurrent solitary brain metastases in 28 patients were treated in a Phase I study of interstitial irradiation and hyperthermia. Patient age ranged from 18 to 65 years, and the Karnofsky Performance Status scores ranged from 40 to 90%. There were 13 glioblastomas, 10 anaplastic astrocytomas, 3 melanomas, and 3 adenocarcinomas. Catheters were implanted stereotactically after computed tomography-based preplanning. Hyperthermia was administered before and after brachytherapy, using one to six 2450- or 915-MHz helical coil microwave antennas and one to three multisensor fiberoptic thermometry probes. The goal was to heat as much of the tumor as possible to 42.5 degrees C for 30 minutes. Within 30 minutes after the first hyperthermia treatment, implant catheters were afterloaded with high-activity iodine-125 seeds delivering tumor doses of 32.6 to 61.0 Gy. Most patients had no sensation of heating. Complications included seizures in 5 patients, reversible neurological changes in 9 patients, a scalp burn in 1, and infections in 3. Of 28 evaluable 2-month follow-up scans, 11 showed definite improvement in the radiological appearance of the tumor, 4 were slightly improved, 7 were stable, and 6 showed tumor progression. Ten patients underwent reoperation for persistent tumor and/or necrosis. Eleven of 28 patients are alive 40 to 97 weeks after treatment. Thirteen patients died of a brain tumor, 2 died of extracranial melanoma metastases, 1 died of new brain melanoma metastases, and 1 died of a pulmonary embolus. The median survival was 55 weeks overall. Median survival has not yet been reached for the anaplastic astrocytoma subgroup. We conclude that interstitial brain hyperthermia using helical coil microwave antennas is technically feasible. The level of toxicity is acceptable, and the computed tomographic response rate is encouraging.