Sebastian Adeberg

Long-term outcome after radiotherapy in patients with atypical and malignant meningiomas--clinical results in 85 patients treated in a single institution leading to optimized guidelines for early radiation therapy.

PURPOSE Previously, we could show that the new World Health Organization (WHO) classification of meningiomas significantly correlated with outcome in patients with atypical and anaplastic histology. In the present work, we analyzed our long-term experience in radiotherapy for atypical and malignant meningioma diagnosed according to the most recent WHO categorization system. PATIENTS AND METHODS Sixty-two patients with atypical and 23 patients with malignant meningioma have been treated with radiotherapy. Sixty percent of all patients received radiotherapy (RT) after surgical resection, 19% at disease progression and 8.3% as a primary treatment. Radiation was applied using different techniques including fractionated stereotactic RT (FSRT), intensity-modulated RT, and combination treatment with carbon ions. The median PTV was 156.0 mL. An average dose of 57.6 Gy (range, 30-68.4 Gy) in 1.8-3 Gy fractions was applied. All patients were followed regularly including clinical-neurological follow-up as well as computed tomographies or magnetic resonance imaging. RESULTS Overall survival was impacted significantly by histological grade, with 81% and 53% at 5 years for atypical or anaplastic meningiomas, respectively. This difference was significant at p = 0.022. Eighteen patients died of tumor progression during follow-up. Progression-free survival was 95% and 50% for atypical, and 63% and 13% for anaplastic histology at 2 and 5 years. This difference was significant at p = 0.017. Despite histology, we could not observe any prognostic factors including age, resection status, or Karnofsky performance score. However, preexisting clinical symptoms observed in 63 patients improved in 29.3% of these patients. CONCLUSION RT resulted in improvement of preexisting clinical symptoms; outcome is comparable to other series reported in the literature. RT should be offered after surgical resection after initial diagnosis to increase progression-free survival as well as overall survival. Novel clinical concepts are under investigation to further improve outcome in patients with high-grade meningiomas.

Skull base meningiomas: Long-term results and patient self-reported outcome in 507 patients treated with fractionated stereotactic radiotherapy (FSRT) or intensity modulated radiotherapy (IMRT)

PURPOSE To evaluate long-term outcome of high-precision photon radiotherapy in 507 patients with skull base meningiomas. METHODS AND MATERIALS At the time of radiation therapy, most patients presented with clinical symptoms including double vision, headache, nausea, trigeminal or facial nerve dysfunction or exophthalmus. In general tumors extended into several regions of the skull base. In 54%, prior neurosurgical intervention was performed, which was a partial resection or biopsy in 266 patients. Treatment was delivered using a 6 MV linear accelerator or the tomotherapy system. Fractionated stereotactic radiotherapy (FSRT) was applied in 376 patients (74%) and intensity modulated radiotherapy (IMRT) in 131 patients (26%). A median total dose of 57.6 Gy (range 25-68 Gy) was prescribed in median (range 1.6-5 Gy). To evaluate long-term toxicity as well as quality of life (QOL), we sent out a detailed questionnaire put together with special questions regarding the skull base location of the tumors. Special focus was long-term sequelae including visual deficits, cranial nerve deficits, headaches, fatigue or any other symptoms impairing overall QOL. The median follow-up time was 107 months (range 1-270 months). RESULTS Overall treatment was well tolerated. Local control for the whole cohort was 95% at 5 years and 88% at 10 years. Patients with benign histology had significant higher local control than high-grade meningiomas. For benign meningiomas, local control was 91% at 10 years. For high-risk meningiomas, local control was 81% at 5 years and 53% at 10 years. QOL was unchanged in 47.7% of the patients, and 37.5% showed improvement. Most patients reported an improvement of symptoms or steady state; in only few patients disorders worsened over time or side effects developed. CONCLUSION Precision photon radiotherapy leads to long-term tumor control with minimal side effects, but also with preservation of QOL in patients with skull base meningiomas.

TERT Promoter Mutations and Risk of Recurrence in Meningioma

The World Health Organization (WHO) classification and grading system attempts to predict the clinical course of meningiomas based on morphological parameters. However, because of high interobserver variation of some criteria, more reliable prognostic markers are required. Here, we assessed the TERT promoter for mutations in the hotspot regions C228T and C250T in meningioma samples from 252 patients. Mutations were detected in 16 samples (6.4% across the cohort, 1.7%, 5.7%, and 20.0% of WHO grade I, II, and III cases, respectively). Data were analyzed by t test, Fishers exact test, log-rank test, and Cox proportional hazard model. All statistical tests were two-sided. Within a mean follow-up time in surviving patients of 68.1 months, TERT promoter mutations were statistically significantly associated with shorter time to progression (P < .001). Median time to progression among mutant cases was 10.1 months compared with 179.0 months among wild-type cases. Our results indicate that the inclusion of molecular data (ie, analysis of TERT promoter status) into a histologically and genetically integrated classification and grading system for meningiomas increases prognostic power. Consequently, we propose to incorporate the assessment of TERT promoter status in upcoming grading schemes for meningioma.

A comparison of long-term survivors and short-term survivors with glioblastoma, subventricular zone involvement: a predictive factor for survival?

ObjectiveLong-term survival is rare in patients with glioblastoma (GBM). We set out to determine prognostic factors for patients with favorable and poor prognosis in regard of tumor localization to the subventricular zone (SZV).MethodsWe reviewed the clinical records, pre-operative and post-operative MRI imaging of 50 LTS long-term survivors (LTS) (> 3 years) and 50 short-term survivors (STS) (< 1 year) with glioblastoma. These groups were matched for clinical characteristics being consistently associated with prolonged or shortened survival. All patients had undergone initial surgery or biopsy to confirm GBM diagnosis followed by radio- or chemoradiotherapy.ResultsLTS had a median progression-free survival PFS of 25, 4 months (2, 3–97, 8 months) and overall-survival (OS) of 55, 9 months (38, 2-98, 6 months) compared to STS who had a significantly lower PFS of 4, 2 months (1, 4–10, 2 months) and OS of 6, 6 months (2, 2–11, 6 months) (each p < 0,001).Survival analysis showed that age under 60 years (p < 0,001), total resection status (p < 0,001) and tumor localization without SVZ contact (p = 0,05) were significant factors for prolonged survival.ConclusionOur findings underline that survival in GBM patients is heterogeneous and influenced by multiple factors. This study confirms that tumor location with regard to the SVZ is significantly associated with survival.

Glioblastoma Recurrence Patterns After Radiation Therapy With Regard to the Subventricular Zone

PURPOSE We evaluated the influence of tumor location and tumor spread in primary glioblastoma (GBM), with respect to the subventricular zone (SVZ), on recurrence behavior, progression-free survival (PFS), and overall survival (OS). METHODS AND MATERIALS 607 patients (376 male and 231 female) with a median age of 61.3 years (range, 3.0-87.9 years) and primary GBM treated with radiation therapy (RT) from 2004 to 2012 at a single institution were included in this retrospective study. Preoperative images and follow-up examination results were assessed to evaluate tumor location. Tumors were classified according to the tumor location in relation to the SVZ. RESULTS The median PFS of the study population was 5.2 months (range, 1-91 months), and the median OS was 13.8 months (range, 1-102 months). Kaplan-Meier analysis showed that tumor location in close proximity to the SVZ was associated with a significant decline in PFS and OS (4.8 and 12.3 months, respectively; each P<.001). Furthermore, in cases where tumors were involved with the SVZ, distant cerebral progression (43.8%; P=.005) and multifocal progression (39.8%; P=.008) were more common. Interestingly, opening of the ventricle during the previous surgery showed no impact on PFS and OS. CONCLUSION GBM in close proximity to the SVZ was associated with decreased survival and had a higher risk of multifocal or distant progression. Ventricle opening during surgery had no effect on survival rates.

Melanotic Tumors of the Nervous System are Characterized by Distinct Mutational, Chromosomal and Epigenomic Profiles

Melanotic tumors of the nervous system show overlapping histological characteristics but differ substantially in their biological behavior. In order to achieve a better delineation of such tumors, we performed an in‐depth molecular characterization. Eighteen melanocytomas, 12 melanomas, and 14 melanotic and 14 conventional schwannomas (control group) were investigated for methylome patterns (450k array), gene mutations associated with melanotic tumors and copy number variants (CNVs). The methylome fingerprints assigned tumors to entity‐specific groups. Methylation groups also showed a substantial overlap with histology‐based diagnosis suggesting that they represent true biological entities. On the molecular level, melanotic schwannomas were characterized by a complex karyotype with recurrent monosomy of chromosome 22q and variable whole chromosomal gains and recurrent losses commonly involving chromosomes 1, 17p and 21. Melanocytomas carried GNAQ/11 mutations and presented with CNV involving chromosomes 3 and 6. Melanomas were frequently mutated in the TERT promoter, harbored additional oncogene mutations and showed recurrent chromosomal losses involving chromosomes 9, 10 and 6q, as well as gains of 22q. Together, melanotic nervous system tumors have several distinct mutational and chromosomal alterations and can reliably be distinguished by methylome profiling.

Prior surgical intervention and tumor size impact clinical outcome after precision radiotherapy for the treatment of optic nerve sheath meningiomas (ONSM)

PurposeWe analyzed our long-term experience with fractionated stereotactic radiotherapy (FSRT) in patients with meningioma of the optic nerve sheath (ONSM).Patients and MethodsBetween January 1991 and January 2010, 40 patients with ONSM were treated using FSRT. Of these, 19 patients received radiotherapy as primary treatment, and 21 patients were treated after surgical resection. The median target volume was 9.2 ml, median total dose was 54 Gy in median single fractions of 1,8 Gy.ResultsLocal progression-free survival was 100%. Median survival after FSRT was 60 months (range 4-228 months). In all patients overall toleration of FSRT was very good. Acute toxicity was mild. Prior to RT, 29 patients complained about any kind of visual impairment including visual field deficits, diplopia or amaurosis. Prior surgical resection was identified as a negative prognostic factor for visual outcome, whereas patients with larger tumor volumes demonstrated a higher number of patients with improvement of pre-existing visual deficits.ConclusionLong-term outcome after FSRT for ONSM shows improved vision in patients not treated surgically prior to RT; moreover, the best improvement of visual deficits are observed in patients with larger target volumes. The absence of tumor recurrences supports that FSRT is a strong alternative to surgical resection especially in small tumors without extensive compression of normal tissue structures

The influence of hyperglycemia during radiotherapy on survival in patients with primary glioblastoma.

Background and purpose. Metabolism in tumor cells depends mainly on glycolysis and thus hyperglycemia has been shown to influence tumor properties in various tumor entities. In this retrospective study we set out to determine if hyperglycemic serum levels during radiation therapy impact patient survival and progression patterns in primary glioblastoma (GBM). Material and methods. We retrospectively analyzed glucose serum levels, survival and progression patterns on magnetic resonance imaging (MRI) in 262 GBM patients receiving radiation therapy. Hyperglycemia was classified as mild (> 180 mg/dL) or excessive (≥ 300 mg/dL), and isolated (one hyperglycemic event) or persistent (≥ 3 hyperglycemic events). The multivariate Cox proportional hazards ratio was used to assess the influence of cofactors on survival. Results. Persistent mild (HR = 2.23; p < 0.001) and excessive hyperglycemia (HR = 2.51; p < 0.001) were associated with a decrease in overall survival rates, even when considering the covariate corticosteroid therapy. Here metabolic imbalances did not affect the progression-free interval (p = 0.402), the occurrence of distant (p = 0.587) and multifocal progression (p = 0.445). Conclusion. Our findings support the theory that hyperglycemia during radiation therapy in GBM patients is an unfavorable prognostic cofactor for survival and is detrimental to the survival rates independent of corticosteroid therapy. However, no significant effects of hyperglycemic metabolism on the progression-free interval and recurrence patterns were found.

Nine-year Experience: Prophylactic Cranial Irradiation in Extensive Disease Small-cell Lung Cancer

Background In 2007, the European Organization for Research and Treatment of Cancer (EORTC) study (ClinicalTrials.gov identifier, NCT00016211) demonstrated a beneficial effect on overall survival (OS) with the use of prophylactic cranial irradiation (PCI) for extensive disease (ED) small‐cell lung cancer (SCLC). Nevertheless, debate is ongoing regarding the role of PCI, because the patients in that trial did not undergo magnetic resonance imaging (MRI) of the brain before treatment. Also, a recent Japanese randomized trial showed a detrimental effect of PCI on OS in patients with negative pretreatment brain MRI findings. Materials and Methods We examined the medical records of 136 patients with ED SCLC who had initially responded to chemotherapy and undergone PCI from 2007 to 2015. The outcomes, radiation toxicity, neurologic progression‐free survival, and OS after PCI were analyzed. Survival and correlations were calculated using log‐rank and univariate Cox proportional hazard ratio analyses. Results The median OS and the median neurologic progression‐free survival after PCI was 12 and 19 months, respectively. No significant survival difference was seen for patients who had undergone MRI before PCI compared with patients who had undergone contrast‐enhanced computed tomography (P = .20). Univariate analysis for OS did not show a statistically significant effect for known cofactors. Conclusion In the present cohort, PCI was associated with improved survival compared with the PCI arm of the EORTC trial, with a nearly doubled median OS period. Also, the median OS was prolonged by 2 months compared with the irradiation arm of the Japanese trial. Micro‐Abstract In 2007, a European Organization for Research and Treatment of Cancer (EORTC) study demonstrated a beneficial effect on overall survival (OS) with the use of prophylactic cranial irradiation (PCI) in extensive disease small‐cell lung cancer. Nevertheless, debate is ongoing regarding the role of PCI, because the patients in that trial did not undergo imaging of the brain before treatment. Also, a recent Japanese randomized trial showed a detrimental effect of PCI on OS in patients with negative pretreatment brain magnetic resonance imaging findings. Of our patients, 87% underwent brain imaging before PCI. In the present retrospective analysis, we found that PCI leads to a nearly doubled median OS compared with the irradiation arm of the EORTC trial, with a 2‐month prolonged median OS compared with the irradiation arm of the Japanese trial.

Outcome in patients with small cell lung cancer re-irradiated for brain metastases after prior prophylactic cranial irradiation

OBJECTIVES Patients with brain metastases from small-cell lung cancer (SCLC) who underwent prior prophylactic cranial irradiation (PCI) are often treated with a second course of whole brain radiation therapy (Re-WBRT) or stereotactic radiosurgery (SRS) for purposes of palliation in symptomatic patients, hope for increased life expectancy or even as an alternative to untolerated steroids. Up to date there is only limited data available regarding the effect of this treatment. This study examines outcomes in patients in a single institution who underwent cerebral re-irradiation after prior PCI. METHODS We examined the medical records of 76 patients with brain metastases who had initially received PCI between 2008 and 2015 and were subsequently irradiated with a second course of cerebral radiotherapy. Patients underwent re-irradiation using either Re-WBRT (88%) or SRS (17%). The outcomes, including symptom palliation, radiation toxicity, and overall survival (OS) following re-irradiation were analyzed. Survival and correlations were calculated using log-rank, univariate, and multivariate Cox proportional hazards-ratio analyses. Treatment-related toxicity was classified according to CTCAE v4.0. RESULTS Median OS of all patients was 3 months (range 0-12 months). Median OS after Re-WBRT was 3 months (range 0-12 months). Median OS after SRS was 5 months (range 0-12 months). Karnofsky performance status scale (KPS ≥50%) was significantly associated with improved OS in both univariate (HR 2772; p=0,009) and multivariate analyses (HR 2613; p=0,024) for patients receiving Re-WBRT. No unexpected toxicity was observed and the observed toxicity remained consistently low. Symptom palliation was achieved in 40% of symptomatic patients. CONCLUSIONS In conclusion, cerebral re-irradiation after prior PCI is beneficial for symptom palliation and is associated with minimal side effects in patients with SCLC. Our survival data suggests that it is primarily useful in patients with adequate performance status.