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Radiotherapy (RT) of the brain is a common treatment for patients with high-grade gliomas and brain metastases. It has previously been shown that reactivation of cytomegalovirus (CMV) frequently occurs during RT of the brain. This causes neurological decline, demands antiviral treatment, and is associated with a worse prognosis. CMV-specific T cells are characterized by a differentiated effector memory phenotype and CD45RA+ CCR7- effector memory T (T EMRA ) cells were shown to be enriched in CMV seropositive individuals. In this study, we investigated the distribution of T EMRA cells and their subsets in the peripheral blood of healthy donors and, for the first time, prospectively within the scope of the prospective Glio-CMV-01 clinical trial of patients with high-grade glioma and brain metastases during radiation therapy as a potential predictive marker. First, we developed a multicolor flow cytometry-based assay to monitor the frequency and distribution of T EMRA cells in a longitudinal manner. The CMV serostatus and age were considered as influencing factors. We revealed that patients who had a reactivation of CMV have significantly higher amounts of CD8+ T EMRA cells. Further, the distribution of the subsets of T EMRA cells based on the expression of CD27, CD28, and CD57 is highly dependent on the CMV serostatus. We conclude that the percentage of CD8+ T EMRA cells out of all CD8+ T cells has the potential to serve as a biomarker for predicting the risk of CMV reactivation during RT of the brain. Furthermore, this study highlights the importance of taking the CMV serostatus into account when analyzing T EMRA cells and their subsets.

Purpose: If routine diagnostics are inconclusive, neurologic deterioration and death of patients with brain cancer are attributed to tumor or therapy. Therefore, diagnosing symptoms of encephalopathy caused by human cytomegalovirus (HCMV) reactivation remains uncommon. We investigated the role of HCMV reactivation in neurologic decline and clinical outcome after the start of radiochemotherapy., Experimental Design: HCMV analyses and extended MRI studies including additional independent retrospective neuroradiologic evaluation were performed at predetermined intervals and in case of sudden neurologic decline for 118 adult patients: 63 histologically proven high-grade gliomas, 55 with brain metastases. Immunophenotyping from simultaneously taken whole-blood samples was carried out to detect immune cells serving as prognostic marker for HCMV-associated complications. Symptomatic viremia and overall survival (OS) were the endpoints., Results: Twenty-four percent (28/118) of all patients (12/44 glioblastoma, 3/13 anaplastic astrocytoma; 8/31 non-small cell lung cancer (NSCLC), 13/24 other brain metastases) developed HCMV-viremia during or within 4 weeks after radiotherapy; 21 of 28 patients experienced concurrent major neurologic decline, reversible by antiviral treatment. Identified by immunophenotyping, pretherapeutically low basophil counts predicted a high-risk for HCMV-associated encephalopathy (glioblastoma: P = 0.002, NSCLC: P = 0.02). Median OS was substantially reduced after HCMV-associated encephalopathy without MRI signs of tumor progression [glioblastoma: 99 vs. 570 days (calculated 1-year OS: 22% vs. 69%; P = 0.01) and NSCLC: 47 vs. 219 days (calculated 1-year OS: 0% vs. 32%; P = 0.02)]., Conclusions: For patients with brain cancer, HCMV reactivation after the start of radiochemotherapy is a frequent risk for cognitively detrimental but treatable encephalopathy and premature death. Routinely performed HCMV diagnostics, assessing basophil counts and study-based anti-viral regimens, are necessary to combat this hidden threat. See related commentary by Lawler et al., p. 3077 ., (©2020 American Association for Cancer Research.)

Introduction: Despite a large number of trials, the role of bevacizumab (BEV) in the treatment of recurrent high-grade gliomas is still controversial. Evidence regarding an effect on overall survival in this context is ultimately inconclusive. At the Department of Radiation Oncology at Erlangen, Germany we treated a large cohort of patients with recurrent gliomas where bevacizumab use was determined exclusively by the health care provider's approval of reimbursement., Methods: 61 patients (between 06/2008 and 01/2014) with recurrent high-grade gliomas had reimbursement requests for BEV sent to their health insurance. 37 patients out of 61 (60.7%) had their requests approved and therefore received bevacizumab (BEV-arm) as part of their treatment. The remaining 24 (39.3%) patients received standard therapy without bevacizumab (non-BEV-arm). Survival endpoints were defined with reference to the first BEV request to the health insurance provider., Results: Median overall survival (OS) for the whole cohort was 7.0 months. OS was significantly better for BEV vs. Non-BEV patients (median, 10.3 vs. 4.2 months, logrank p = 0.023). There was an increased BEV benefit in cases of higher-order recurrences (first order recurrence BEV vs. Non-BEV, 12.5 vs. 10.2 months, p = 0.578) (second or higher order of recurrence, 9.9 vs. 2.6 months, p = 0.010). On multivariate analysis for overall survival the prognostic impact of bevacizumab (HR = 0.43, p = 0.034) remained significant., Conclusion: Our results suggest an influence of BEV on overall survival in a heavily pretreated patient population suffering from high-grade gliomas with BEV benefit being greatest in case of second or later recurrence.

Due to its superior soft tissue contrast, magnetic resonance imaging (MRI) is essential for many radiotherapy treatment indications. This is especially true for treatment planning in intracranial tumors, where MRI has a long-standing history for target delineation in clinical practice. Despite its routine use, care has to be taken when selecting and acquiring MRI studies for the purpose of radiotherapy treatment planning. Requirements on MRI are particularly demanding for intracranial stereotactic radiotherapy, where accurate imaging has a critical role in treatment success. However, MR images acquired for routine radiological assessment are frequently unsuitable for high-precision stereotactic radiotherapy as the requirements for imaging are significantly different for radiotherapy planning and diagnostic radiology. To assure that optimal imaging is used for treatment planning, the radiation oncologist needs proper knowledge of the most important requirements concerning the use of MRI in brain stereotactic radiotherapy. In the present review, we summarize and discuss the most relevant issues when using MR images for target volume delineation in intracranial stereotactic radiotherapy.

Objectives: It is controversial whether concurrent chemoradiotherapy (CRT) with temozolomide is feasible and beneficial in elderly patients with glioblastoma., Materials and Methods: Retrospective analysis of 74 elderly glioblastoma patients (65 y and above) treated with concurrent CRT with temozolomide. Factors influencing prognosis and feasibility of CRT were investigated., Results: The median overall survival was 11.3 months. Univariate analysis showed a significant difference in median overall survival for cumulative dose of concurrent temozolomide (optimal cutoff, 2655 mg/m; 13.9 mo for >2655 mg/m vs. 4.9 mo for ≤2655 mg/m; P=0.0216, adjusted for multiple testing). Furthermore, cumulative dose of concurrent temozolomide >2655 mg/m was a significant independent prognostic parameter in multivariate analysis (hazard ratio, 0.33; P=0.002). Hematotoxicity was the most common cause of treatment interruption or discontinuation in patients with an insufficient cumulative temozolomide dose. Prognostic factors for successful performance of CRT with a cumulative dose of concurrent temozolomide >2655 mg/m were female sex (odds ratio [OR], 0.174; P=0.006), age (OR, 0.826 per year; P=0.017), and pretreatment platelet count (OR, 1.013 per 1000 platelets/µL; P=0.001). For easy clinical application of the model an online calculator was developed, which is available at http://www.OldTMZ.com., Conclusions: The probability of successful performance of concurrent CRT with temozolomide can be estimated based on the patient's age, sex, and pretreatment platelet count using the model developed in this study. Thus, a subgroup of elderly glioblastoma patients suitable for chemoradiation with temozolomide can be identified.

Background: Neurological decline during radio(chemo)therapy of the brain is often attributed to disease progression or side effects of radiotherapy. Diagnosis of opportunistic neurotropic infections such as cytomegalovirus (CMV) infections is uncommon, even though high-grade gliomas and some brain metastases are known to contain CMV particles. We prospectively examined the frequency of CMV encephalopathy during radiotherapy of the brain., Methods: Fifty patients requiring whole-brain radiotherapy for brain metastases (n = 27) or local radio(chemo)therapy of the brain for high-grade gliomas (n = 23) were observed in the prospective observational GLIO-CMV-01 study. MRIs and blood samples were obtained before, halfway through, and at the end of radiotherapy. MRIs were screened for disease progression or increased intracranial pressure. Blood was tested for anti-CMV immunoglobulin (Ig)M, anti-CMV IgG, and CMV DNA., Results: Thirty-two of 50 (64%) patients were positive for anti-CMV IgG before radio(chemo)therapy. Fifteen of those 32 (48%) developed viremia during or up to 28 days after treatment. Thirteen of those 15 (87%) required treatment for CMV-associated encephalopathy. MRIs were negative for disease progression, edema, or bleeding. None of the patients negative for anti-CMV IgG developed viremia, suggesting a reactivation rather than a primary infection.In the group at risk consisting of anti-CMV IgG+ patients, age >65 (P = .004) and the amount of dexamethasone taken during radio(chemo)therapy (P = .004) were associated with an increased risk for CMV-associated encephalopathy. One hundred and fifty days after the start of radio(chemo)therapy, survival was 74% (14/19) (no encephalopathy) versus 54% (7/13) (encephalopathy) (odds ratio, 0.42; 95% CI, 0.03-1.86; P = .25)., Conclusion: CMV reactivation frequently causes encephalopathy during radio(chemo)therapy of the brain. The unexpected high incidence of this infection makes it highly clinically relevant for every treating physician., (© The Author(s) 2016. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objectives: Marital status is a well-described prognostic factor in patients with gliomas but the observed survival difference is unexplained in the available population-based studies., Methods: A series of 57 elderly glioblastoma patients (≥70 years) were analyzed retrospectively. Patients received radiotherapy or chemoradiation with temozolomide. The prognostic significance of marital status was assessed. Disease complications, toxicity, and treatment delivery were evaluated in detail., Results: Overall survival was significantly higher in married than in unmarried patients (median, 7.9 vs. 4.0 months; p = 0.006). The prognostic significance of marital status was preserved in the multivariate analysis (HR, 0.41; p = 0.011). Married patients could receive significantly higher daily temozolomide doses (mean, 53.7 mg/m² vs. 33.1 mg/m²; p = 0.020), were more likely to receive maintenance temozolomide (45.7 % vs. 11.8 %; p = 0.016), and had to be hospitalized less frequently during radiotherapy (55.0 % vs. 88.2 %; p = 0.016). Of the patients receiving temozolomide, married patients showed significantly lower rates of hematologic and liver toxicity. Most complications were infectious or neurologic in nature. Complications of any grade were more frequent in unmarried patients (58.8 % vs. 30.0 %; p = 0.041) with the incidence of grade 3-5 complications being particularly elevated (47.1 % vs. 15.0 %; p = 0.004)., Conclusion: We found poorer treatment delivery as well as an unexpected severe increase in toxicity and disease complications in elderly unmarried glioblastoma patients. Marital status may be an important predictive factor for clinical decision-making and should be addressed in further studies.

Introduction: For both patients with high-grade gliomas and multiple cerebral metastases, radio(chemo)therapy is the standard therapy. Neurological decline during treatment is rarely attributed to infections of the brain but to tumor progression or side effects of radiotherapy., Case Reports: We present 4 cases of cytomegalovirus (CMV) viremia associated with neurological deterioration, which occurred during or shortly after radiotherapy and/or chemotherapy of the brain (brain metastases 2, high-grade glioma 1, carcinoma infiltrating brain 1). In all cases, neurological decline was sudden and unexpected, and causes such as increased intracranial pressure or tumor progression could be excluded radiologically. Treatment with dexamethasone and mannitol had no or only very short-term effects. General infections were either excluded or receding before the neurological symptoms occurred. All patients presented with decreasing levels of thrombocytes. In all cases, CMV (re)activation could be proven using blood test for CMV-DNA. The anti-CMV-IgG status suggested reactivation rather than a primary infection. One patient died within 72 h of onset of the symptoms (results of CMV tests were received postmortem). Diagnosis of 3 patients allowed successful administration of antiviral treatment, which greatly improved the general and neurological conditions of the patients within 48 h., Discussion: Neurological deterioration during RT is hardly ever attributed to viral infections. These cases suggest that CMV reactivation and subsequent infection might actually be causative and has to be considered and treated., Conclusion: Further prospective studies verifying and investigating this observation in terms of frequency and clinical relevance seem indicated.

The recurrence of glioblastoma (rGBM) is inevitable and often short-term. Therefore, information on the prognosis and effectiveness of tumor-specific versus purely palliative approaches should be more in-depth than a mere list of available treatment options for patients in this situation. However, follow-up data on the course of the disease in unselected patient populations after completion of primary treatment are scarce. This single-center analysis investigated the rate and number of glioblastoma recurrences after initial radiotherapy in 189 consecutive GM patients, focusing on the incidence of early death and the frequency of tumor-specific treatment (TST) versus best-supportive care (BSC) as well as the outcomes for the different approaches. In 61 % of initial population first recurrence (rGBM) could be determined by histology or imaging. 47 % received TST. 58 % of the patients with rGBM and TST were diagnosed with a second recurrence. Up to five recurrences were treated. 35-45 % of patients died before undergoing imaging studies to confirm the next recurrence. Multivariate analysis identified male sex and KPS score as independent factors (p < 0.01) for the choice of TST over BSC. Median overall survival from the diagnosis of first recurrence was 267 days in the TST group versus 65 days in patients receiving BSC (p < 0.0001). Nearly half of all rGBM patients received second-line TST, but a remarkably high proportion died early. Gender and KPS played a role in the choice of TST over BSC for recurrence treatment.