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Background Addition of temozolomide (TMZ) to radiotherapy (RT) improves overall survival (OS) in patients with glioblastoma (GBM), but previous studies suggest that patients with tumors harboring an unmethylated MGMT promoter derive minimal benefit. The aim of this open-label, phase III CheckMate 498 study was to evaluate the efficacy of nivolumab (NIVO) + RT compared with TMZ + RT in newly diagnosed GBM with unmethylated MGMT promoter. Methods Patients were randomized 1:1 to standard RT (60 Gy) + NIVO (240 mg every 2 weeks for eight cycles, then 480 mg every 4 weeks) or RT + TMZ (75 mg/m2 daily during RT and 150–200 mg/m2/day 5/28 days during maintenance). The primary endpoint was OS. Results A total of 560 patients were randomized, 280 to each arm. Median OS (mOS) was 13.4 months (95% CI, 12.6 to 14.3) with NIVO + RT and 14.9 months (95% CI, 13.3 to 16.1) with TMZ + RT (hazard ratio [HR], 1.31; 95% CI, 1.09 to 1.58; P = .0037). Median progression-free survival was 6.0 months (95% CI, 5.7 to 6.2) with NIVO + RT and 6.2 months (95% CI, 5.9 to 6.7) with TMZ + RT (HR, 1.38; 95% CI, 1.15 to 1.65). Response rates were 7.8% (9/116) with NIVO + RT and 7.2% (8/111) with TMZ + RT; grade 3/4 treatment-related adverse event (TRAE) rates were 21.9% and 25.1%, and any-grade serious TRAE rates were 17.3% and 7.6%, respectively. Conclusions The study did not meet the primary endpoint of improved OS; TMZ + RT demonstrated a longer mOS than NIVO + RT. No new safety signals were detected with NIVO in this study. The difference between the study treatment arms is consistent with the use of TMZ + RT as the standard of care for GBM. ClinicalTrials.gov NCT02617589

Supplementary Figure Legends 1 - 3 are displayed

Pericyte coverage in GL261 control tumors is shown (CollagenIV, red; desmin, green)

Supplementary Figure 3 demonstrates that dual anti-angiogenic and PD-1 therapy normalized the vasculature at the morphological level

Supplementary Figure 1 showing PD-L1 expression in human GBM

Gating strategy for the delineation of glioma tumor infiltrating lymphocytes.

Legends for movies 1-4

File with supporting methods and tables

Supplementary Figure 2 illustrates PD-L1 expression in the GL261 glioma model

Pericyte coverage after PD-1 monotherapy (CollagenIV, red; desmin, green)

Aflibercept/AMG386 combined with anti-PD-1 therapy improves the vasculature as evidenced by desmin staining (CollagenIV, red; desmin, green)

Glioblastoma (GBM) is a non-T-cell–inflamed cancer characterized by an immunosuppressive microenvironment that impedes dendritic cell maturation and T-cell cytotoxicity. Proangiogenic cytokines such as VEGF and angiopoietin-2 (Ang-2) have high expression in glioblastoma in a cell-specific manner and not only drive tumor angiogenesis and vascular permeability but also negatively regulate T-lymphocyte and innate immune cell responses. Consequently, the alleviation of immunosuppression might be a prerequisite for successful immune checkpoint therapy in GBM. We here combined antiangiogenic and immune checkpoint therapy and demonstrated improved therapeutic efficacy in syngeneic, orthotopic GBM models. We observed that blockade of VEGF, Ang-2, and programmed cell death protein-1 (PD-1) significantly extended survival compared with vascular targeting alone. In the GBM microenvironment, triple therapy increased the numbers of CTLs, which inversely correlated with myeloid-derived suppressor cells and regulatory T cells. Transcriptome analysis of GBM microvessels indicated a global vascular normalization that was highest after triple therapy. Our results propose a rationale to overcome tumor immunosuppression and the current limitations of VEGF monotherapy by integrating the synergistic effects of VEGF/Ang-2 and PD-1 blockade to reinforce antitumor immunity through a normalized vasculature.

Supplementary Figure S3. Maximum change from baseline in the sum of target lesions and treatment duration ("other tumor types", intrahepatic cholangiocarcinoma, glioblastoma).

Purpose: Rechallenge with temozolomide (TMZ) at first progression of glioblastoma after temozolomide chemoradiotherapy (TMZ/RT→TMZ) has been studied in retrospective and single-arm prospective studies, applying temozolomide continuously or using 7/14 or 21/28 days schedules. The DIRECTOR trial sought to show superiority of the 7/14 regimen.Experimental Design: Patients with glioblastoma at first progression after TMZ/RT→TMZ and at least two maintenance temozolomide cycles were randomized to Arm A [one week on (120 mg/m2 per day)/one week off] or Arm B [3 weeks on (80 mg/m2 per day)/one week off]. The primary endpoint was median time-to-treatment failure (TTF) defined as progression, premature temozolomide discontinuation for toxicity, or death from any cause. O6-methylguanine DNA methyltransferase (MGMT) promoter methylation was prospectively assessed by methylation-specific PCR.Results: Because of withdrawal of support, the trial was prematurely closed to accrual after 105 patients. There was a similar outcome in both arms for median TTF [A: 1.8 months; 95% confidence intervals (CI), 1.8–3.2 vs. B: 2.0 months; 95% CI, 1.8–3.5] and overall survival [A: 9.8 months (95% CI, 6.7–13.0) vs. B: 10.6 months (95% CI, 8.1–11.6)]. Median TTF in patients with MGMT-methylated tumors was 3.2 months (95% CI, 1.8–7.4) versus 1.8 months (95% CI, 1.8–2) in MGMT-unmethylated glioblastoma. Progression-free survival rates at 6 months (PFS-6) were 39.7% with versus 6.9% without MGMT promoter methylation.Conclusions: Temozolomide rechallenge is a treatment option for MGMT promoter-methylated recurrent glioblastoma. Alternative strategies need to be considered for patients with progressive glioblastoma without MGMT promoter methylation. Clin Cancer Res; 21(9); 2057–64. ©2015 AACR.

Purpose:BAY1436032, an inhibitor of mutant isocitrate dehydrogenase 1 (mIDH1), was active against multiple IDH1-R132X solid tumors in preclinical models. This first-in-human study was designed to determine the safety and pharmacokinetics of BAY1436032, and to evaluate its potential pharmacodynamics and antitumor effects.Patients and Methods:The study comprised of dose escalation and dose expansion cohorts. BAY1436032 tablets were orally administered twice daily on a continuous basis in subjects with mIDH1 solid tumors.Results:In dose escalation, 29 subjects with various tumor types were administered BAY1436032 across five doses (150–1,500 mg twice daily). BAY1432032 exhibited a relatively short half-life. Most evaluable subjects experienced target inhibition as indicated by a median maximal reduction of plasma R-2-hydroxyglutarate levels of 76%. BAY1436032 was well tolerated and an MTD was not identified. A dose of 1,500 mg twice daily was selected for dose expansion, where 52 subjects were treated in cohorts representing four different tumor types [lower grade glioma (LGG), glioblastoma, intrahepatic cholangiocarcinoma, and a basket cohort of other tumor types]. The best clinical outcomes were in subjects with LGG (n = 35), with an objective response rate of 11% (one complete response and three partial responses) and stable disease in 43%. As of August 2020, four of these subjects were in treatment for >2 years and still ongoing. Objective responses were observed only in LGG.Conclusions:BAY1436032 was well tolerated and showed evidence of target inhibition and durable objective responses in a small subset of subjects with LGG.

Supplementary Table S12. NGS analysis of select tumor-associated genes in archival tumor tissue obtained from a subset of subjects.

Supplementary Figure 1. MMSE assessment at study entry, during treatment, and at follow-up

Supplementary Methods, Supplementary Results, Supplementary Tables S1-S11

Supplementary Tables 1-7. Supplementary Table 1. Safety and tolerability. Supplementary Table 2. Outcome by MGMT promoter methylation status and treatment arm. Supplementary Table 3. Outcome by interval from last TMZ administration and MGMT promoter methylation status. Supplementary Table 4. Adherence to Mini Mental Status data collection over the course of the study. Supplementary Table 5. Treatment effect (Arm B versus Arm A) on EORTC-QLQ-C30 and -BN20 scales evaluated at timepoint 90 days Supplementary Table 6. Absolute changes of (0-100) score points of quality of life (as assessed by the EORTC-QLQ-C30 and -BN20 scales) within one treatment cycle of 28 days in Arms A and B, along with local p-values for difference in slopes. Supplementary Table 7. Adherence to EORTC-QLQ-BN20 and -C30 data collection over the course of the study.

Background The incidence of spinal cord gliomas, particularly in adults is low, and the role of chemotherapy has remained unclear. Methods We performed a multicenter, retrospective study of 21 patients diagnosed with spinal cord glioma who received chemotherapy at any time during the disease course. Benefit from chemotherapy was estimated by magnetic resonance imaging. Data on radiotherapy were taken into consideration. Results Thirteen patients were diagnosed with astrocytic gliomas World Health Organization (WHO) grades 1-4, the remaining eight patients with ependymomas WHO grades 1 or 3. Most patients had more than one neurosurgical intervention. Median age at time of first chemotherapy was 33 years (range 21-67 years). Seven patients had chemotherapy combined with radiotherapy as first-line treatment. Two patients had chemoradiotherapy at recurrence, without prior tumor-specific treatment beyond surgery. One patient received chemotherapy alone as first-line treatment and 2 patients had chemotherapy alone at recurrence, without prior treatment. Nine patients had received radiation therapy at an earlier time and chemotherapy was given at time of further recurrences. Best responses in astrocytomas were as follows: chemotherapy alone—2 stable disease (SD) and 3 progressive disease (PD); chemoradiotherapy—1 complete response, 3 SD, and 4 PD. Best responses in ependymomas were as follows: chemotherapy alone—1 partial response, 5 SD, and 1 PD; chemoradiotherapy—1 SD. Conclusions Spinal cord gliomas represent a heterogeneous group of tumors. Survival outcomes in response to chemotherapy in adult spinal cord glioma patients vary substantially, but individual patients appear to derive benefit from chemotherapy.

Purpose Classification and treatment of WHO grade II/III gliomas have dramatically changed. Implementing molecular markers into the WHO classification raised discussions about the significance of grading and clinical trials showed overall survival (OS) benefits for combined radiochemotherapy. As molecularly stratified treatment data outside clinical trials are scarce, we conducted this retrospective study. Methods We identified 343 patients (1995–2015) with newly diagnosed WHO grade II/III gliomas and analyzed molecular markers, patient characteristics, symptoms, histology, treatment, time to treatment failure (TTF) and OS. Results IDH-status was available for all patients (259 mutant, 84 IDH1-R132H-non-mutant). Molecular subclassification was possible in 173 tumors, resulting in diagnosis of 80 astrocytomas and 93 oligodendrogliomas. WHO grading remained significant for OS in astrocytomas/IDH1-R132H-non-mutant gliomas (p p = 0.27). Chemotherapy (and temozolomide in particular) showed inferior OS compared to radiotherapy in astrocytomas (median 6.1/12.1 years; p = 0.03) and oligodendrogliomas (median 13.2/not reached (n.r.) years; p = 0.03). While radiochemotherapy improved TTF in oligodendroglioma (median radiochemotherapy n.r./chemotherapy 3.8/radiotherapy 7.3 years; p p Conclusion This is one of the largest retrospective, real-life datasets reporting treatment and outcome in low-grade gliomas incorporating molecular markers. Current histologic grading features remain prognostic in astrocytomas while being insignificant in oligodendroglioma with interfering treatment effects. Chemotherapy (temozolomide) was less effective than radiotherapy in both astrocytomas and oligodendrogliomas while radiochemotherapy showed the highest TTF in oligodendrogliomas.

Aims Changes in metabolism are known to contribute to tumour phenotypes. If and how metabolic alterations in brain tumours contribute to patient outcome is still poorly understood. Epigenetics impact metabolism and mitochondrial function. The aim of this study is a characterisation of metabolic features in molecular subgroups of isocitrate dehydrogenase mutant (IDHmut) and isocitrate dehydrogenase wildtype (IDHwt) gliomas. Methods We employed DNA methylation pattern analyses with a special focus on metabolic genes, large-scale metabolism panel immunohistochemistry (IHC), qPCR-based determination of mitochondrial DNA copy number and immune cell content using IHC and deconvolution of DNA methylation data. We analysed molecularly characterised gliomas (n = 57) for in depth DNA methylation, a cohort of primary and recurrent gliomas (n = 22) for mitochondrial copy number and validated these results in a large glioma cohort (n = 293). Finally, we investigated the potential of metabolic markers in Bevacizumab (Bev)-treated gliomas (n = 29). Results DNA methylation patterns of metabolic genes successfully distinguished the molecular subtypes of IDHmut and IDHwt gliomas. Promoter methylation of lactate dehydrogenase A negatively correlated with protein expression and was associated with IDHmut gliomas. Mitochondrial DNA copy number was increased in IDHmut tumours and did not change in recurrent tumours. Hierarchical clustering based on metabolism panel IHC revealed distinct subclasses of IDHmut and IDHwt gliomas with an impact on patient outcome. Further quantification of these markers allowed for the prediction of survival under anti-angiogenic therapy. Conclusion A mitochondrial signature was associated with increased survival in all analyses, which could indicate tumour subgroups with specific metabolic vulnerabilities.

BACKGROUND AND PURPOSE: Preclinical evidence points toward a metabolic reprogramming in isocitrate dehydrogenase (IDH) mutated tumor cells with down-regulation of the expression of genes that encode for glycolytic metabolism. We noninvasively investigated lactate and Cr concentrations, as well as intracellular pH using 1H/phosphorus 31 (31P) MR spectroscopy in a cohort of patients with gliomas. MATERIALS AND METHODS: Thirty prospectively enrolled, mostly untreated patients with gliomas met the spectral quality criteria (World Health Organization II [n = 7], III [n = 16], IV [n = 7]; IDH-mutant [n = 23]; IDH wild-type [n = 7]; 1p/19q codeletion [n = 9]). MR imaging protocol included 3D 31P chemical shift imaging and 1H single-voxel spectroscopy (point-resolved spectroscopy sequence at TE = 30 ms and TE = 97 ms with optimized echo spacing for detection of 2-hydroxyglutarate) from the tumor area. Values for absolute metabolite concentrations were calculated (phantom replacement method). Intracellular pH was determined from 31P chemical shift imaging. RESULTS: At TE = 97 ms, lactate peaks can be fitted with little impact of lipid/macromolecule contamination. We found a significant difference in lactate concentrations, lactate/Cr ratios, and intracellular pH when comparing tumor voxels of patients with IDH-mutant with those of patients with IDH wild-type gliomas, with reduced lactate levels and near-normal intracellular pH in patients with IDH-mutant gliomas. We additionally found evidence for codependent effects of 1p/19q codeletion and IDH mutations with regard to lactate concentrations for World Health Organization tumor grades II and III, with lower lactate levels in patients exhibiting the codeletion. There was no statistical significance when comparing lactate concentrations between IDH-mutant World Health Organization II and III gliomas. CONCLUSIONS: We found indirect evidence for metabolic reprogramming in IDH-mutant tumors with significantly lower lactate concentrations compared with IDH wild-type tumors and a near-normal intracellular pH.

BACKGROUND Glioblastoma (GBM) is an aggressive primary tumor of the central nervous system. Current interdisciplinary treatment strategies outside clinical trials include maximal safe resection, followed by treatment with radiation and an alkylating chemotherapy. Based on the results of the positive phase III trial EF-14, the addition of Tumor Treating Fields (TTFields) to temozolomide (TMZ) maintenance therapy brought an additional treatment method to clinical routine. The prospective non-interventional study TIGER (TTFields In GErmany in Routine Clinical Care) documents the use of TTFields in routine clinical care with a particular focus on health-related quality of life (HRQoL) within 4 months after starting therapy, treatment compliance and duration. MATERIAL AND METHODS This multi-center prospective non-interventional study in Germany (NCT03258021) included ndGBM patients eligible for TTFields therapy. Following their consent to participate in the study, patients received a comprehensive introduction to the therapy and their baseline demographic data were collected. Information on TTFields therapy decision is evaluated based on a dedicated TTFields questionnaire at baseline in both arms, follow-up information on how patients cope with the therapy is collected two months after TTFields treatment start, if applicable. HRQoL was assessed in patients deciding for TTFields therapy at baseline as well as at 2 months and 4 months thereafter using the EORTC-QLQ-C30/BN-20 questionnaires. RESULTS Between August 2017 and November 2019, 710 patients (259 female/451 male) were enrolled at 81 participating centers. The mean age was 58.5 years (range: 19.0–85.0; Cut-off: August 31, 2020). The overall baseline characteristics of the study group reflects a typical GBM population. Of these, 582 (82%) decided to start TTFields and 128 (18%) refused TTFields treatment. Health-related QoL did not decline during TTFields therapy except for itchy skin, comparable to the results of the EF-14 phase 3 trial. A detailed analysis of the cohort as well as their reported QoL will be presented. CONCLUSION The TIGER study is the largest non-interventional trial on the use of TTFields in routine clinical care. The use of TTFields in patients with ndGBM did not impair HRQoL during the follow-up period, except for more itchy skin.

Glioblastoma (GBM) is a non-T-cell–inflamed cancer characterized by an immunosuppressive microenvironment that impedes dendritic cell maturation and T-cell cytotoxicity. Proangiogenic cytokines such as VEGF and angiopoietin-2 (Ang-2) have high expression in glioblastoma in a cell-specific manner and not only drive tumor angiogenesis and vascular permeability but also negatively regulate T-lymphocyte and innate immune cell responses. Consequently, the alleviation of immunosuppression might be a prerequisite for successful immune checkpoint therapy in GBM. We here combined antiangiogenic and immune checkpoint therapy and demonstrated improved therapeutic efficacy in syngeneic, orthotopic GBM models. We observed that blockade of VEGF, Ang-2, and programmed cell death protein-1 (PD-1) significantly extended survival compared with vascular targeting alone. In the GBM microenvironment, triple therapy increased the numbers of CTLs, which inversely correlated with myeloid-derived suppressor cells and regulatory T cells. Transcriptome analysis of GBM microvessels indicated a global vascular normalization that was highest after triple therapy. Our results propose a rationale to overcome tumor immunosuppression and the current limitations of VEGF monotherapy by integrating the synergistic effects of VEGF/Ang-2 and PD-1 blockade to reinforce antitumor immunity through a normalized vasculature.

Summary Background There is an urgent need for more effective therapies for glioblastoma. Data from a previous unrandomised phase 2 trial suggested that lomustine-temozolomide plus radiotherapy might be superior to temozolomide chemoradiotherapy in newly diagnosed glioblastoma with methylation of the MGMT promoter. In the CeTeG/NOA-09 trial, we aimed to further investigate the effect of lomustine-temozolomide therapy in the setting of a randomised phase 3 trial. Methods In this open-label, randomised, phase 3 trial, we enrolled patients from 17 German university hospitals who were aged 18–70 years, with newly diagnosed glioblastoma with methylated MGMT promoter, and a Karnofsky Performance Score of 70% and higher. Patients were randomly assigned (1:1) with a predefined SAS-generated randomisation list to standard temozolomide chemoradiotherapy (75 mg/m 2 per day concomitant to radiotherapy [59–60 Gy] followed by six courses of temozolomide 150–200 mg/m 2 per day on the first 5 days of the 4-week course) or to up to six courses of lomustine (100 mg/m 2 on day 1) plus temozolomide (100–200 mg/m 2 per day on days 2–6 of the 6-week course) in addition to radiotherapy (59–60 Gy). Because of the different schedules, patients and physicians were not masked to treatment groups. The primary endpoint was overall survival in the modified intention-to-treat population, comprising all randomly assigned patients who started their allocated chemotherapy. The prespecified test for overall survival differences was a log-rank test stratified for centre and recursive partitioning analysis class. The trial is registered with ClinicalTrials.gov, number NCT01149109. Findings Between June 17, 2011, and April 8, 2014, 141 patients were randomly assigned to the treatment groups; 129 patients (63 in the temozolomide and 66 in the lomustine-temozolomide group) constituted the modified intention-to-treat population. Median overall survival was improved from 31·4 months (95% CI 27·7–47·1) with temozolomide to 48·1 months (32·6 months–not assessable) with lomustine-temozolomide (hazard ratio [HR] 0·60, 95% CI 0·35–1·03; p=0·0492 for log-rank analysis). A significant overall survival difference between groups was also found in a secondary analysis of the intention-to-treat population (n=141, HR 0·60, 95% CI 0·35–1·03; p=0·0432 for log-rank analysis). Adverse events of grade 3 or higher were observed in 32 (51%) of 63 patients in the temozolomide group and 39 (59%) of 66 patients in the lomustine-temozolomide group. There were no treatment-related deaths. Interpretation Our results suggest that lomustine-temozolomide chemotherapy might improve survival compared with temozolomide standard therapy in patients with newly diagnosed glioblastoma with methylated MGMT promoter. The findings should be interpreted with caution, owing to the small size of the trial. Funding German Federal Ministry of Education and Research.

Simple Summary MRI plays an important role in the classification of structural brain changes and quantitative MRI can provide more and different information than conventional MRI. A comparison with neuropathological parameters helps to expand the understanding of (patho)physiological concepts but has hardly been carried out so far. In this prospective study, we correlated quantitative MRI data with histological features of 25 patients with isocitrate dehydrogenase (IDH) wild-type glioma. We found that the relative shortening of T1 relaxation time after the application of contrast agent was pronounced in the presence of tumor cells and vascular proliferates, indicating a disruption of the blood brain barrier (BBB). T2′ relaxation time, depending on local deoxyhemoglobin concentration, correlated with the vessel density but not with immunopositivity for endogenous markers of hypoxia. Abstract Quantitative MRI allows to probe tissue properties by measuring relaxation times and may thus detect subtle changes in tissue composition. In this work we analyzed different relaxation times (T1, T2, T2* and T2′) and histological features in 321 samples that were acquired from 25 patients with newly diagnosed IDH wild-type glioma. Quantitative relaxation times before intravenous application of gadolinium-based contrast agent (GBCA), T1 relaxation time after GBCA as well as the relative difference between T1 relaxation times pre-to-post GBCA (T1rel) were compared with histopathologic features such as the presence of tumor cells, cell and vessel density, endogenous markers for hypoxia and cell proliferation. Image-guided stereotactic biopsy allowed for the attribution of each tissue specimen to its corresponding position in the respective relaxation time map. Compared to normal tissue, T1 and T2 relaxation times and T1rel were prolonged in samples containing tumor cells. The presence of vascular proliferates was associated with higher T1rel values. Immunopositivity for lactate dehydrogenase A (LDHA) involved slightly longer T1 relaxation times. However, low T2′ values, suggesting high amounts of deoxyhemoglobin, were found in samples with elevated vessel densities, but not in samples with increased immunopositivity for LDHA. Taken together, some of our observations were consistent with previous findings but the correlation of quantitative MRI and histologic parameters did not confirm all our pathophysiology-based assumptions.

OBJECTIVE Glioblastoma (GBM) is widely treated with surgery, chemoradiation and TTFields in combination with chemotherapy. Since the introduction of TTFields to first-line GBM treatment, prescribing physicians in Germany are interested to gain additional knowledge on the use in clinical practice. The TIGER study was designed to assess the therapy decision making process, safety and efficacy of TTFields in clinical routine, as well as evaluating quality of life (QoL) within 4 months after start of therapy, treatment compliance and duration. METHODS This multi-center prospective non-interventional study in Germany (NCT03258021) included newly diagnosed GBM patients eligible for TTFields therapy. Within the study, after receiving introduction to TTFields therapy, patients could decide for or against receiving TTFields. The study was designed to recruit 500 patients for each group, with and without TTFields. Demographic data, QoL and reasons for therapy decision 2–4 months after treatment start are assessed using the EORTC-QLQ-C30/BN-20 and a TTFields questionnaire, respectively, with 18 months follow-up. RESULTS At the last data cut-off (31st March, 2020), the median follow-up was 11 months (range: 0–28 months) and 581 (82%) of the 710 recruited patients in the trial had decided for TTFields therapy. According to preliminary analysis, this patient population represents a typical GBM population regarding median age (59 years, range: 19.0–85.0), gender (37 % female), median KPS (90, range: 40–100) and MGMT promoter methylation status (44% methylated). In this population 49 % received complete resection, 33 % partial resection and 19 % biopsy. CONCLUSION The TIGER study allows prospective and systematic analysis of TTFields treatment decision making and use of typical GBM patient population in routine clinical care. In addition, the study allows the evaluation of compliance and treatment duration. Here, we will present an updated analysis of the TIGER study.

Purpose: BAY1436032, an inhibitor of mutant isocitrate dehydrogenase 1 (mIDH1), was active against multiple IDH1-R132X solid tumors in preclinical models. This first-in-human study was designed to determine the safety and pharmacokinetics of BAY1436032, and to evaluate its potential pharmacodynamics and antitumor effects. Patients and Methods: The study comprised of dose escalation and dose expansion cohorts. BAY1436032 tablets were orally administered twice daily on a continuous basis in subjects with mIDH1 solid tumors. Results: In dose escalation, 29 subjects with various tumor types were administered BAY1436032 across five doses (150–1,500 mg twice daily). BAY1432032 exhibited a relatively short half-life. Most evaluable subjects experienced target inhibition as indicated by a median maximal reduction of plasma R-2-hydroxyglutarate levels of 76%. BAY1436032 was well tolerated and an MTD was not identified. A dose of 1,500 mg twice daily was selected for dose expansion, where 52 subjects were treated in cohorts representing four different tumor types [lower grade glioma (LGG), glioblastoma, intrahepatic cholangiocarcinoma, and a basket cohort of other tumor types]. The best clinical outcomes were in subjects with LGG (n = 35), with an objective response rate of 11% (one complete response and three partial responses) and stable disease in 43%. As of August 2020, four of these subjects were in treatment for >2 years and still ongoing. Objective responses were observed only in LGG. Conclusions: BAY1436032 was well tolerated and showed evidence of target inhibition and durable objective responses in a small subset of subjects with LGG.

Simple Summary: Targeted therapies are of growing interest to physicians in cancer treatment. These drugs target specific genes and proteins involved in the growth and survival of cancer cells. Brain tumor therapy is complicated by the fact that not all drugs can penetrate the blood brain barrier and reach their target. We explored the non-invasive method, Magnetic Resonance Spectroscopy, for monitoring drug penetration and its effects in live animals bearing brain tumors. We were able to show the presence of the investigated drug in mouse brains and its on-target activity. Abstract: Background: BAY1436032 is a fluorine-containing inhibitor of the R132X-mutant isocitrate dehydrogenase (mIDH1). It inhibits the mIDH1-mediated production of 2-hydroxyglutarate (2-HG) in glioma cells. We investigated brain penetration of BAY1436032 and its effects using 1H/19F-Magnetic Resonance Spectroscopy (MRS). Methods: 19F-Nuclear Magnetic Resonance (NMR) Spectroscopy was conducted on serum samples from patients treated with BAY1436032 (NCT02746081 trial) in order to analyze 19F spectroscopic signal patterns and concentration-time dynamics of protein-bound inhibitor to facilitate their identification in vivo MRS experiments. Hereafter, 30 mice were implanted with three glioma cell lines (LNT-229, LNT-229 IDH1-R132H, GL261). Mice bearing the IDH-mutated glioma cells received 5 days of treatment with BAY1436032 between baseline and follow-up 1H/19F-MRS scan. All other animals underwent a single scan after BAY1436032 administration. Mouse brains were analyzed by liquid chromatography-mass spectrometry (LC-MS/MS). Results: Evaluation of 1H-MRS data showed a decrease in 2-HG/total creatinine (tCr) ratios from the baseline to post-treatment scans in the mIDH1 murine model. Whole brain concentration of BAY1436032, as determined by 19F-MRS, was similar to total brain tissue concentration determined by Liquid Chromatography with tandem mass spectrometry (LC-MS/MS), with a signal loss due to protein binding. Intratumoral drug concentration, as determined by LC-MS/MS, was not statistically different in models with or without R132X-mutant IDH1 expression. Conclusions: Non-invasive monitoring of mIDH1 inhibition by BAY1436032 in mIDH1 gliomas is feasible.

Introduction: Gliomatosis cerebri (GC) is defined by diffuse, widespread glial tumor growth affecting three or more cerebral lobes. Previous studies in gliomas found no distinct histological or molecular GC subtype, yet the presence of GC is associated with worse median overall survival (OS). Here, we explored whether differing therapeutic strategies in first-line treatment could account for this. Methods: From our University Cancer Center database, 47 patients with histological diagnosis of WHO grade II or III glioma and GC imaging pattern were identified. GC criteria were confirmed by independent review. Patients with WHO grade II or III glioma with non-GC pattern served as control cohort (n = 343). Results: Within the GC patient cohort, lower WHO grade, mutated isocitrate dehydrogenase 1 (IDH1) status, and absence of contrast enhancement were associated with better OS. Compared to the control cohort, patients with GC had significantly shorter OS independent of histological diagnosis or IDH1 mutation status. Patients with GC preferentially received chemotherapy alone (62 vs. 18%), and less frequently radiochemotherapy (21 vs. 27%). OS was significantly shorter in the GC cohort compared to the non-GC cohort both for chemotherapy (3.9 vs. 7.6 years, p = 0.0085) and for combined radiochemotherapy (1.1 vs. 8.4 years, p < 0.0001). However, when only patients who received biopsy plus chemotherapy were analyzed, the differences lost statistical significance (3.5 vs. 6.6 years, p = 0.196). Conclusion: We found major differences in the selection of first-line therapies of GC versus non-GC patients. Our results suggest that these differences may partly account for the worse prognosis of GC patients.

Importance Clinical outcomes for glioblastoma remain poor. Treatment with immune checkpoint blockade has shown benefits in many cancer types. To our knowledge, data from a randomized phase 3 clinical trial evaluating a programmed death-1 (PD-1) inhibitor therapy for glioblastoma have not been reported. Objective To determine whether single-agent PD-1 blockade with nivolumab improves survival in patients with recurrent glioblastoma compared with bevacizumab. Design, Setting, and Participants In this open-label, randomized, phase 3 clinical trial, 439 patients with glioblastoma at first recurrence following standard radiation and temozolomide therapy were enrolled, and 369 were randomized. Patients were enrolled between September 2014 and May 2015. The median follow-up was 9.5 months at data cutoff of January 20, 2017. The study included 57 multicenter, multinational clinical sites. Interventions Patients were randomized 1:1 to nivolumab 3 mg/kg or bevacizumab 10 mg/kg every 2 weeks until confirmed disease progression, unacceptable toxic effects, or death. Main Outcomes and Measures The primary end point was overall survival (OS). Results A total of 369 patients were randomized to nivolumab (n = 184) or bevacizumab (n = 185). TheMGMTpromoter was methylated in 23.4% (43/184; nivolumab) and 22.7% (42/185; bevacizumab), unmethylated in 32.1% (59/184; nivolumab) and 36.2% (67/185; bevacizumab), and not reported in remaining patients. At median follow-up of 9.5 months, median OS (mOS) was comparable between groups: nivolumab, 9.8 months (95% CI, 8.2-11.8); bevacizumab, 10.0 months (95% CI, 9.0-11.8); HR, 1.04 (95% CI, 0.83-1.30);P = .76. The 12-month OS was 42% in both groups. The objective response rate was higher with bevacizumab (23.1%; 95% CI, 16.7%-30.5%) vs nivolumab (7.8%; 95% CI, 4.1%-13.3%). Grade 3/4 treatment-related adverse events (TRAEs) were similar between groups (nivolumab, 33/182 [18.1%]; bevacizumab, 25/165 [15.2%]), with no unexpected neurological TRAEs or deaths due to TRAEs. Conclusions and Relevance Although the primary end point was not met in this randomized clinical trial, mOS was comparable between nivolumab and bevacizumab in the overall patient population with recurrent glioblastoma. The safety profile of nivolumab in patients with glioblastoma was consistent with that in other tumor types. Trial Registration ClinicalTrials.gov Identifier:NCT02017717

We evaluated patterns of tumor growth in patients with newly diagnosed MGMT-non-methylated glioblastoma who were assigned to undergo radiotherapy in conjunction with bevacizumab/irinotecan (BEV/IRI) or standard temozolomide (TMZ) within the randomized phase II GLARIUS trial. In 142 patients (94 BEV/IRI, 48 TMZ), we reviewed magnetic resonance imaging scans at baseline and first tumor recurrence. Based on contrast-enhanced T1-weighted and fluid-attenuated inversion recovery images, we assessed tumor growth patterns and tumor invasiveness. Tumor growth patterns were classified as either multifocal or local at baseline and recurrence; at first recurrence, we additionally assessed whether distant lesions appeared. Invasiveness was determined as either diffuse or non-diffuse. Associations with treatment arms were calculated using Fisher's exact test. At baseline, 115 of 142 evaluable patients (81%) had a locally confined tumor. Between treatment arms, there was no significant difference in the fraction of tumors that changed from an initially local tumor growth pattern to a multifocal pattern (12 and 13%, p = 0.55). Distant lesions appeared in 17% (BEV/IRI) and 13% (TMZ) of patients (p = 0.69). 15% of patients in the BEV/IRI arm and 8% in the TMZ arm developed a diffuse growth pattern from an initially non-diffuse pattern (p = 0.42). The tumor growth and invasiveness patterns do not differ between BEV/IRI and TMZ-treated MGMT-non-methylated glioblastoma patients in the GLARIUS trial. BEV/IRI was not associated with an increased rate of multifocal, distant, or highly invasive tumors at the time of recurrence.

Previous ex vivo spectroscopic data from tissue samples revealed differences in phospholipid metabolites between isocitrate dehydrogenase mutated (IDHmut) and IDH wildtype (IDHwt) gliomas. We investigated whether these changes can be found in vivo using 1H-decoupled 31P magnetic resonance spectroscopic imaging (MRSI) with 3D chemical shift imaging (CSI) at 3 T in patients with low and high-grade gliomas. The study included 33 prospectively enrolled, mostly untreated patients who met spectral quality criteria according to the World Health Organization (WHO II n = 7, WHO III n = 17, WHO IV n = 9; 25 patients IDHmut, 8 patients IDHwt). The MRSI protocol included 1H decoupled 31P MRSI with 3D CSI (3D 31P CSI), 2D 1H CSI and a 1H single voxel spectroscopy sequence (TE 30 ms) from the tumor area. For 1H MRS, absolute metabolite concentration values were calculated (phantom replacement method). For 31P MRS, metabolite intensity ratios were calculated for the choline (C) and ethanolamine (E)-containing metabolites. In our patient cohort we did not find significant differences for the ratio of phosphocholine (PC) and phosphoethanolamine (PE), PC/PE, (p = 0.24) for IDHmut compared to IDHwt gliomas. Furthermore, we found no elevated ratios of glycerophosphocholine (GPC) and glycerophosphoethanolamine (GPE), GPC/GPE, (p = 0.68) or GPC/PE (p = 0.12) for IDHmut gliomas. Even the ratio (PC+GPC)/(PE+GPE) showed no significant differences with respect to mutation status (p = 0.16). Nonetheless, changes related to tumor grade regarding intracellular pH (pHi) and phospholipid metabolism as well as absolute metabolite concentrations of co-registered 2D 1H CSI data for tumor and control tissue showed the anticipated results. Using 3D-CSI data acquisition, in vivo 31P MR spectroscopic measurement of phospholipid metabolites could not distinguish between IDHmut and IDHwt.

Purpose In solid tumors, changes in the expression/activity of plasma membrane ion transporters facilitate proton efflux and enable tumor cells to maintain a higher intracellular pH (pHi), while the microenvironment (pHe) is commonly more acidic. This supports various tumor-promoting mechanisms. We propose that these changes in pH take place before a magnetic resonance imaging (MRI)-detectable brain tumor recurrence occurs. Materials and Methods We enrolled 66 patients with recurrent glioblastoma, treated with bevacizumab. Patients received a baseline and 8-week follow-up MRI including 1H/31P MRSI (spectroscopy) on a 3T clinical scanner, until progressive disease according to Response Assessment in Neuro-Oncology (RANO) criteria occurred. Fourteen patients showed a distant or diffuse tumor recurrence (subsequent tumor) during treatment and were therefore selected for further evaluation. At the site of the subsequent tumor, an area of interest for MRSI voxel selection was retrospectively defined on radiographically unaffected baseline MRI sequences. Results Before treatment, pHi in the area of interest (subsequent tumor) was significantly higher than pHi of the contralateral normal-appearing tissue (control; P

(1) Background: The phase 2 Regorafenib in Relapsed Glioblastoma (REGOMA) trial indicated a survival benefit for patients with first recurrence of a glioblastoma when treated with the multikinase inhibitor regorafenib (REG) instead of lomustine. The aim of this retrospective study was to investigate REG penetration to cerebrospinal fluid (CSF), treatment efficacy, and effects on magnetic resonance imaging (MRI) in patients with recurrent high-grade gliomas. (2) Methods: Patients were characterized by histology, adverse events, steroid treatment, overall survival (OS), and MRI growth pattern. REG and its two active metabolites were quantified by liquid chromatography/tandem mass spectrometry in patients’ serum and CSF. (3) Results: 21 patients mainly with IDH-wildtype glioblastomas who had been treated with REG were retrospectively identified. Thirteen CFS samples collected from 3 patients of the cohort were available for pharmacokinetic testing. CSF levels of REG and its metabolites were significantly lower than in serum. Follow-up MRI was available in 19 patients and showed progressive disease (PD) in all but 2 patients. Two distinct MRI patterns were identified: 7 patients showed classic PD with progression of contrast enhancing lesions, whereas 11 patients showed a T2-dominant MRI pattern characterized by a marked reduction of contrast enhancement. Median OS was significantly better in patients with a T2-dominant growth pattern (10 vs. 27 weeks respectively, p = 0.003). Diffusion restrictions were observed in 13 patients. (4) Conclusion: REG and its metabolites were detectable in CSF. A distinct MRI pattern that might be associated with an improved OS was observed in half of the patient cohort. Treatment response in the total cohort was poor.

OBJECTIVE Survival for the most common brain tumor, glioblastoma (GBM), has not improved since 2005, despite numerous phase 3 trials. The phase 3 EF-14 trial demonstrated significantly improved overall, progression-free and long-term survival in newly diagnosed GBM (ndGBM) patients by addition of TTFields to adjuvant temozolomide chemotherapy. As there is very high interest among prescribing physicians from all disciplines to further evaluate these effects in routine clinical care, the aim of the TIGER study is to assess safety and efficacy of TTFields in routine care and reasons for patients refusing TTFields treatment, quality of life, treatment duration and compliance. METHODS The TIGER study is a multi-centre, prospective, non-interventional study in Germany (NCT03258021). All ndGBM patients who are eligible for TTFields therapy are asked for consent for study-participation and comprehensively introduced to the therapy to allow them to make a conscious positive or negative therapy decision. At baseline and 2–4 months after treatment start, demographic data, the QoL and reasons for therapy decision are evaluated utilizing the EORTC-QLQ-C30/BN-20 and TTFields questionnaire. Inclusion of 1000 patients is planned (500 with positive/negative treatment decision, respectively) with a follow-up period of 18 months. RESULTS At the last data cut-off (May 2019), 497 patients have made a decision regarding treatment with TTFields. Within this population, 84% of patients decided to undergo TTFields therapy. The median age of patients included in the trial is currently 58.3 years (19–85). 91% of patients report that the prospect of treatment success considerably or strongly affects treatment decision. Most recent data will be presented at the meeting. CONCLUSION Systematic and prospective data assessment for using TTFields in routine clinical care including patient’s therapy decision can be evaluated in TIGER. Additionally, the study supports the analysis of treatment duration and usage rate, which could drive future assessment of TTFields treatment duration.

BACKGROUND Chemotherapy is a treatment option in patients diagnosed with anaplastic gliomas or glioblastomas of the spinal cord, or with recurrent lower graded WHO spinal gliomas that are no longer amenable to local treatment. The low incidence of spinal cord gliomas, particularly in adults, limits the ability to perform clinical trials. The role of chemotherapy in these tumors has remained unclear. MATERIAL AND METHODS We performed a retrospective study of 22 patients diagnosed with spinal gliomas who were treated with chemotherapy at any time during the disease course. Benefit from chemotherapy was estimated by applying Response assessment in neuro-oncology criteria. Data on radiotherapy, as well as the number of neurosurgical interventions were taken into consideration. RESULTS Most patients were diagnosed with astrocytoma WHO grade I-IV (N=14), the remaining patients were diagnosed with ependymoma (N=8). Median follow-up from start of chemotherapy was 92 months (95% CI, 72.6–111.4). The O6-methylguanyl-DNA-methyltransferase(MGMT)promoter methylation status was available in tumors of 12 patients: 9 tumors (75%) had an unmethylated MGMTpromoter. More than 50% of the patients had more than one neurosurgical intervention. After prior surgery 10 patients in the first-line setting had chemotherapy combined with radiotherapy, while 3 patients received chemotherapy only. The remaining 9 patients had initially received radiation therapy and chemotherapy was given at time of recurrence. In patients diagnosed with astrocytoma mainly temozolomide (TMZ) was applied (N=10), while one patient received CCNU and three patients had combination chemotherapy. Patients diagnosed with ependymoma had hydroxyurea (N=1), CCNU (N=1), TMZ (N=3) or combination chemotherapy (N=3). In the group of patients who had chemotherapy combined with radiation, response rates were as follows: anaplastic astrocytoma 3 stable diseases (SD), glioblastoma 1 complete response (CR) and 1 SD, and anaplastic ependymoma 1 SD. After chemotherapy in the group of patients previously irradiated, the following response rates were observed: 1 SD in pilocytic astrocytoma, 1 SD in diffuse astrocytoma, 3 SD in myxopapillary ependymoma, and 2 SD and 1 partial response (PR) in anaplastic ependymoma. All other patients experienced progressive disease. There was no indication for a favorable prognostic role ofMGMTpromoter methylation. CONCLUSION Spinal cord gliomas represent a heterogeneous group of tumors. Survival outcomes in response to chemotherapy in adult spinal glioma patients vary substantially, but individual patients appear to derive benefit from chemotherapy.

BACKGROUND The term gliomatosis cerebri (GC) refers to glial brain tumors with widespread tumor expansion affecting three or more cerebral lobes. Formerly considered a distinct tumor entity, recent studies found no difference in the mutational profile of glial tumors with GC growth pattern compared to non-GC gliomas. Thus, in the new WHO classification of brain tumors, GC is no longer included as a separate diagnosis. While the presence of gliomas with GC growth pattern is associated with worse overall survival (OS), the underlying factors remain to be identified. Here, we asked whether differing therapeutic strategies in first line treatment could account for the worse outcome of patients with GC growth pattern and grade II and III histology. MATERIAL AND METHODS From the patient data bank of the University Cancer Center (UCT) Frankfurt, 47 patients with histological diagnosis of WHO grade II or III glioma, and with record of GC imaging pattern were identified. GC tumor expansion was confirmed by review of MRI scans prior to treatment initiation. Patients with WHO grade II or III glioma without GC growth pattern served as control cohort (n=379). IDH mutational status was available for 75% of GC tumors (IDH R132H mutated 32%; non-mutated 43%) and 69% of non-GC tumors (IDH R132H mutated 57%; non-mutated 12%). RESULTS Within the GC patient cohort, patients with tumors without contrast enhancement, lower WHO grade and mutated IDH status showed better OS. Compared to the control cohort, patients with GC had significantly shorter OS. This was independent of histological diagnosis or IDH mutation status. Patients with GC more frequently underwent radiochemotherapy (17% vs. 9% in the non-GC cohort), and drastically more often received chemotherapy alone (51% vs. 5%). We then analyzed OS in GC and non-GC patients that had received the same first line treatments. For radiochemotherapy in GC versus non-GC patients, OS was 1.1 years vs. 12.7 years (p =0.0075, log-rank test). For upfront chemotherapy alone, OS was significantly shorter in the GC cohort than in the non-GC cohort (3,6 years vs. undefined, p =0.0016, log-rank test). CONCLUSION Differences in first-line treatment cannot account for the worse prognosis of patients with GC imaging pattern. Further studies are needed to pinpoint biological or clinical factors that might influence responsiveness to therapy and prognosis of GC tumors.

Summary Background The CeTeG/NOA-09 trial showed significantly longer overall survival with combined lomustine–temozolomide therapy compared with standard temozolomide for patients with glioblastoma with methylated MGMT promoter. The trial also aimed to investigate the effect of lomustine–temozolomide therapy on health-related quality of life (HRQOL) and neurocognitive function, which we report here. Methods In this randomised, multicentre, open-label, phase 3 trial, newly diagnosed, chemoradiotherapy-naive patients with MGMT-methylated glioblastoma, aged 18–70 years, with a Karnofsky performance score of 70% or higher, were recruited and enrolled at 17 university hospitals in Germany. Patients received standard radiotherapy (60 Gy) and were randomly assigned (1:1, stratified by centre by allocating complete blocks of six to a centre, without masking) to either six 6-week courses of oral combined lomustine (100 mg/m2 on day 1) plus temozolomide (100–200 mg/m2 on days 2–6) or standard oral temozolomide (75 mg/m2 daily during radiotherapy plus six 4-week courses of temozolomide [150–200 mg/m2] on days 1–5, every 4 weeks). The primary endpoint was overall survival. HRQOL, assessed using the European Organisation for Research and Treatment of Cancer (EORTC) quality of life questionnaire core-30 and the EORTC brain cancer module (BN20); and neurocognitive function, assessed using the Mini Mental State Examination (MMSE), plus a neurocognitive test battery (NOA-07), including Trail Making Test A and B (TMT-A and B), working memory tests, and tests for lexical (Controlled Oral Word Association [COWA]) and semantic verbal fluency, were secondary endpoints analysed in the modified intention-to-treat population (mITT; all randomly assigned patients who received at least one dose of study chemotherapy). We used linear mixed-model analyses to investigate differences between treatment groups regarding HRQOL (clinically relevant ≥10 points) and MMSE scores (clinically relevant ≥3 points). The trial is registered with ClinicalTrials.gov , NCT01149109 . Findings Between June 17, 2011 and April 8, 2014, 141 patients were randomly assigned and 129 patients began treatment and were included in the mITT population (63 in the temozolomide and 66 in the lomustine–temozolomide group). Median follow-up for HRQOL (the item global health) was 19·4 months (IQR 7·8–38·6), for MMSE was 15·3 months (4·1–29·6), and for COWA was 11·0 months (0–27·5). We found no significant impairment regarding any item of HRQOL in the lomustine–temozolomide group (difference between the groups for global health 0·30 [95% CI −0·23 to 0·83]; p=0·26). Differences in MMSE were in favour of the temozolomide group (difference −0·11 [95% CI −0·19 to −0·03]; p=0·0058) but were not clinically relevant (1·76/30 points over 4 years). We found no significant difference between the groups in any subtest of the neurocognitive test battery (difference for COWA 0·04 [95% CI −0·01 to 0·09]; p=0·14). Interpretation The absence of systematic and clinically relevant changes in HRQOL and neurocognitive function combined with the survival benefit of lomustine–temozolomide versus temozolomide alone suggests that a long-term net clinical benefit exists for patients with newly diagnosed glioblastoma with methylation of the MGMT promoter and supports the use of lomustine–temozolomide as a treatment option for these patients. Funding German Federal Ministry of Education and Research.

The value of bevacizumab (BEV) in recurrent glioblastoma is unclear. Imaging parameters and progression-free survival (PFS) are problematic endpoints. Few data exist on clinical factors influencing overall survival (OS) in unselected patients with recurrent glioblastoma exposed to BEV. We retrospectively analyzed 174 patients with recurrent glioblastoma treated with BEV at two German brain tumor centers. We evaluated general patient characteristics, MGMT status, pretreatment, concomitant oncologic treatment and overall survival. Karnofsky performance score, number of prior chemotherapies, number of prior recurrences and combined treatment with irinotecan (IRI) were significantly associated with OS in univariate analysis. We did not find differences in OS related to sex, age, histology, MGMT status, prior surgical treatment or number of prior radiotherapies. Combined treatment with IRI and higher KPS both remained significantly associated with prolonged survival in multivariate analysis, but patients receiving IRI co-treatment had less advanced disease. Grouping into clinically relevant categories revealed an OS of 16.9 months from start of BEV in patients with first recurrence and KPS ≥ 80 % (n = 25). In contrast, in patients with second recurrence and KPS

The phase II GLARIUS trial assigned patients with newly diagnosed, O-6-methylguanine-DNA methyltransferase promoter non-methylated glioblastoma to experimental bevacizumab/irinotecan (BEV/IRI) or standard temozolomide (TMZ). To identify subpopulations with a particularly favorable course, we assessed the prognostic potential of magnetic resonance imaging (MRI) markers before treatment onset. MRIs at baseline (before treatment onset) were analyzed for T1-hyperintense and diffusion-restricted lesions; as well as the presence of both hyperintense and diffusion-restricted (double positive) lesions. The MRI findings were correlated with overall and progression-free survival. MRI scans were evaluable in 71% of the GLARIUS modified intention-to-treat population (n = 121 of 170; 88 patients in the BEV/IRI arm, and 33 patients in the TMZ control arm). Diffusion-restricted and T1 hyperintense lesions were present in 60% and 65% of patients in BEV/IRI arm, while 57% and 63% were found in the TMZ arm, respectively. Double positive lesions were found in 37% of BEV/IRI patients and in 39% of TMZ patients. Neither the presence of T1-hyperintense, diffusion-restricted lesions, nor double positive lesions were associated with improved survival. Baseline T1-hyperintense and diffusion-restricted lesions are not suitable to predict progression-free or overall survival of patients treated with bevacizumab/irinotecan or temozolomide.

The CeTeG/NOA-09 trial demonstrated a significant survival benefit of radiotherapy with CCNU/temozolomide (TMZ) combination therapy compared to standard TMZ therapy as first-line treatment of O6-methylguanine-DNA methyltransferase (MGMT)-promotor hypermethylated glioblastoma. Quality of life (QoL) assessment was a secondary objective to investigate if CCNU/TMZ combination chemotherapy has a detrimental effect on patient’s QoL. PATIENTS AND METHODS: Patients (n=141) received standard radiotherapy and were randomized (1:1) for CCNU/TMZ or standard TMZ. The modified intention-to-treat population consisting of 129 patients was analyzed. At least every three months, Karnofsky performance score (KPS) was determined and QoL was measured using the EORTC-QLQ C30 and BN20 questionnaires. A longitudinal mixed-model analysis was used to evaluate differences between treatment arms in the course of KPS and QoL over time. Time to first deterioration was analyzed using a Cox regression model. RESULTS: Over a period of four years, longitudinal mixed-model analysis detected no significant impairment of QoL or KPS in the CCNU/TMZ arm as compared to the TMZ arm. Time to deterioration was prolonged in one QoL domain, motor dysfunction, for patients in the experimental arm. CONCLUSION: Intensified alkylating chemotherapy with CCNU/TMZ for patients with MGMT promotor-methylated glioblastoma did not lead to a reduction of QoL or KPS compared to TMZ standard therapy.

BACKGROUND: The effectivity and safety of TTFields in newly diagnosed GBM was recently demonstrated by the final analysis of the large, randomized controlled EF-14 Trial. To capture the clinical value of new cancer treatments, the American Society of Clinical Oncology (ASCO) and the European Society for Medical Oncology (ESMO) have both developed assessment frameworks. We quantified the clinical value of the TTFields treatment in GBM by applying ASCO and ESMO frameworks to the EF-14 trial data. MATERIALS/ METHODS: The EF-14 Trial (n=695) proved the effect of adding TTFields to maintenance temozolomide (TMZ) for newly diagnosed glioblastoma patients. The ESMO Magnitude of Clinical Benefit Scale (MCBS) and the ASCO Net Health Benefit (NHB frameworks provide separate calculations for adjuvant therapies and treatments for advanced diseases. We applied both classifications to the EF-14 trial data as required by the framework rules. Quality of life data from the EF-14 Trial was also included. Additionally, we identified reference points from the literature to understand the NHB and MCBS results for TTFields in GBM. RESULTS: Applying the ASCO framework to the EF-14 data resulted in a NHB score of 56/62 (adjuvant/advanced). Those were among the highest scores identified in the literature search. Additionally, the ASCO framework valued the reduction in cancer-related symptoms (e.g., pain, weakness of legs) with TTFields. Applying the ESMO framework resulted in MCBS scores of A/5 (adjuvant/advanced), which are the highest scores achievable in the ESMO framework. The ESMO framework valued the Health Related Quality of Life (HRQoL) gain during deterioration-free survival time with TTFields. CONCLUSIONS: Both the ASCO and ESMO frameworks suggest, that adding TTFields to maintenance TMZ for newly diagnosed glioblastoma patients provides patients with significant clinical benefits. The high scores underline the fact, that treatment with TTFields extended progression free and overall survival without additional systemic toxicities.

Ventriculoperitoneal shunts equipped with a reservoir and a valve to manually switch off the shunt function can be used for intraventricular injections of therapeutics in patients suffering from a communicating hydrocephalus caused by leptomeningeal metastases. These shunt devices avoid the risk of injecting therapeutics through the distal leg of the shunt system into the intraperitoneal space, which may cause toxicity. Furthermore, regular intraventricular injections of chemotherapeutics help to maintain sufficient concentrations in the ventricular space. Therefore, ventriculoperitoneal shunts equipped with an on-off valve are a useful tool to reliably inject chemotherapeutics into the ventricles. In order to systematically assess feasibility, safety, and efficacy of this procedure, we performed a retrospective analysis of all patients with leptomeningeal metastases who had received a shunt system at our institution. In total, six adult patients had a ventriculoperitoneal shunt equipped with an on-off valve implanted. Out of these six patients, two patients subsequently received intraventricular injections of chemotherapeutics. The configuration of the valve setting and the intraventricular injections were easily feasible in the setting of a neuro-oncology department. The complication of a shunt leakage occurred in one patient following the first intraventricular injection. No extra-central nervous system (CNS) toxicities were observed. In summary, ventriculoperitoneal shunts with on-off valves are useful tools for reliable intraventricular administration of therapeutics.