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Background: Tumor Treating Fields (TTFields) are alternating electric fields that disrupt cancer cell processes. TTFields therapy is approved for recurrent glioblastoma (rGBM), and newly-diagnosed (nd) GBM (with concomitant temozolomide for ndGBM; US), and for grade IV glioma (EU). We present an updated global, post-marketing surveillance safety analysis of patients with CNS malignancies treated with TTFields therapy., Methods: Safety data were collected from routine post-marketing activities for patients in North America, Europe, Israel, and Japan (October 2011-October 2022). Adverse events (AEs) were stratified by age, sex, and diagnosis., Results: Overall, 25,898 patients were included (diagnoses: ndGBM [68%], rGBM [26%], anaplastic astrocytoma/oligodendroglioma [4%], other CNS malignancies [2%]). Median (range) age was 59 (3-103) years; 66% patients were male. Most (69%) patients were 18-65 years; 0.4% were < 18 years; 30% were > 65 years. All-cause and TTFields-related AEs occurred in 18,798 (73%) and 14,599 (56%) patients, respectively. Most common treatment-related AEs were beneath-array skin reactions (43%), electric sensation (tingling; 14%), and heat sensation (warmth; 12%). Treatment-related skin reactions were comparable in pediatric (39%), adult (42%), and elderly (45%) groups, and in males (41%) and females (46%); and similar across diagnostic subgroups (ndGBM, 46%; rGBM, 34%; anaplastic astrocytoma/oligodendroglioma, 42%; other, 40%). No TTFields-related systemic AEs were reported., Conclusions: This long-term, real-world analysis of > 25,000 patients demonstrated good tolerability of TTFields in patients with CNS malignancies. Most therapy-related AEs were manageable localized, non-serious skin events. The TTFields therapy safety profile remained consistent across subgroups (age, sex, and diagnosis), indicative of its broad applicability., (© 2024. The Author(s).)

Purpose: In the randomized CeTeG/NOA-09 trial, lomustine/temozolomide (CCNU/TMZ) was superior to TMZ therapy regarding overall survival (OS) in MGMT promotor-methylated glioblastoma. Progression-free survival (PFS) and pseudoprogression rates (about 10%) were similar in both arms. Further evaluating this discrepancy, we analyzed patterns of postprogression survival (PPS) and MRI features at first progression according to modified RANO criteria (mRANO)., Methods: We classified the patients of the CeTeG/NOA-09 trial according to long vs. short PPS employing a cut-off of 18 months and compared baseline characteristics and survival times. In patients with available MRIs and confirmed progression, the increase in T 1 -enhancing, FLAIR hyperintense lesion volume and the change in ADC mean value of contrast-enhancing tumor upon progression were determined., Results: Patients with long PPS in the CCNU/TMZ arm had a particularly short PFS (5.6 months). PFS in this subgroup was shorter than in the long PPS subgroup of the TMZ arm (11.1 months, p = 0.01). At mRANO-defined progression, patients of the CCNU/TMZ long PPS subgroup had a significantly higher increase of mean ADC values (p = 0.015) and a tendency to a stronger volumetric increase in T 1 -enhancement (p = 0.22) as compared to long PPS patients of the TMZ arm., Conclusion: The combination of survival and MRI analyses identified a subgroup of CCNU/TMZ-treated patients with features that sets them apart from other patients in the trial: short first PFS despite long PPS and significant increase in mean ADC values upon mRANO-defined progression. The observed pattern is compatible with the features commonly observed in pseudoprogression suggesting mRANO-undetected pseudoprogressions in the CCNU/TMZ arm of CeTeG/NOA-09., (© 2023. The Author(s).)

Purpose: In the randomized phase III trial CeTeG/NOA-09, temozolomide (TMZ)/lomustine (CCNU) combination therapy was superior to TMZ in newly diagnosed MGMT methylated glioblastoma, albeit reporting more frequent hematotoxicity. Here, we analyze high grade hematotoxicity and its prognostic relevance in the trial population., Methods: Descriptive and comparative analysis of hematotoxicity adverse events ≥ grade 3 (HAE) according to the Common Terminology of Clinical Adverse Events, version 4.0 was performed. The association of HAE with survival was assessed in a landmark analysis. Logistic regression analysis was performed to predict HAE during the concomitant phase of chemotherapy., Results: HAE occurred in 36.4% and 28.6% of patients under CCNU/TMZ and TMZ treatment, respectively. The median onset of the first HAE was during concomitant chemotherapy (i.e. first CCNU/TMZ course or daily TMZ therapy), and 42.9% of patients with HAE receiving further courses experienced repeat HAE. Median HAE duration was similar between treatment arms (CCNU/TMZ 11.5; TMZ 13 days). Chemotherapy was more often discontinued due to HAE in CCNU/TMZ than in TMZ (19.7 vs. 6.3%, p = 0.036). The occurrence of HAE was not associated with survival differences (p = 0.76). Regression analysis confirmed older age (OR 1.08) and female sex (OR 2.47), but not treatment arm, as predictors of HAE., Conclusion: Older age and female sex are associated with higher incidence of HAE. Although occurrence of HAE was not associated with shorter survival, reliable prediction of patients at risk might be beneficial to allow optimal management of therapy and allocation of supportive measures., Trial Registration: NCT01149109., (© 2023. The Author(s).)

Introduction: This study aimed to test the diagnostic significance of FET-PET imaging combined with machine learning for the differentiation between multiple sclerosis (MS) and glioma II°-IV°., Methods: Our database was screened for patients in whom FET-PET imaging was performed for the diagnostic workup of newly diagnosed lesions evident on MRI and suggestive of glioma. Among those, we identified patients with histologically confirmed glioma II°-IV°, and those who later turned out to have MS. For each group, tumor-to-brain ratio (TBR) derived features of FET were determined. A support vector machine (SVM) based machine learning algorithm was constructed to enhance classification ability, and Receiver Operating Characteristic (ROC) analysis with area under the curve (AUC) metric served to ascertain model performance., Results: A total of 41 patients met selection criteria, including seven patients with MS and 34 patients with glioma. TBR values were significantly higher in the glioma group (TBRmax glioma vs. MS: p = 0.002; TBRmean glioma vs. MS: p = 0.014). In a subgroup analysis, TBR values significantly differentiated between MS and glioblastoma (TBRmax glioblastoma vs. MS: p = 0.0003, TBRmean glioblastoma vs. MS: p = 0.0003) and between MS and oligodendroglioma (ODG) (TBRmax ODG vs. MS: p = 0.003; TBRmean ODG vs. MS: p = 0.01). The ability to differentiate between MS and glioma II°-IV° increased from 0.79 using standard TBR analysis to 0.94 using a SVM based machine learning algorithm., Conclusions: FET-PET imaging may help differentiate MS from glioma II°-IV° and SVM based machine learning approaches can enhance classification performance.

Introduction: Tumor Treating Fields (TTFields; antimitotic treatment) delivers low-intensity, intermediate-frequency, alternating electric fields through skin-applied transducer arrays. TTFields (200 kHz) was FDA-approved in glioblastoma (GBM), based on the phase 3 EF-11 (recurrent GBM, rGBM) and EF-14 (newly diagnosed GBM, ndGBM) trials. The most common TTFields-related adverse event (AE) in both trials was array-associated skin irritation. We now report on TTFields-related AEs in the real-world, clinical practice setting., Methods: Unsolicited, post-marketing surveillance data from TTFields-treated patients (October 2011-February 2019) were retrospectively analyzed using MedDRA v21.1 preferred terms, stratified by region (US, EMEA [Europe, Middle East, Africa], Japan), diagnosis (ndGBM, rGBM, anaplastic astrocytoma/oligodendroglioma, other brain tumors), and age (< 18 [pediatric], 18-64 [adults], ≥ 65 [elderly]; years of age)., Results: Of 11,029 patients, 53% were diagnosed with ndGBM and 39% were diagnosed with rGBM at any line of disease recurrence. Most were adults (73%), 26% were elderly, and the male-to-female ratio was ~ 2:1 (close to published ratios of typical GBM populations). The most commonly reported TTFields-related AE was array-associated skin reaction, occurring in patients with ndGBM (38%), rGBM (29%), anaplastic astrocytoma/oligodendroglioma (38%), and other brain tumors (31%); as well as 37% of pediatric, 34% of adult, and 36% of elderly patients. Most skin AEs were mild/moderate and manageable. Other TTFields-related AEs in patients with ndGBM/rGBM included under-array heat sensation (warmth; 11%, 10%, respectively) and electric sensation (tingling; 11%, 9%, respectively), and headache (7%, 6%, respectively)., Conclusions: This TTFields safety surveillance analysis in > 11,000 patients revealed no new safety concerns, with a favorable safety profile comparable with published TTFields/GBM trials. The safety profile remained consistent among subgroups, suggesting feasibility in multiple populations, including elderly patients.

Purpose: 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., Methods: 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., Results: 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., Conclusions: 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 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 < 80 %, OS was 3.6 months (n = 27). Our observational data support an early use of BEV in patients with good performance status. The benefit of co-treatment with IRI in our cohort seems to be the result of biased patient recruitment.

This retrospective series explores temozolomide monotherapy in elderly patients with primary CNS lymphoma (PCNSL) and severe comorbidities. In 17 patients (62-90 years old), the complete response rate was 47%, median progression-free survival was 5 months, and median overall survival was 21 months. Five of 17 patients (29.4%) had prolonged responses for at least 12 months and survived for more than 24 months. Three of these patients had a methylated O(6)-methylguanine-DNA methyltransferase (MGMT) promoter, while the MGMT status was not assessable in the remaining two patients. Temozolomide monotherapy appears to be effective in a subgroup of elderly PCNSL patients and deserves further evaluation.