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Purpose: FGFR genomic alterations (amplification, mutations, and/or fusions) occur in ∼8% of gliomas, particularly FGFR1 and FGFR3. We conducted a multicenter open-label, single-arm, phase II study of a selective FGFR1-3 inhibitor, infigratinib (BGJ398), in patients with FGFR-altered recurrent gliomas., Patients and Methods: Adults with recurrent/progressive gliomas harboring FGFR alterations received oral infigratinib 125 mg on days 1 to 21 of 28-day cycles. The primary endpoint was investigator-assessed 6-month progression-free survival (PFS) rate by Response Assessment in Neuro-Oncology criteria. Comprehensive genomic profiling was performed on available pretreatment archival tissue to explore additional molecular correlations with efficacy., Results: Among 26 patients, the 6-month PFS rate was 16.0% [95% confidence interval (CI), 5.0-32.5], median PFS was 1.7 months (95% CI, 1.1-2.8), and objective response rate was 3.8%. However, 4 patients had durable disease control lasting longer than 1 year. Among these, 3 had tumors harboring activating point mutations at analogous positions of FGFR1 (K656E; n = 2) or FGFR3 (K650E; n = 1) in pretreatment tissue; an FGFR3-TACC3 fusion was detected in the other. Hyperphosphatemia was the most frequently reported treatment-related adverse event (all-grade, 76.9%; grade 3, 3.8%) and is a known on-target toxicity of FGFR inhibitors., Conclusions: FGFR inhibitor monotherapy with infigratinib had limited efficacy in a population of patients with recurrent gliomas and different FGFR genetic alterations, but durable disease control lasting more than 1 year was observed in patients with tumors harboring FGFR1 or FGFR3 point mutations or FGFR3-TACC3 fusions. A follow-up study with refined biomarker inclusion criteria and centralized FGFR testing is warranted., (©2022 The Authors; Published by the American Association for Cancer Research.)

Patients with malignant glioma who are also diagnosed with one or more primary neoplasms of other organs present a unique challenge in both determining prognosis and clinical management. The overlapping impact of the malignancies and their treatment result in confounding variables that may adversely affect optimal management of such patients. Additionally, the glioma-related characteristics and survival outcome of these patients is not well-defined. In this retrospective chart and data review from our longitudinal database, we identified patients with malignant glioma including anaplastic glioma and glioblastoma, diagnosed between January 2005 and June 2011, who were also diagnosed with other non-CNS primary neoplasms. Patients with known genetic syndromes were excluded. The data was analyzed to determine the clinical characteristics and glioma-related survival. A total of 204 patients with malignant glioma (165 glioblastoma and 39 anaplastic glioma) were identified. There was no significant difference in the overall survival or progression-free survival between patients with malignant glioma plus non-CNS primary neoplasm when compared with patients with malignant glioma only. In patients with glioblastoma and non-CNS malignancy, the duration between diagnosis of glioblastoma and non-CNS neoplasms did not significantly alter glioma-related survival. Patients with malignant glioma who were diagnosed with other non-CNS malignancy have survival outcome comparable to those with malignant glioma only. The duration between diagnosis of glioblastoma and diagnosis of non-CNS neoplasms did not affect survival. Further prospective studies specifically addressing survival and molecular characteristics of patients with malignant glioma plus non-CNS cancers are recommended.

Bevacizumab (BEV) is widely used for treatment of patients with recurrent glioblastoma. It is not known if there are differences in outcome between early versus delayed BEV treatment of recurrent glioblastoma. We examined the relationship between the time of starting BEV treatment and outcomes in patients with recurrent glioblastoma. In this retrospective chart review, we identified patients with recurrent glioblastoma diagnosed between 2005 and 2011 who were treated with BEV alone or BEV-containing regimens. Data was analyzed to determine overall survival (OS) from time of diagnosis and progression free survival (PFS) from time of starting BEV. A total of 298 patients were identified, 112 patients received early BEV, 133 patients received delayed BEV, and 53 patients were excluded because they either progressed within 3 months of radiation or received BEV at the time of diagnosis. There was no significant difference in PFS between patients that received early BEV and those that received delayed BEV (5.2 vs. 4.3 months, p = 0.2). Patients treated with delayed BEV had longer OS when compared to those treated with early BEV (25.9 vs. 20.8 months, p = 0.005). In patients with recurrent glioblastoma, there was no significant difference in PFS from the time of starting BEV between early and delayed BEV. Although patients treated with delayed BEV seemed to have longer OS, a conclusion regarding OS outcome requires further prospective trials. These results may indicate that delaying treatment with BEV is not detrimental for survival of patients with recurrent glioblastoma.

Background: Patients with recurrent glioblastoma benefiting from bevacizumab are often treated indefinitely due to concerns regarding rebound tumor recurrence upon discontinuation. However, treatment is discontinued for reasons other than disease progression in a subset of these patients, the characteristics and outcomes of which are poorly defined., Methods: Of 342 adults with recurrent glioblastoma in our database treated with bevacizumab, 82 received treatment for ≥ 6 months; of these, bevacizumab was discontinued for reasons other than tumor progression in 18 patients (Bev-D) and for disease progression in the remainder (Bev-S). The impact of discontinuation on outcome was assessed with discontinuation as a time-dependent covariate in a Cox hazards model for progression-free survival., Results: There was no difference in hazard rates for progression between Bev-D and Bev-S groups; the adjusted hazard ratio for progression using discontinuation as a time-dependent covariate was 0.91 (95% CI:0.47, 1.78). The median PFS after bevacizumab-discontinuation was 27 weeks (95% CI:15-NR). At progression, a higher proportion of Bev-D patients had local progression compared with the Bev-S patients. Salvage therapy in Bev-D patients yielded a PFS-26 weeks of 47% (95% CI:23%-94%) with a median PFS of 23 weeks (95% CI:12-NR), vs. 5% (95% CI: 1%-21%) and 9 weeks (95% CI: 6-11) in Bev-S patients (HR:0.3;CI, 0.1-0.6) (P = .0007)., Conclusions: Bevacizumab discontinuation unrelated to disease progression does not appear to cause rebound recurrence or worsen PFS in patients who benefit from bevacizumab. Additionally, Bev-D patients had an improved response to salvage therapy, findings which provide a strong basis for a prospective study., (© The Author(s) 2014. 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.)

We have tested the predictive value of apparent diffusion coefficient (ADC) histogram analysis in stratifying progression-free survival (PFS) and overall survival (OS) in bevacizumab-treated patients with recurrent glioblastoma multiforme (GBM) from the multi-center BRAIN study. Available MRI's from patients enrolled in the BRAIN study (n = 97) were examined by generating ADC histograms from areas of enhancing tumor on T1 weighted post-contrast images fitted to a two normal distribution mixture curve. ADC classifiers including the mean ADC from the lower curve (ADC-L) and the mean lower curve proportion (LCP) were tested for their ability to stratify PFS and OS by using Cox proportional hazard ratios and the Kaplan-Meier method with log-rank test. Mean ADC-L was 1,209 × 10(-6)mm(2)/s ± 224 (SD), and mean LCP was 0.71 ± 0.23 (SD). Low ADC-L was associated with worse outcome. The hazard ratios for 6-month PFS, overall PFS, and OS in patients with less versus greater than mean ADC-L were 3.1 (95 % confidence interval: 1.6, 6.1; P = 0.001), 2.3 (95 % CI: 1.3, 4.0; P = 0.002), and 2.4 (95 % CI: 1.4, 4.2; P = 0.002), respectively. In patients with ADC-L <1,209 and LCP >0.71 versus ADC-L >1,209 and LCP <0.71, there was a 2.28-fold reduction in the median time to progression, and a 1.42-fold decrease in the median OS. The predictive value of ADC histogram analysis, in which low ADC-L was associated with poor outcome, was confirmed in bevacizumab-treated patients with recurrent GBM in a post hoc analysis from the multi-center (BRAIN) study.

The initial management of patients with malignant gliomas depends on accurate histologic diagnosis which, in turn, directs appropriate treatment planning. However, the diagnosis of recurrent disease is often based solely on radiological data which can occasionally be misinterpreted as showing recurrent tumor. Lack of awareness of conditions that mimic recurrent tumor and potentially confound radiological diagnosis can lead to inappropriate therapeutic decisions. We report the case of a patient whose imaging studies suggested recurrence of malignant glioma; however, surgical resection of the lesion guided by MRI scans resulted in the correct diagnosis of papillary endothelial hyperplasia and led to appropriate management of this condition that mimicked tumor recurrence. In this report, we provide a comprehensive review of this rare entity and emphasize the importance of adequately pursuing appropriate diagnostic considerations prior to making definitive treatment decisions.

We evaluated the efficacy of temozolomide (TMZ) or lomustine (CCNU) in combination with 6-thioguanine, capecitabine, and celecoxib for the treatment of recurrent high-grade glioma. Forty-three patients with recurrent glioblastoma and 31 patients with recurrent anaplastic glioma (AG) were enrolled in this open-label, non-comparative study. Patients previously treated with TMZ received CCNU while all others received TMZ; all patients received 6-thioguanine, capecitabine, and celecoxib. Endpoints were 12-month progression-free survival (PFS) for patients with AG, 6-month PFS for patients with glioblastoma, duration of PFS, and MRI-based objective response rates. Results from the TMZ and CCNU treatment arms were combined in the final analysis because there was no statistically significant difference between them. Thirty-eight patients with glioblastoma were treated with the lomustine-based regimen, and five received the TMZ-based regimen. For the 43 glioblastoma patients, the objective response rate was 12 and 33% had stable disease; the 6-month PFS was 14% and median overall survival 32 weeks. For the 31 AG patients, the combined objective response rate was 26 and 42% had stable disease; the 12 month PFS was 44%. Treatment was reasonably well tolerated with hematological toxicity common and more frequent with CCNU than TMZ. The combination therapy with 6-thioguanine, capecitabine and celecoxib plus CCNU or TMZ does not appear to be more effective than other alkylating agent schedules for patients with recurrent glioblastoma. The combination, however, is promising for patients with recurrent high-grade AG.

Purpose: This phase III open-label study compared the efficacy and safety of enzastaurin versus lomustine in patients with recurrent glioblastoma (WHO grade 4)., Patients and Methods: Patients were randomly assigned 2:1 to receive 6-week cycles of enzastaurin 500 mg/d (1,125-mg loading dose, day 1) or lomustine (100 to 130 mg/m(2), day 1). Assuming a 45% improvement in progression-free survival (PFS), 397 patients were required to provide 80% power to achieve statistical significance at a one-sided level of .025., Results: Enrollment was terminated at 266 patients (enzastaurin, n = 174; lomustine, n = 92) after a planned interim analysis for futility. Patient characteristics were balanced between arms. Median PFS (1.5 v 1.6 months; hazard ratio [HR] = 1.28; 95% CI, 0.97 to 1.70), overall survival (6.6 v 7.1 months; HR = 1.20; 95% CI, 0.88 to 1.65), and 6-month PFS rate (P = .13) did not differ significantly between enzastaurin and lomustine, respectively. Stable disease occurred in 38.5% and 35.9% of patients and objective response occurred in 2.9% and 4.3% of patients, respectively. Time to deterioration of physical and functional well-being and symptoms did not differ between arms (HR = 1.12; P = .54). Four patients discontinued enzastaurin because of drug-related serious adverse events (AEs). Eleven patients treated with enzastaurin died on study (four because of AEs; one was drug-related). All four deaths that occurred in patients receiving lomustine were disease-related. Grade 3 to 4 hematologic toxicities were significantly higher with lomustine (46 events) than with enzastaurin (one event; P < or = .001)., Conclusion: Enzastaurin was well tolerated and had a better hematologic toxicity profile but did not have superior efficacy compared with lomustine in patients with recurrent glioblastoma.

Background: Laboratory and clinical data suggest that the anti-angiogenic agent, thalidomide, if combined with cytotoxic agents, may be effective against recurrent glioblastoma multiforme (GBM)., Objectives: To determine 6-month progression-free survival (6PFS) and toxicity of temozolomide plus thalidomide in adults with recurrent GBM., Patients and Methods: Eligible patients had recurrent GBM after surgery, radiotherapy, and/or adjuvant chemotherapy. Temozolomide was given at 150-200 mg/m(2)/day on days 1-5 of each 28-day cycle. Thalidomide was given orally at 400 mg at bedtime (days 1-28) and increased to 1,200 mg as tolerated. Patients were evaluated with magnetic resonance imaging scans every 56 days. The study was designed to detect an increase of the historical 6PFS for GBM from 10 to 30%., Results: Forty-four patients were enrolled, 43 were evaluable for efficacy and safety. The study population included 15 women, 29 men; median age was 53 years (range 32-84); median Karnofsky performance status was 80% (range 60-100%). Thirty-six (82%) patients were chemotherapy-naïve. There were 57 reports of toxicity of grade 3 or greater. Non-fatal grade 3-4 granulocytopenia occurred in 15 patients (34%). The objective response rate was 7%. The estimated probability of being progression-free at 6 months with this therapy is 24% [95% confidence interval (C.I.) 12-38%]. The median time to progression is 15 weeks (95% C.I. 10-20 weeks). There was no observed correlation between serum levels of vascular endothelial growth factor, basic fibroblast growth factor, and IL-8 and the 6PFS outcome., Conclusion: This drug combination was reasonably safe, but with little indication of improvement compared to temozolomide alone.

Purpose: Since anaplastic gliomas (AG) depend on matrix metalloproteinases for tumor cell invasion and angiogenesis, we undertook this phase II study to evaluate the matrix metalloproteinase inhibitor marimastat (MT), combined with the alkylator temozolomide (TMZ) in patients with recurrent AG, looking for improved outcomes., Patients and Methods: Patients were treated every 28 days with TMZ at 150-200 mg/m2 once daily on days 1-5 and MT at 25 mg twice daily on days 8-28. Results were compared to our database of anaplastic glioma patients treated at recurrence. A subanalysis of the relationship between MT-induced joint-related toxicity and anticonvulsant status was carried out., Results: Forty-nine patients were enrolled; all were assessable for toxicity, and 46 were included in the efficacy analysis. Joint and muscle complaints occurred in 32 patients (65%); 1 patient was removed from the study due to toxicity. The best protocol response was a complete response in 1 patient and a partial response in 2 patients (3/46=7%, 95% confidence interval (CI)=1, 18). Median time to progression was 24 weeks (95% CI=16, 56), and the progression-free survival (PFS) rate was 48% at 6 months (95% CI=35%, 65%), which surpassed the protocol objective of 40%. Sub-analysis showed a positive impact of joint-related toxicity due to MT on PFS whether or not patients were taking CYP450 enzyme-inducing anticonvulsants., Conclusions: Even though this regimen is more efficacious than our comparator of historical controls in recurrent AG, the regimen was roughly equivalent to single-agent TMZ and was associated with additional toxicity. The sub-analysis suggests pharmacokinetic and drug-drug interactions which may positively impact responses to MT.

Objectives: Anaplastic oligodendrogliomas (AO) are uncommon primary brain tumors whose natural history, prognosis, and optimal management are not yet fully understood. However, they are associated with a better prognosis and response to multimodality therapy based on specific molecular changes. In this multicenter retrospective study, we analyzed the clinical characteristics of patients with AO to identify prognostic factors that influence time to progression (TTP) and survival., Methods: A retrospective search of the brain tumor databases of three institutions (the University of Texas M. D. Anderson Cancer Center, the University of California at San Francisco, and the University of Utah) for patients between 1977 and 1995 with histologically confirmed AO identified a cohort of 106 patients that was further analyzed in this study. Initial treatment included surgery alone (n = 12) or surgery followed by one of the following: radiotherapy (RT) alone (n = 49), chemotherapy alone (n = 4), chemotherapy followed by RT (n = 10), RT followed by chemotherapy (n = 20), and others (n = 11)., Results: The median age at diagnosis was 43 years, and the median Karnofsky performance score (KPS) was 90. The overall median survival was 7.3 years, and the 5-year survival rate was 62%. Univariate analysis of several clinical variables showed that only age (p < 0.0001) and KPS (p = 0.04) correlated significantly with survival. Fifty patients had disease progression after initial therapy. The median TTP was 48 months. Age at diagnosis was the only variable that correlated significantly with TTP., Conclusions: A trend towards longer survival with a greater extent of resection was evident. The relative efficacy of various treatment modalities could not be definitively determined because of the heterogeneity of the therapies used. Overall, patients with AO have a better prognosis after therapy compared with those who have other malignant gliomas., (Copyright 2003 S. Karger AG, Basel)