Who Is In Charge, and Who Should Be? The Disciplinary Role of the Commander in Military Justice Systems

BackgroundStandard therapy for newly diagnosed glioblastoma is radiotherapy plus temozolomide. In this phase 3 study, we evaluated the effect of the addition of bevacizumab to radiotherapy-temozolomide for the treatment of newly diagnosed glioblastoma. MethodsWe randomly assigned patients with supratentorial glioblastoma to receive intravenous bevacizumab (10 mg per kilogram of body weight every 2 weeks) or placebo, plus radiotherapy (2 Gy 5 days a week; maximum, 60 Gy) and oral temozolomide (75 mg per square meter of body-surface area per day) for 6 weeks. After a 28-day treatment break, maintenance bevacizumab (10 mg per kilogram intravenously every 2 weeks) or placebo, plus temozolomide (150 to 200 mg per square meter per day for 5 days), was continued for six 4-week cycles, followed by bevacizumab monotherapy (15 mg per kilogram intravenously every 3 weeks) or placebo until the disease progressed or unacceptable toxic effects developed. The coprimary end points were investigator-assessed progression-free survival and overall survival. ResultsA total of 458 patients were assigned to the bevacizumab group, and 463 patients to the placebo group. The median progression-free survival was longer in the bevacizumab group than in the placebo group (10.6 months vs. 6.2 months; stratified hazard ratio for progression or death, 0.64; 95% confidence interval [CI], 0.55 to 0.74; P<0.001). The benefit with respect to progression-free survival was observed across subgroups. Overall survival did not differ significantly between groups (stratified hazard ratio for death, 0.88; 95% CI, 0.76 to 1.02; P=0.10). The respective overall survival rates with bevacizumab and placebo were 72.4% and 66.3% at 1 year (P=0.049) and 33.9% and 30.1% at 2 years (P=0.24). Baseline health-related quality of life and performance status were maintained longer in the bevacizumab group, and the glucocorticoid requirement was lower. More patients in the bevacizumab group than in the placebo group had grade 3 or higher adverse events (66.8% vs. 51.3%) and grade 3 or higher adverse events often associated with bevacizumab (32.5% vs. 15.8%). ConclusionsThe addition of bevacizumab to radiotherapy-temozolomide did not improve survival in patients with glioblastoma. Improved progression-free survival and maintenance of baseline quality of life and performance status were observed with bevacizumab; however, the rate of adverse events was higher with bevacizumab than with placebo.

Phase 1 dose-escalation study of the antiplacental growth factor monoclonal antibody RO5323441 combined with bevacizumab in patients with recurrent glioblastoma

Background We conducted a phase 1 dose-escalation study of RO5323441, a novel antiplacental growth factor (PlGF) monoclonal antibody, to establish the recommended dose for use with bevacizumab and to investigate the pharmacokinetics, pharmacodynamics, safety/tolerability, and preliminary clinical efficacy of the combination. Methods Twenty-two participants with histologically confirmed glioblastoma in first relapse were treated every 2 weeks with RO5323441 (625 mg, 1250 mg, or 2500 mg) plus bevacizumab (10 mg/kg). A standard 3 + 3 dose-escalation trial design was used. Results RO5323441 combined with bevacizumab was generally well tolerated, and the maximum tolerated dose was not reached. Two participants experienced dose-limiting toxicities (grade 3 meningitis associated with spinal fluid leak [1250 mg] and grade 3 cerebral infarction [2500 mg]). Common adverse events included hypertension (14 participants, 64%), headache (12 participants, 55%), dysphonia (11 participants, 50%) and fatigue (6 participants, 27%). The pharmacokinetics of RO5323441 were linear, over-the-dose range, and bevacizumab exposure was unaffected by RO5323441 coadministration. Modulation of plasmatic angiogenic proteins, with increases in VEGFA and decreases in FLT4, was observed. Dynamic contrast-enhanced/diffusion-weighted MRI revealed large decreases in vascular parameters that were maintained through the dosing period. Combination therapy achieved an overall response rate of 22.7%, including one complete response, and median progression-free and overall survival of 3.5 and 8.5 months, respectively. Conclusion The toxicity profile of RO5323441 plus bevacizumab was acceptable and manageable. The observed clinical activity of the combination does not appear to improve on that obtained with single-agent bevacizumab in patients with recurrent glioblastom

Zotiraciclib (TG02) for newly diagnosed glioblastoma in the elderly or for recurrent glioblastoma:The EORTC 1608 STEAM trial

Background: Zotiraciclib (TG02) is an oral multi-cyclin dependent kinase (CDK) inhibitor thought to inhibit tumor growth via CDK-9-dependent depletion of survival proteins such as c-MYC and MCL-1 which are frequently overexpressed in glioblastoma. Methods: EORTC 1608 (NCT03224104) (STEAM) had a three parallel group (A,B,C) phase Ib, open-label, non-randomized, multicenter design in IDH wild-type newly diagnosed glioblastoma or anaplastic astrocytoma. Groups A and B explored the maximum tolerated dose (MTD) of TG02 in elderly patients, in combination with hypofractionated radiotherapy alone (group A) or temozolomide alone (group B), according to O6-methylguanine DNA methyltransferase promoter methylation status determined centrally. Group C explored single agent activity of TG02 at first relapse after temozolomide chemoradiotherapy with a primary endpoint of progression-free survival at 6 months (PFS-6). Tumor expression of CDK-9, c-MYC and MCL-1 was determined by immunohistochemistry.Results: The MTD was 150 mg twice weekly in combination with radiotherapy alone (group A) or temozolomide alone (group B). Two dose-limiting toxicities were observed at 150 mg: one in group A (grade 3 seizure), one in group B (multiple grade 1 events). Main toxicities included neutropenia, gastrointestinal disorders and hepatotoxicity. PFS-6 in group C was 6.7%. CDK-9, c-MYC and MCL-1 were confirmed to be expressed and their expression was moderately cross-correlated. High protein levels of MCL-1 were associated with inferior survival. Conclusions: TG02 exhibits overlapping toxicity with alkylating agents and low single agent clinical activity in recurrent glioblastoma. The role of CDK-9 and its down-stream effectors as prognostic factors and therapeutic targets in glioblastoma warrants further study.</p

Negative Survival Impact of High Radiation Doses to Neural Stem Cells Niches in an IDH-Wild-Type Glioblastoma Population

Aims: Assess the impact of radiation doses to neural stem cell (NSC) niches in patients with IDH-wild-type glioblastoma.Materials and Methods: Fifty patients were included in the study. NSC niches [SubVentricular Zone (SVZ) and Sub Granular Zone (SGZ)] were contoured by fusing CT scans and pre-therapy MRI, Tumor location defined ipsilateral and contralateral SVZ and SGZ. Prognostic significance of clinical, biological and dosimetric parameters were examined. We generated a Recursive Partitioning Analysis (RPA) model with independent prognostic classes.Results: Median follow-up: 23.8 months. Event free and overall survival (OS): 10 and 19.1 months. Incomplete surgery, PTV (planning target volume), ipsilateral SVZ or NSC niche mean dose &gt; 57.4 Gy, contralateral NSC niche mean dose &gt; 35 Gy and bilateral NSC niche mean dose &gt; 44 Gy were significantly correlated with reduced OS. Only EGFR amplification was an independent prognostic factor (p = 0.019) for OS. RPA generated independent risk groups: 1 (low risk): [ipsilateral NSC mean dose (INMD) &lt; 58.01 Gy and methylated MGMT promoter], 2: (INMD &lt; 58.01 Gy and unmethylated MGMT promoter and contralateral SVZ mean dose &lt; 18.6 Gy; p = 0.43), 3: (INMD &lt; 58.01 Gy and unmethylated MGMT promoter and contralateral SVZ mean dose &gt; 18.6 Gy; p = 0.002) and 4: (very high risk) (INMD &gt; 58.01 Gy; p &lt; 0.001).Conclusion: High radiation doses to ipsilateral NSC and contralateral SVZ could have a negative impact on overall survival in IDH-wild-type glioblastoma population

Comparison of ADC metrics and their association with outcome for patients with newly diagnosed glioblastoma being treated with radiation therapy, temozolomide, erlotinib and bevacizumab

To evaluate metrics that describe changes in apparent diffusion coefficient (ADC) and to examine their association with clinical outcome for patients with newly diagnosed GBM who were participating in a Phase II clinical trial of treatment with radiation (RT), temozolomide, erlatonib and bevacizumab. Thirty six patients were imaged after surgery but prior to therapy and at regular follow-up time points. The following ADC metrics were evaluated: (1) histogram percentiles within the T2-hyperintense lesion (T2L) at serial follow-ups; (2) parameters obtained by fitting a two-mixture normal distribution to the histogram within the contrast-enhancing lesion (CEL) at baseline; (3) parameters obtained using both traditional and graded functional diffusion maps within the CEL and T2L. Cox Proportional Hazards models were employed to assess the association of the ADC parameters with overall survival (OS) and progression-free survival (PFS). A lower ADC percentile value within the T2L at early follow-up time points was associated with worse outcome. Of particular interest is that, even when adjusting for clinical prognostic factors, the ADC(10%) within the T2L at 2 months was strongly associated with OS (p < 0.001) and PFS (p < 0.007). fDM metrics showed an association with OS and PFS within the CEL when considered by univariate analysis, but not in the T2L. Our study emphasizes the value of ADC metrics obtained from the T2L at the post-RT time point as non-invasive biomarkers for assessing residual tumor in patients with newly diagnosed GBM being treated with combination therapy that includes the anti-angiogenic agent bevacizumab