Jürgen Meixensberger

Temozolomide chemotherapy alone versus radiotherapy alone for malignant astrocytoma in the elderly: the NOA-08 randomised, phase 3 trial

BACKGROUND Radiotherapy is the standard care in elderly patients with malignant astrocytoma and the role of primary chemotherapy is poorly defined. We did a randomised trial to compare the efficacy and safety of dose-dense temozolomide alone versus radiotherapy alone in elderly patients with anaplastic astrocytoma or glioblastoma. METHODS Between May 15, 2005, and Nov 2, 2009, we enrolled patients with confirmed anaplastic astrocytoma or glioblastoma, age older than 65 years, and a Karnofsky performance score of 60 or higher. Patients were randomly assigned 100 mg/m(2) temozolomide, given on days 1-7 of 1 week on, 1 week off cycles, or radiotherapy of 60·0 Gy, administered over 6-7 weeks in 30 fractions of 1·8-2·0 Gy. The primary endpoint was overall survival. We assessed non-inferiority with a 25% margin, analysed for all patients who received at least one dose of assigned treatment. This trial is registered with ClinicalTrials.gov, number NCT01502241. FINDINGS Of 584 patients screened, we enrolled 412. 373 patients (195 randomly allocated to the temozolomide group and 178 to the radiotherapy group) received at least one dose of treatment and were included in efficacy analyses. Median overall survival was 8·6 months (95% CI 7·3-10·2) in the temozolomide group versus 9·6 months (8·2-10·8) in the radiotherapy group (hazard ratio [HR] 1·09, 95% CI 0·84-1·42, p(non-inferiority)=0·033). Median event-free survival (EFS) did not differ significantly between the temozolomide and radiotherapy groups (3·3 months [95% CI 3·2-4·1] vs 4·7 [4·2-5·2]; HR 1·15, 95% CI 0·92-1·43, p(non-inferiority)=0·043). Tumour MGMT promoter methylation was seen in 73 (35%) of 209 patients tested. MGMT promoter methylation was associated with longer overall survival than was unmethylated status (11·9 months [95% CI 9·0 to not reached] vs 8·2 months [7·0-10·0]; HR 0·62, 95% CI 0·42-0·91, p=0·014). EFS was longer in patients with MGMT promoter methylation who received temozolomide than in those who underwent radiotherapy (8·4 months [95e% CI 5·5-11·7] vs 4·6 [4·2-5·0]), whereas the opposite was true for patients with no methylation of the MGMT promoter (3·3 months [3·0-3·5] vs 4·6 months [3·7-6·3]). The most frequent grade 3-4 intervention-related adverse events were neutropenia (16 patients in the temozolomide group vs two in the radiotherapy group), lymphocytopenia (46 vs one), thrombocytopenia (14 vs four), raised liver-enzyme concentrations (30 vs 16), infections (35 vs 23), and thromboembolic events (24 vs eight). INTERPRETATION Temozolomide alone is non-inferior to radiotherapy alone in the treatment of elderly patients with malignant astrocytoma. MGMT promoter methylation seems to be a useful biomarker for outcomes by treatment and could aid decision-making. FUNDING Merck Sharp & Dohme.

Brain tissue oxygen guided treatment supplementing ICP/CPP therapy after traumatic brain injury

Objective: To evaluate the effects of a brain tissue oxygen (Ptio2) guided treatment in patients with traumatic brain injury. Methods: Ptio2 was monitored in 93 patients with severe traumatic brain injury. Forty patients admitted from 1993 to 1996 were treated with intracranial pressure/cerebral perfusion pressure (ICP/CPP) management alone (ICP < 20 mm Hg, CPP > 70 mm Hg). Fifty three patients admitted from 1997 to 2000 were treated using ICP/CPP management, but in this second group CPP was also increased as individually required to raise the Ptio2 above 1.33 kPa (10 mm Hg) (Ptio2 guided group). Results: Cerebral hypoxic phases with Ptio2 values below 1.33 kPa occurred significantly less often in the Ptio2 guided group. Ptio2 values were higher over the whole monitoring period. No statistical differences could be observed in outcome at six months, despite a positive trend in the Ptio2 guided group. Conclusions: Cerebral hypoxic events can be reduced significantly by increasing cerebral perfusion pressure as required. To show a clear beneficial effect of Ptio2 guided cerebral perfusion pressure management on outcome, a multicentre randomised trial needs to be undertaken.

Arachnoid cysts associated with subdural hematomas and hygromas: analysis of 16 cases, long-term follow-up, and review of the literature.

OBJECTIVE Subdural hematomas and hygromas are infrequently encountered complications of arachnoid cysts of the middle cranial fossa and are particularly rare with cysts of other regions. Reports in the literature focus on casuistic observations. Therapeutic recommendations often include fenestration or extirpation of the cyst wall, in addition to evacuation of the space-occupying lesion. This study evaluates the results of and rationale for a more conservative approach, usually without cyst removal. METHODS Sixteen cases of complicated arachnoid cysts, from a total of 658 patients with subdural hematomas or hygromas, were analyzed retrospectively together with 75 other cases reported in the literature. Additionally, 94 magnetic resonance imaging scans from 89 patients with untreated arachnoid cysts, from a total of 11,487 examinations, were reviewed for signs of hemorrhagic complications. RESULTS Arachnoid cysts of the middle cranial fossa were found in 2.43% of patients with chronic subdural hematomas or hygromas. This indicated a fivefold greater prevalence of arachnoid cysts, compared with our magnetic resonance imaging-examined patient group. Only two patients with untreated cysts showed signs of hemorrhage in magnetic resonance imaging scans. An excellent or good therapeutic result was achieved with evacuation of the subdural fluid by drainage or craniotomy in 13 cases and with conservative treatment in two cases. Only one patient underwent additional fenestration of the cyst wall. No additional symptoms from the arachnoid cysts occurred in a follow-up period of up to 14 years after therapy. CONCLUSIONS We do not generally consider it necessary to perform cyst diversion or fenestration at the time of drainage of a hematoma or hygroma in previously asymptomatic arachnoid cysts.

Continuous assessment of cerebrovascular autoregulation after traumatic brain injury using brain tissue oxygen pressure reactivity.

Objective:To evaluate whether two newly developed indexes of brain tissue oxygen pressure reactivity (ORx and bPtio2) provide information on the status of cerebrovascular autoregulation after traumatic brain injury. This was accomplished by analyzing the relationship between these indexes and an index of cerebrovascular pressure reactivity (PRx). PRx is an established parameter for estimation of cerebrovascular autoregulation. Design:Retrospective analysis of prospectively collected data. Setting:Neurosurgical intensive care unit of a university hospital. Patients:Twenty-seven patients suffering from severe traumatic brain injury. Interventions:Continuous monitoring of mean arterial blood pressure, intracranial pressure, cerebral perfusion pressure, and partial pressure of brain tissue oxygen (Ptio2) was performed for an average of 6.5 days. ORx was calculated as a moving correlation coefficient between values of cerebral perfusion pressure and Ptio2. The bPtio2 was calculated as a moving value of the slope of the linear regression function between cerebral perfusion pressure and Ptio2. PRx was calculated as a moving correlation coefficient between values for intracranial pressure and mean arterial blood pressure. Outcome was assessed at 6 months after traumatic brain injury (Glasgow Outcome Scale). Measurements and Main Results:Both ORx and bPtio2 correlated significantly with PRx (r = .55 for ORx, r = .52 for bPtio2, p < .01). PRx and ORx showed a significantly negative correlation to the monitored Ptio2 values (r = −.42 for PRx, r = −.41 for ORx, p < .05) and outcome (r = −.52 for PRx, r = −.62 for ORx, p < .01), whereas bPtio2 did not. Conclusions:ORx and, to a lesser extent, bPtio2 correlated with the autoregulatory marker PRx and provide additional information about the status of cerebrovascular autoregulation after traumatic brain injury. The data also suggested that patients with impaired autoregulation are at increased risk for secondary cerebral hypoxia.

Effects of decompressive craniectomy on brain tissue oxygen in patients with intracranial hypertension.

This report examined the intraoperative course of partial pressure of brain tissue oxygen (PtiO2) and intracranial pressure (ICP) during surgical decompressive craniectomy for medically intractable intracranial hypertension due to diffuse brain swelling in three patients after severe subarachnoid haemorrhage and aneurysm coiling. The mean ICP decreased from 59 mm Hg to 10 mm Hg in a two step fashion, relating to bone flap removal and dural opening. Simultaneously, PtiO2 increased rapidly from 0.8 kPa (6 mm Hg) to 3.07 kPa (23 mm Hg). PtiO2 and ICP remained at non-critical ranges postoperatively. Despite these beneficial effects on ICP and PtiO2, the patients’ clinical status remained poor with two in a persistent vegetative state and one dead.

Bortezomib Sensitizes Primary Human Astrocytoma Cells of WHO Grades I to IV for Tumor Necrosis Factor–Related Apoptosis-Inducing Ligand–Induced Apoptosis

Purpose: Malignant gliomas are the most aggressive human brain tumors without any curative treatment. The antitumor effect of tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) in gliomas has thus far only been thoroughly established in tumor cell lines. In the present study, we investigated the therapeutic potential of TRAIL in primary human glioma cells. Experimental Design: We isolated primary tumor cells from 13 astrocytoma and oligoastrocytoma patients of all four WHO grades of malignancy and compared the levels of TRAIL-induced apoptosis induction, long-term tumor cell survival, caspase, and caspase target cleavage. Results: We established a stable culture model for isolated primary human glioma cells. In contrast to cell lines, isolated primary tumor cells from all investigated glioma patients were highly TRAIL resistant. Regardless of the tumor heterogeneity, cotreatment with the proteasome inhibitor bortezomib efficiently sensitized all primary glioma samples for TRAIL-induced apoptosis and tremendously reduced their clonogenic survival. Due to the pleiotropic effect of bortezomibenhanced TRAIL DISC formation upon TRAIL triggering, down-regulation of cFLIPL and activation of the intrinsic apoptosis pathway seem to cooperatively contribute to the antitumor effect of bortezomib/TRAIL cotreatment. Conclusion: TRAIL sensitivity of tumor cell lines is not a reliable predictor for the behavior of primary tumor cells. The widespread TRAIL resistance in primary glioma cells described here questions the therapeutic clinical benefit of TRAIL as a monotherapeutic agent. Overcoming TRAIL resistance by bortezomib cotreatment might, however, provide a powerful therapeutic option for glioma patients.

Correlation of continuously monitored regional cerebral blood flow and brain tissue oxygen

SummaryBackground. The purpose of this study was to investigate the relationship between continuously monitored regional cerebral blood flow (CBF) and brain tissue oxygen (PtiO2).Methods. Continuous advanced multimodal neuromonitoring including monitoring of PtiO2 (Licox, GMS) and CBF (QFlow, Hemedex) was performed in eight patients after severe subarachnoid haemorrhage (n=5) and traumatic brain injury (n=3) for an average of 9.6 days. Parameters were measured using a flexible polarographic PtiO2-probe and a thermal diffusion CBF-microprobe.Findings. Regarding the whole monitoring period in all patients, the data indicated a significant correlation between CBF and PtiO2 (r=0.36). In 72% of 400 analysed intervals of 30 minutes duration with PtiO2 changes larger than 5 mmHg, a strong correlation between CBF and PtiO2 existed (r > 0.6). In 19% of intervals a still statistically significant correlation was observed (0.3 < r < 0.6). During the remaining 9% no correlation was found (r < 0.3). Regarding the clinical stability of the monitoring devices, the CBF monitoring system allowed monitoring of CBF in 64% of the time when PtiO2 monitoring was possible only. Phases of non-monitoring were mostly due to fever of the patient, when the system does not allow monitoring to avoid overheating of the cerebral tissue.Conclusions. This study suggests a correlation between CBF and PtiO2. The level of PtiO2 seems to be predominately determined by regional CBF, since changes in PtiO2 were correlated in 90% of episodes to simultaneous changes of CBF.

MGMT Promoter Methylation Is a Strong Prognostic Biomarker for Benefit from Dose-Intensified Temozolomide Rechallenge in Progressive Glioblastoma: The DIRECTOR Trial.

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.

Effects of cerebrovascular pressure reactivity-guided optimization of cerebral perfusion pressure on brain tissue oxygenation after traumatic brain injury

Objective:To evaluate the concept of a cerebrovascular pressure reactivity-guided optimal cerebral perfusion pressure after traumatic brain injury by analyzing the relationship between optimal cerebral perfusion pressure and brain tissue oxygen. Design:Prospective observational cohort study. Setting:Neurosurgical intensive care unit of a university hospital. Patients:Thirty-eight patients after head injury. Interventions: Continuous computerized monitoring of mean arterial pressure, intracranial pressure, and brain tissue oxygen for 5.3 ± 2.6 days. The index of cerebrovascular pressure reactivity was calculated as a moving correlation coefficient between spontaneous low-frequency fluctuations of mean arterial pressure and intracranial pressure. Optimal cerebral perfusion pressure was defined as the cerebral perfusion pressure level with the lowest average index of cerebrovascular pressure reactivity. Measurements and Main Results:Optimal cerebral perfusion pressure could be identified in 32 of 38 patients. Median optimal cerebral perfusion pressure was between 70 and 75 mm Hg (range, 60–100 mm Hg). Below the level of optimal cerebral perfusion pressure, brain tissue oxygen decreased in parallel to cerebral perfusion pressure, whereas brain tissue oxygen reached a plateau above optimal cerebral perfusion pressure. Optimal cerebral perfusion pressure correlated significantly with the cerebral perfusion pressure level, where brain tissue oxygen reached its plateau (r = .79; p < .01). Average brain tissue oxygen at optimal cerebral perfusion pressure was 24.5 ± 6.0 mm Hg. Conclusions:This study supports the concept of cerebrovascular pressure reactivity-based individual optimal cerebral perfusion pressure. Driving cerebral perfusion pressure in excess of optimal cerebral perfusion pressure does not yield improvements in brain tissue oxygen after head injury and should be avoided, whereas cerebral perfusion pressure below optimal cerebral perfusion pressure may result in secondary cerebral ischemia.

The first evaluation of brain shift during functional neurosurgery by deformation field analysis

Stereotactic surgery is based on a high degree of accuracy in defining and localising intracranial targets and placing surgical tools. Brain shift can influence its accuracy significantly. Deep brain stimulation of the subthalamic nucleus can markedly change the quality of life of patients with advanced Parkinson’s disease, but the outcome depends on the quality of electrode placement. A patient is reported in whom the placement of the second electrode was not successful. Deformation field analysis of pre- and postoperative three dimensional magnetic resonance images showed an intraoperative brain movement of 2 mm in the region of the subthalamic nucleus (the target point). Electrode repositioning resulted in efficient stimulation effects. This case report shows the need to reduce risk factors for intraoperative brain movement and demonstrates the ability of deformation field analysis to quantify this complication.