Kea Franz

Extent of resection and survival in glioblastoma multiforme: identification of and adjustment for bias.

OBJECTIVEThe influence of the degree of resection on survival in patients with glioblastoma multiforme is still under discussion. The highly controlled 5-aminolevulinic acid study provided a unique platform for addressing this question as a result of the high frequency of “complete” resections, as revealed by postoperative magnetic resonance imaging scans achieved by fluorescence-guided resection and homogeneous patient characteristics. METHODSTwo hundred forty-three patients with glioblastoma multiforme per protocol from the 5-aminolevulinic acid study were analyzed. Patients with complete and incomplete resections as revealed by early magnetic resonance imaging scans were compared. Prognostic factors that might cause bias regarding resection and influence survival (e.g., tumor size, edema, midline shift, location, age, Karnofsky Performance Scale score, National Institutes of Health Stroke Scale score) were used for analysis of overall survival. Time to reintervention (chemotherapy, reoperation) was analyzed further to exclude bias regarding second-line therapies. RESULTSTreatment bias was identified in patients with complete (n = 122) compared with incomplete resection (n = 121), i.e., younger age and less frequent eloquent tumor location. Other factors, foremost preoperative tumor size, were identical. Patients without residual tumor survived longer (16.7 versus 11.8 mo, P < 0.0001). In multivariate analysis, only residual tumor, age, and Karnofsky Performance Scale score were significantly prognostic. To account for distribution bias, patients were stratified for age (>60 or ≤60 yr) and eloquent location. Survival advantages from complete resection remained significant within subgroups, and age/eloquent location were no longer unevenly distributed. Reinterventions occurred marginally earlier in patients with residual tumor (6.7 versus 9.5 mo, P = 0.0582). CONCLUSIONTreatment bias was demonstrated regarding resection and second-line therapies. However, bias and imbalances were controllable in the cohorts available from the 5-aminolevulinic acid study so that the present data now provide Level 2b evidence (Oxford Centre for Evidence-based Medicine) that survival depends on complete resection of enhancing tumor in glioblastoma multiforme.

Intraoperative MRI guidance and extent of resection in glioma surgery: a randomised, controlled trial.

BACKGROUND Intraoperative MRI is increasingly used in neurosurgery, although there is little evidence for its use. We aimed to assess efficacy of intraoperative MRI guidance on extent of resection in patients with glioma. METHODS In our prospective, randomised, parallel-group trial, we enrolled adults (≥18 years) with contrast enhancing gliomas amenable to radiologically complete resection who presented to Goethe University (Frankfurt, Germany). We randomly assigned patients (1:1) with computer-generated blocks of four and a sealed-envelope design to undergo intraoperative MRI-guided surgery or conventional microsurgery (control group). Surgeons and patients were unmasked to treatment group allocation, but an independent neuroradiologist was masked during analysis of all preoperative and postoperative imaging data. The primary endpoint was rate of complete resections as established by early postoperative high-field MRI (1·5 T or 3·0 T). Analysis was done per protocol. This study is registered with ClinicalTrials.gov, number NCT01394692. FINDINGS We enrolled 58 patients between Oct 1, 2007, and July 1, 2010. 24 (83%) of 29 patients randomly allocated to the intraoperative MRI group and 25 (86%) of 29 controls were eligible for analysis (four patients in each group had metastasis and one patient in the intraoperative MRI group withdrew consent after randomisation). More patients in the intraoperative MRI group had complete tumour resection (23 [96%] of 24 patients) than did in the control group (17 [68%] of 25, p=0·023). Postoperative rates of new neurological deficits did not differ between patients in the intraoperative MRI group (three [13%] of 24) and controls (two [8%] of 25, p=1·0). No patient for whom use of intraoperative MRI led to continued resection of residual tumour had neurological deterioration. One patient in the control group died before 6 months. INTERPRETATION Our study provides evidence for the use of intraoperative MRI guidance in glioma surgery: such imaging helps surgeons provide the optimum extent of resection. FUNDING None.

Cerebral Gliomas: Diffusional Kurtosis Imaging Analysis of Microstructural Differences

PURPOSE To characterize the non-Gaussian diffusion patterns of cerebral glioma microstructure with respect to the different glioma grades by using a new method called diffusional kurtosis (DK) imaging. MATERIALS AND METHODS In this study with institutional review board approval and patient consent, diffusional measures of mean kurtosis (MK), fractional anisotropy (FA), and apparent diffusion coefficient (ADC) were compared prospectively. Data were normalized to the contralateral white matter. A Mann-Whitney test was used to compare each histologic glioma subtype regarding the diffusion measurements. Receiver operating characteristic curves were used to test for the parameter with the best sensitivity and specificity for glioma grade discrimination. RESULTS In 34 patients with cerebral gliomas (five World Health Organization [WHO] grade II astrocytomas, 13 WHO grade III astrocytomas, and 16 WHO grade IV glioblastomas multiforme), significantly different diffusion patterns were found among the three glioma groups. MK values increased with higher glioma malignancy, whereas ADCs tended to decrease with higher malignancy; FA values did not differ significantly among tumor groups. Significant differences between astrocytoma grades WHO II and WHO III were demonstrated only by DK values. Area under the receiver operating characteristic curve was highest for normalized MK (0.972) during testing to discriminate between low- and high-grade gliomas. CONCLUSION This study demonstrates specific diffusion patterns for low- and high-grade gliomas, showing that DK imaging is able to depict microstructural changes within glioma tissue and is able to help differentiate among glioma grades. (c) RSNA, 2010.

Counterbalancing risks and gains from extended resections in malignant glioma surgery: a supplemental analysis from the randomized 5-aminolevulinic acid glioma resection study. Clinical article.

OBJECT Accumulating data suggest more aggressive surgery in patients with malignant glioma to improve outcome. However, extended surgery may increase morbidity. The randomized Phase III 5-aminolevulinic acid (ALA) study investigated 5-ALA-induced fluorescence as a tool for improving resections. An interim analysis demonstrated more frequent complete resections with longer progression-free survival (PFS). However, marginal differences were found regarding neurological deterioration and the frequency of additional therapies. Presently, the authors focus on the latter aspects in the final study population, and attempt to determine how safety might be affected by cytoreductive surgery. METHODS Patients with malignant gliomas were randomized for fluorescence-guided (ALA group) or conventional white light (WL) (WL group) microsurgery. The final intent-to-treat population consisted of 176 patients in the ALA and 173 in the WL group. Primary efficacy variables were contrast-enhancing tumor on early MR imaging and 6-month PFS. Among secondary outcome measures, the National Institutes of Health Stroke Scale (NIH-SS) score and the Karnofsky Performance Scale (KPS) score were used for assessing neurological function. RESULTS More frequent complete resections and improved PFS were confirmed, with higher median residual tumor volumes in the WL group (0.5 vs 0 cm(3), p = 0.001). Patients in the ALA group had more frequent deterioration on the NIH-SS at 48 hours. Patients at risk were those with deficits unresponsive to steroids. No differences were found in the KPS score. Regarding outcome, a combined end point of risks and neurological deficits was attempted, which demonstrated results in patients in the ALA group to be superior to those in participants in the WL group. Interestingly, the cumulative incidence of repeat surgery was significantly reduced in ALA patients. When stratified by completeness of resection, patients with incomplete resections were quicker to deteriorate neurologically (p = 0.0036). CONCLUSIONS Extended resections performed using a tool such as 5-ALA-derived tumor fluorescence, carries the risk of temporary impairment of neurological function. However, risks are higher in patients with deficits unresponsive to steroids.

Glioblastoma therapy in the elderly and the importance of the extent of resection regardless of age

OBJECT The objective of this study was to analyze whether age influences the outcome of patients with glioblastoma and whether elderly patients with glioblastoma can tolerate the same aggressive treatment as younger patients. METHODS Data from 361 consecutive patients with newly diagnosed cerebral glioblastoma (2000-2006) who underwent regular follow-up evaluation from initial diagnosis until death were prospectively entered into a database. Patients underwent resection (complete, subtotal, or partial) or biopsy, depending on tumor size, location, and Karnofsky Performance Scale score. Following surgery, all patients underwent adjuvant treatment consisting of radiotherapy, chemotherapy, or combined treatment. Patients older than 65 years of age were defined as elderly (146 total). RESULTS Two hundred thirty-four patients underwent tumor resection (complete 26%, subtotal 29%, and partial 45%). One hundred twenty-seven underwent biopsy. Mean patient age was 61 years, and overall survival was 11.6 ± 12.1 months. The overall survival of elderly patients (9.1 ± 11.6 months) was significantly lower than that of younger patients (14.9 ± 16.7 months; p = 0.0001). Stratifying between resection or biopsy, age was a negative prognostic factor in patients undergoing biopsy (4.0 ± 7.1 vs 7.9 ± 8.7 months; p = 0.007), but not in patients undergoing tumor resection (13.0 ± 8.5 vs 13.3 ± 14.5 months; p = 0.86). Survival of elderly patients undergoing complete tumor resection was 17.7 ± 8.1 months. CONCLUSIONS In this series of patients with glioblastoma, age was a prognostic factor in patients undergoing biopsy, but not in patients undergoing resection. Tumor location and patient clinical status may prohibit extensive resection, but resection should not be withheld from patients only on the basis of age. In elderly patients with glioblastoma, undergoing resection to the extent feasible, followed by adjuvant therapies, is warranted.

Usefulness of intraoperative ultra low-field magnetic resonance imaging in glioma surgery.

OBJECTIVE The aim of this study was to demonstrate the usefulness of a mobile, intraoperative 0.15-T magnetic resonance imaging (MRI) scanner in glioma surgery. METHODS We analyzed our prospectively collected database of patients with glial tumors who underwent tumor resection with the use of an intraoperative ultra low-field MRI scanner (PoleStar N-20; Odin Medical Technologies, Yokneam, Israel/Medtronic, Louisville, CO). Sixty-three patients with World Health Organization Grade II to IV tumors were included in the study. All patients were subjected to postoperative 1.5-T imaging to confirm the extent of resection. RESULTS Intraoperative image quality was sufficient for navigation and resection control in both high- and low-grade tumors. Primarily enhancing tumors were best detected on T1-weighted imaging, whereas fluid-attenuated inversion recovery sequences proved best for nonenhancing tumors. Intraoperative resection control led to further tumor resection in 12 (28.6%) of 42 patients with contrast-enhancing tumors and in 10 (47.6%) of 21 patients with noncontrast-enhancing tumors. In contrast-enhancing tumors, further resection led to an increased rate of complete tumor resection (71.2 versus 52.4%), and the surgical goal of gross total removal or subtotal resection was achieved in all cases (100.0%). In patients with noncontrast-enhancing tumors, the surgical goal was achieved in 19 (90.5%) of 21 cases, as intraoperative MRI findings were inconsistent with postoperative high-field imaging in 2 cases. CONCLUSION The use of the PoleStar N-20 intraoperative ultra low-field MRI scanner helps to evaluate the extent of resection in glioma surgery. Further tumor resection after intraoperative scanning leads to an increased rate of complete tumor resection, especially in patients with contrast-enhancing tumors. However, in noncontrast- enhancing tumors, the intraoperative visualization of a complete resection seems less specific, when compared with postoperative 1.5-T MRI.

ERGO: A pilot study of ketogenic diet in recurrent glioblastoma

Limiting dietary carbohydrates inhibits glioma growth in preclinical models. Therefore, the ERGO trial (NCT00575146) examined feasibility of a ketogenic diet in 20 patients with recurrent glioblastoma. Patients were put on a low-carbohydrate, ketogenic diet containing plant oils. Feasibility was the primary endpoint, secondary endpoints included the percentage of patients reaching urinary ketosis, progression-free survival (PFS) and overall survival. The effects of a ketogenic diet alone or in combination with bevacizumab was also explored in an orthotopic U87MG glioblastoma model in nude mice. Three patients (15%) discontinued the diet for poor tolerability. No serious adverse events attributed to the diet were observed. Urine ketosis was achieved at least once in 12 of 13 (92%) evaluable patients. One patient achieved a minor response and two patients had stable disease after 6 weeks. Median PFS of all patients was 5 (range, 3–13) weeks, median survival from enrollment was 32 weeks. The trial allowed to continue the diet beyond progression. Six of 7 (86%) patients treated with bevacizumab and diet experienced an objective response, and median PFS on bevacizumab was 20.1 (range, 12–124) weeks, for a PFS at 6 months of 43%. In the mouse glioma model, ketogenic diet alone had no effect on median survival, but increased that of bevacizumab-treated mice from 52 to 58 days (p<0.05). In conclusion, a ketogenic diet is feasible and safe but probably has no significant clinical activity when used as single agent in recurrent glioma. Further clinical trials are necessary to clarify whether calorie restriction or the combination with other therapeutic modalities, such as radiotherapy or anti-angiogenic treatments, could enhance the efficacy of the ketogenic diet.

Postoperative radiotherapy and concomitant temozolomide for elderly patients with glioblastoma

BACKGROUND The addition of temozolomide (TMZ) to radiotherapy (RT) improves survival of patients with glioblastoma (GB) when compared to postoperative RT alone in patients up to 65 years of age. In older patients, RT alone has remained the standard of care because there is concern that radiochemotherapy causes excess toxicity and is less efficacious in this population, but no randomized trials have been reported. We retrospectively assessed feasibility, toxicity and outcome in elderly patients treated at a single institution with RT and concomitant TMZ. PATIENT AND METHODS Between 04/1999 and 9/2009, 51 patients ≥65 years (median age 70 years, range 65-84) with GB were treated by RT (total dose 60 Gy in 30 fractions) and concomitant TMZ (75 mg/m(2)/day throughout RT). Biopsy only had been performed in 23 patients (45.1%), 15 patients (29.4%) had undergone partial resection, and 13 patients (25.5%) macroscopically complete resection. Adjuvant TMZ was applied in 10 of 51 patients. RESULTS Median overall survival (OS) and progression-free survival (PFS) were 11.5 (95% CI, 6.7-16.3) and 5.5 months (95% CI, 3.7-7.3 months), respectively, in the total cohort. After complete resection, partial resection and biopsy, median OS was 27.4, 15.5 and 7.9 months (p=0.002), respectively. In multivariate Cox proportional hazards regression models extent of resection (p<0.0001) and Karnofskys performance score (p=0.002) were significant independent prognostic factors for OS. RT with concomitant TMZ was well tolerated in the majority of patients and could be completed as scheduled in 30 patients (59%). Five patients (10%) discontinued RT because of disease progression (n=4) or toxicity (pneumonia, n=1). Another 16 patients interrupted concomitant chemotherapy (cytopenia: 9; pneumonia: 2; transaminase elevation: 2; rash: 3). CONCLUSION RT with concomitant TMZ is a feasible regimen with acceptable toxicity in elderly patients. The promising outcome in patients with good performance status and patients with gross total resections are notable.

Low field intraoperative MRI-guided surgery of gliomas: A single center experience

INTRODUCTION The aim of this article is to report on our experience in using a low field intraoperative MRI (iMRI) system in glioma surgery and to summarize the hitherto use and benefits of iMRI in glioma surgery. PATIENTS AND METHODS Between July 2004 and May 2009, a total of 103 patients harboring gliomas underwent tumor resection with the use of a mobile low field iMRI in our institution. Surgeries were performed as standard micro-neurosurgical procedures using regular instrumentarium. All patients underwent early postoperative high field MRI to determine the extent of resection. Adjuvant treatment was conducted according to histopathological grading and standard of care. RESULTS All tumors could be reliably visualized on intraoperative imaging. Intraoperative imaging revealed residual tumor tissue in 51 patients (49.5%), leading to further tumor resection in 31 patients (30.1%). Extended resection did not translate into a higher rate of neurological deficits. When analyzing survival of patients with glioblastoma, patients undergoing complete tumor resection did significantly better than patients with residual tumor (50% survival rate at 57.8 weeks vs. 33.8 weeks, log rank test p=0.003), while younger age did not influence survival (p=0.12). CONCLUSION Low field iMRI is a helpful tool in modern neurosurgery and facilitates brain tumor resection to a maximum safe extent. Its use translates into a better prognosis for these patients with devastating tumors. Future studies covering the use of iMRI will need to be conducted in a prospective, randomized fashion to prove the true benefit of iMRI in glioma surgery.

Influence of iMRI-guidance on the extent of resection and survival of patients with glioblastoma multiforme.

Intraoperative MRI (iMRI) is used in glioma surgery mainly to determine the extent of resection, allowing surgeons to immediately continue resection in case of residual tumor tissue. The aim of this study is to report on the influence of the use of iMRI on the extent of resection and survival of patients with glioblastoma multiforme (GBM). We analyzed our prospectively collected database of patients with GBM operated upon during the initial period after installation of an iMRI; between July 2004 and December 2005, all patients with GBM undergoing intended complete tumor resection were included in this study, while patients undergoing mere tumor biopsy or intended incomplete resection were not. In total, 43 Patients met the inclusion criteria. Of these, 10 patients (23.3%) were operated upon with the help of iMRI while 33 underwent conventional tumor resection. All patients underwent postoperative high-field MR imaging at 1.5 Tesla to determine the extent of resection. Subsequently, all patients received adjuvant treatment. Median patient age was 60.0 years; median overall survival was 70.7 weeks. Radiologically complete tumor resection (P < 0.001) and the administration of temozolomide chemotherapy (P < 0.01) were statistically significant prognostic factors in a multivariate analysis. The rate of complete tumor resections was significantly higher in the iMRI group than in the conventional surgery group (P < 0.05). Patient age was not a prognostic factor in our series of patients (P = 0.22). Intraoperative MRI is a helpful tool to increase the extent of resection in GBM surgery and thereby improve patient survival.