Tag: Glioblastoma

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Management and outcome of high-grade multicentric gliomas

Management and outcome of high-grade multicentric gliomas

Acta Neurochir (2013) 155:2245–2251

Multicentric malignant gliomas are wellseparated tumours in different lobes or hemispheres, without anatomical continuity between lesions. The purpose of this study was to explore the clinical features, the pathology and the outcome according to the management strategies in a consecutive series of patients treated at a single institution. In addition, an analysis of the existing literature is presented.

Methods For the institutional analysis, a retrospective review of all patients who underwent treatment for multicentric gliomas in the last 7 years was performed. For the analysis of the literature, a MEDLINE search with no date limitations was accomplished for surgical treatment of multicentric malignant gliomas.

Results Two hundred and thirty-nine patients with glioma were treated in our department. Eighteen patients (7.5%) with a mean age of 64 years (age range, 37–78 years) presented multicentric malignant gliomas. Thirteen patients (72 %) underwent surgical resection of at least one lesion that was followed by adjuvant treatment in all but one case. Five patients (28 %) underwent stereotactic biopsy and thereafter received chemotherapy. A survival advantage was associated with resection of at least one lesion followed by adjuvant treatment (median overall survival 12 months) compared with 4 months for stereotactic biopsy followed by chemotherapy. Similar results were obtained from the review of the literature.

Conclusions Resection of at least one lesion seems to play a significant role in the management of selected patients with multicentric malignant gliomas. Multi-institutional studies on larger series are warranted to define how aggressively the patients with malignant multicentric gliomas should be treated.

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Blood-based biomarkers for malignant gliomas

Blood-based biomarkers for malignant gliomas

J Neurooncol (2013) 113:345–352

Malignant gliomas remain incurable and present unique challenges to clinicians, radiologists and clinical and translational investigators. One of the major problems in treatment of these tumors is our limited ability to reliably assess tumor response or progression.

The most frequently used neuro-imaging studies (contrast-enhanced MRI and CT) rely on changes of blood–brain barrier (BBB) integrity, providing only an indirect assessment of tumor burden. In addition, the BBB can be altered by commonly used interventions including radiation, glucocorticoids and vascular endothelial growth factor inhibitors, further complicating the interpretation of scans. Newer radiologic techniques including PET and magnetic resonance spectroscopy are theoretically promising but thus far have not meaningfully changed the assessment of patients with malignant gliomas. A tumor-specific, bloodbased biomarker would be of immediate use to clinicians and investigators if sufficiently sensitive and specific.

This review discusses the potential utility of such a biomarker, the general classes of tumor-derived blood-based biomarkers and it summarizes the currently available data on circulating tumor cells, circulating nucleic acids and circulating proteins in patients with malignant gliomas. It is unclear which marker or marker class appears to be the most promising for these tumors.

This article provides thoughts on how novel candidate blood-based markers could be discovered and tested in a more comprehensive way and why these efforts should be among the top priorities in neuro-oncologic research in the coming years.

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Prognostic Value of Residual Fluorescent Tissue in Glioblastoma Patients After Gross Total Resection in 5-Aminolevulinic Acid-Guided Surgery

Prognostic_Value_of_Residual_Fluorescent_Tissue_in

Neurosurgery 72:915–921, 2013

There is evidence in the literature supporting that fluorescent tissue signal in fluorescence-guided surgery extends farther than tissue highlighted in gadolinium in T1 sequence magnetic resonance imaging (MRI), which is the standard to quantify the extent of resection.

OBJECTIVE: To study whether the presence of residual fluorescent tissue after surgery carries a different prognosis for glioblastoma (GBM) cases with complete resection confirmed by MRI.

METHODS: A retrospective review in our center found 118 consecutive patients with high-grade gliomas operated on with the use of fluorescence-guided surgery with 5-aminolevulinic acid. Within that series, the 52 patients with newly diagnosed GBM and complete resection of enhancing tumor (CRET) in early MRI were selected for analysis. We studied the influence of residual fluorescence in the surgical field on overall survival and neurological complication rate. Multivariate analysis included potential relevant factors: age, Karnofsky Performance Scale, O6-methylguanine methyltransferase methylation promoter status, tumor eloquent location, preoperative tumor volume, and adjuvant therapy.

RESULTS: The median overall survival was 27.0 months (confidence interval = 22.4-31.6) in patients with nonresidual fluorescence (n = 25) and 17.5 months (confidence interval = 12.5-22.5) for the group with residual fluorescence (n = 27) (P = .015). The influence of residual fluorescence was maintained in the multivariate analysis with all covariables, hazard ratio = 2.5 (P = .041). The neurological complication rate was 18.5% in patients with nonresidual fluorescence and 8% for the group with residual fluorescence (P = .267).

CONCLUSION: GBM patients with CRET in early MRI and no fluorescent residual tissue had longer overall survival than patients with CRET and residual fluorescent tissue.

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Results of the NeuroBlate System first-in-humans Phase I clinical trial for recurrent glioblastoma

 

NeuroBlate

J Neurosurg 118:1202–1219, 2013

Laser interstitial thermal therapy has been used as an ablative treatment for glioma; however, its development was limited due to technical issues. The NeuroBlate System incorporates several technological advances to overcome these drawbacks. The authors report a Phase I, thermal dose–escalation trial assessing the safety and efficacy of NeuroBlate in recurrent glioblastoma multiforme (rGBM).

Methods. Adults with suspected supratentorial rGBM of 15- to 40-mm dimension and a Karnofsky Performance Status score of ≥ 60 were eligible. After confirmatory biopsy, treatment was delivered using a rigid, gas-cooled, sidefiring laser probe. Treatment was monitored using real-time MRI thermometry, and proprietary software providing predictive thermal damage feedback was used by the surgeon, along with control of probe rotation and depth, to tailor tissue coagulation. An external data safety monitoring board determined if toxicity at lower levels justified dose escalation.

Results. Ten patients were treated at the Case Comprehensive Cancer Center (Cleveland Clinic and University Hospitals–Case Medical Center). Their average age was 55 years (range 34–69 years) and the median preoperative Karnofsky Performance Status score was 80 (range 70–90). The mean tumor volume was 6.8 ± 5 cm3 (range 2.6–19 cm3), the percentage of tumor treated was 78% ± 12% (range 57%–90%), and the conformality index was 1.21 ± 0.33 (range 1.00–2.04). Treatment-related necrosis was evident on MRI studies at 24 and 48 hours. The median survival was 316 days (range 62–767 days). Three patients improved neurologically, 6 remained stable, and 1 worsened. Steroid-responsive treatment-related edema occurred in all patients but one. Three had Grade 3 adverse events at the highest dose.

Conclusions. NeuroBlate represents new technology for delivering laser interstitial thermal therapy, allowing controlled thermal ablation of deep hemispheric rGBM. Clinical trial registration no.: NCT00747253 (ClinicalTrials. gov).

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Multiple resections for patients with glioblastoma: prolonging survival

Prolonged survival GBM

J Neurosurg 118:812–820, 2013

Glioblastoma is the most common and aggressive type of primary brain tumor in adults. These tumors recur regardless of intervention. This propensity to recur despite aggressive therapies has made many perceive that repeated resections have little utility. The goal of this study was to evaluate if patients who underwent repeat resections experienced improved survival as compared with patients with fewer numbers of resections, and whether the number of resections was an independent predictor of prolonged survival.

Methods. The records of adult patients who underwent surgery for an intracranial primary glioblastoma at an academic tertiary-care institution between 1997 and 2007 were retrospectively reviewed. Multivariate proportionalhazards regression analysis was used to identify an association between glioblastoma resection number and survival after controlling for factors known to be associated with survival, such as age, functional status, periventricular location, extent of resection, and adjuvant therapy. Survival as a function of time was plotted using the Kaplan-Meier method, and survival rates were compared using log-rank analysis.

Results. Five hundred seventy-eight patients with primary glioblastoma met the inclusion/exclusion criteria. At last follow-up, 354, 168, 41, and 15 patients underwent 1, 2, 3, or 4 resections, respectively. The median survival for patients who underwent 1, 2, 3, and 4 resections was 6.8, 15.5, 22.4, and 26.6 months (p < 0.05), respectively. In multivariate analysis, patients who underwent only 1 resection experienced shortened survival (relative risk [RR] 3.400, 95% CI 2.423–4.774; p < 0.0001) as compared with patients who underwent 2 (RR 0.688, 95% CI 0.525–0.898; p = 0.0006), 3 (RR 0.614, 95% CI 0.388–0.929; p = 0.02), or 4 (RR 0.600, 95% CI 0.238–0.853; p = 0.01) resections. These results were verified in a case-control evaluation, controlling for age, neurological function, periventricular tumor location, extent of resection, and adjuvant therapy. Patients who underwent 1, 2, or 3 resections had a median survival of 4.5, 16.2, and 24.4 months, respectively (p < 0.05). Additionally, the risk of infections or iatrogenic deficits did not increase with repeated resections in this patient population (p > 0.05).

Conclusions. Patients with glioblastoma will inevitably experience tumor recurrence. The present study shows that patients with recurrent glioblastoma can have improved survival with repeated resections. The findings of this study, however, may be limited by an intrinsic bias associated with patient selection. The authors attempted to minimize these biases by using strict inclusion criteria, multivariate analyses, and case-control evaluation.

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Gross Total Resection Rates in Contemporary Glioblastoma Surgery: Results of an Institutional Protocol Combining 5-Aminolevulinic Acid Intraoperative Fluorescence Imaging and Brain Mapping

Neurosurgery 71:927–936, 2012

Complete resection of contrast-enhancing tumor has been recognized as an important prognostic factor in patients with glioblastoma and is a primary goal of surgery. Various intraoperative technologies have recently been introduced to improve glioma surgery.

OBJECTIVE: To evaluate the impact of using 5-aminolevulinic acid and intraoperative mapping and monitoring on the rate of complete resection of enhancing tumor (CRET), gross total resection (GTR), and new neurological deficits as part of an institutional protocol.

METHODS: One hundred three consecutive patients underwent resection of glioblastoma from August 2008 to November 2010. Eligibility for CRET was based on the initial magnetic resonance imaging assessed by 2 reviewers. The primary end point was the number of patients with CRET and GTR. Secondary end points were volume of residual contrast-enhancing tissue and new postoperative neurological deficits. RESULTS: Fifty-three patients were eligible for GTR/CRET (n = 43 newly diagnosed glioblastoma, n = 10 recurrent); 13 additional patients received surgery for GTR/CRET-ineligible glioblastoma. GTR was achieved in 96% of patients (n = 51, no residual enhancement . 0.175 cm3); CRET was achieved in 89% (n = 47, no residual enhancement). Postoperatively, 2 patients experienced worsening of preoperative hemianopia, 1 patient had a new mild hemiparesis, and another patient sustained sensory deficits.

CONCLUSION: Using 5-aminolevulinic acid imaging and intraoperative mapping/ monitoring together leads to a high rate of CRET and an increased rate of GTR compared with the literature without increasing the rate of permanent morbidity. The combination of safety and resection-enhancing intraoperative technologies was likely to be the major drivers for this high rate of CRET/GTR.

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Prognosis of patients with multifocal glioblastoma

J Neurosurg 117:705–711, 2012

The prognosis of patients with glioblastoma who present with multifocal disease is not well documented. The objective of this study was to determine whether multifocal disease on initial presentation is associated with worse survival.

Methods. The authors retrospectively reviewed records of 368 patients with newly diagnosed glioblastoma and identified 47 patients with multifocal tumors. Each patient with a multifocal tumor was then matched with a patient with a solitary glioblastoma on the basis of age, Karnofsky Performance Scale (KPS) score, and extent of resection, using a propensity score matching methodology. Radiation and temozolomide treatments were also well matched between the 2 cohorts. Kaplan-Meier estimates and log-rank tests were used to compare patient survival.

Results. The incidence of multifocal tumors was 12.8% (47/368). The median age of patients with multifocal tumors was 61 years, 76.6% had KPS scores ≥ 70, and 87.2% underwent either a biopsy or partial resection of their tumors. The 47 patients with multifocal tumors were almost perfectly matched on the basis of age (p = 0.97), extent of resection (p = 1.0), and KPS score (p = 0.80) compared with 47 patients with a solitary glioblastoma. Age (> 65 years), partial resection or biopsy, and low KPS score (< 70) were associated with worse median survival within the multifocal group. In the multifocal group, 19 patients experienced tumor progression on postradiation therapy MRI, compared with 11 patients (26.8%) with tumor progression in the unifocal group (p = 0.08). Patients with multifocal tumors experienced a significantly shorter median overall survival of 6 months (95% CI 4–10 months), compared with the 11-month median survival (95% CI 10–19 months) of the matched solitary glioblastoma group (p = 0.02, log-rank test). Two-year survival rates were 4.3% for patients with multifocal tumors and 29.0% for the unifocal cohort. Patients with newly diagnosed multifocal tumors were found to have an almost 2-fold increase in the hazard of death compared with patients with solitary glioblastoma (hazard ratio 1.8, 95% CI 1.1–3.1; p = 0.02). Tumor samples were analyzed for expression of phosphorylated mitogen-activated protein kinase, phosphatase and tensin homolog, O6-methylguanine-DNA methyltransferase, laminin b1 and b2, as well as epidermal growth factor receptor amplification, and no significant differences in expression profile between the multifocal and solitary glioblastoma groups was found.

Conclusions. Patients with newly diagnosed multifocal glioblastoma on presentation experience significantly worse survival than patients with solitary glioblastoma. Patients with multifocal tumors continue to pose a therapeutic challenge in the temozolomide era and magnify the challenges faced while treating patients with malignant gliomas.

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Safety and efficacy of Gliadel wafers for newly diagnosed and recurrent glioblastoma

Acta Neurochir (2012) 154:1371–1378

Combining Gliadel wafers and radiochemotherapy with TMZ may carry the risk of increased adverse events (AE). We analyzed the efficacy and safety in patients with glioblastoma who underwent multimodal treatment with implantation of Gliadel wafers.

Methods One hundred sixty-five consecutive patients with newly diagnosed (77 patients) or recurrent (88 patients) glioblastoma were studied. Forty-seven patients underwent surgery + Gliadel. The impact of age (≥65 vs. <65), resection extent (gross total vs. partial), use of Gliadel and adjuvant treatment (TMZ vs. other schemes/no adjuvant therapy) on overall survival (OS, for patients with newly diagnosed glioblastoma) and on recurrence-survival (for patients with recurrent glioblastoma) was analyzed with Cox regression. The impact of age, history (newly diagnosed vs. recurrent glioblastoma), number of Gliadel wafers implanted (0 vs. <8 vs. 8), resection extent (gross-total vs. partial) and adjuvant treatment (TMZ vs. other schemes/no adjuvant therapy) on the occurrence of AE and on the occurrence of implantation site-related AE (ISAE) was analyzed with the logistic regression model. Significance was set at p<0.05.

Results Multivariate analysis showed the only factor associated with longer survival, both for newly diagnosed and for recurrent GBM, was resection extent. Both patients with a higher number of wafers implanted and patients with recurrent tumors were significantly at risk for AE and ISAE. Patients with eight Gliadel wafers implanted had a 3-fold increased risk of AE and a 5.6-fold increased risk of ISAE, and patients with recurrent tumor had a 2.8-fold increased risk of AE and a 9.3-fold increased risk of ISAE.

Conclusions Adding Gliadel to standard treatment did not significantly improve the outcome. The toxicity after Gliadel use was significantly higher, both for patients with newly diagnosed and patients with recurrent glioblastoma.

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

J Neurosurg 116:357–364, 2012. DOI: 10.3171/2011.8.JNS102114

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.

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A clinical trial of bevacizumab, temozolomide, and radiation for newly diagnosed glioblastoma

J Neurosurg 116:341–345, 2012.DOI: 10.3171/2011.9.JNS11656

The presence of angiogenesis is a hallmark of glioblastoma (GBM). Vascular endothelial growth factor (VEGF), which drives angiogenesis, provides an additional target for conventional therapy. The authors conducted a prospective clinical trial to test the effectiveness of bevacizumab, an inhibitor of VEGF, in newly diagnosed GBM.

Methods. From 2006 through 2010, 51 eligible patients with newly diagnosed GBM were treated with involvedfield radiation therapy and concomitant temozolomide (75 mg/m2 daily for 42 days) along with bevacizumab (10 mg/ kg every 2 weeks), starting 29 days after surgery. This was followed by 6 cycles of adjuvant temozolomide therapy (150 mg/m2 on Days 1–7 of a 28-day cycle) with bevacizumab administered at 10 mg/kg on Days 8 and 22 of each 28-day cycle.

Results. The 6- and 12-month progression-free survival (PFS) rates were 85.1% and 51%, respectively. The 12- and 24-month overall survival (OS) rates were 85.1% and 42.5%, respectively. Grade III/IV toxicities were noted in 10 patients (19.6%). No treatment-related deaths were observed. Asymptomatic intracranial bleeding was noted in 5 patients.

Conclusions. The addition of bevacizumab to conventional therapy in newly diagnosed GBM appears to improve both PFS and OS in patients with newly diagnosed GBM, with acceptable morbidity. A shift toward diffuse relapse was noted in a significant number of patients. Ongoing Phase III clinical trials will show the true benefit of this antiangiogenic approach.

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Regression of Recurrent Malignant Gliomas With Convection-Enhanced Delivery of Topotecan

Neurosurgery 69:1272–1280, 2011 DOI: 10.1227/NEU.0b013e3182233e24

Convection-enhanced delivery of chemotherapeutics for the treatment of malignant glioma is a technique that delivers drugs directly into a tumor and the surrounding interstitium through continuous, low-grade positive-pressure infusion. This allows high local concentrations of drug while overcoming the limitations imposed by toxicity and the blood-brain barrier in systemic therapies that prevent the use of many potentially effective drugs.

OBJECTIVE: To examine the safety profile of a conventional chemotherapeutic agent, topotecan, via convection-enhanced delivery in the treatment of recurrent malignant gliomas and secondarily to assess radiographic response and survival.

METHODS: We performed a prospective, dose-escalation phase Ib study of the topoisomerase- I inhibitor topotecan given by convection-enhanced delivery in patients with recurrent malignant gliomas.

RESULTS: Significant antitumor activity as described by radiographic changes and prolonged overall survival with minimal drug-associated toxicity was demonstrated. A maximum tolerated dose was established for future phase II studies.

CONCLUSION: Topotecan by convection-enhanced delivery has significant antitumor activity at concentrations that are nontoxic to normal brain. The potential for use of this therapy as a generally effective treatment option for malignant gliomas will be tested in subsequent phase II and III trials

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Postoperative Infection May Influence Survival in Patients With Glioblastoma: Simply a Myth?

Neurosurgery 69:864–869, 2011 DOI: 10.1227/NEU.0b013e318222adfa

It is a prevalent myth that a postoperative infection may actually confer a survival advantage in patients with malignant glioma. This contention is based largely on anecdotal reports. Recently, a single-center study showed there was no survival advantage in those patients who had glioblastoma with postoperative infection.

OBJECTIVE: To examine the impact of postoperative infections on outcome in patients with glioblastoma treated at our center.

METHODS: This study included 197 patients with newly diagnosed primary glioblastoma treated from January 2001 to January 2008. Of the 197 patients, 10 (5.08%) had postoperative bacterial infection. The Kaplan-Meier method, log-rank test, and Breslow test were used in the univariate approach; Cox regression was used in the multivariable approach.

RESULTS: The median survival was 16 months (95% confidence interval [CI], 14-18 mo). The infection group had a significant advantage in the median survival: 30 months (95% CI, 21-39) vs 15 months (95% CI, 13-17) for patients without postoperative infection. This advantage was also confirmed by Cox regression; in fact, patients not developing a postoperative infection showed an adjusted hazard ratio for death of 2.3 (95% CI, 1-5.3).

CONCLUSION: The association between infection and prolonged survival is not definitive; we acknowledge the considerable difficulties in undertaking this type of study in a retrospective manner. Our results can instead stimulate further multicentric studies (to increase the number of patients) or experimental studies using genetically modified bacteria for treatment of glioblastoma.

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Surgery guided by 5-aminolevulinic fluorescence in glioblastoma: volumetric analysis of extent of resection in single-center experience

J Neurooncol (2011) 102:105–113.DOI 10.1007/s11060-010-0296-4

We analyzed the efficacy and applicability of surgery guided by 5-aminolevulinic acid (ALA) fluorescence in consecutive patients with glioblastoma multiforme (GBM).

Thirty-six patients with GBM were operated on using ALA fluorescence. Resections were performed using the fluorescent light to assess the right plane of dissection. In each case, biopsies with different fluorescent quality were taken from the tumor center, from the edges, and from the surrounding tissue. These samples were analyzed separately with hematoxylin–eosin examination and immunostaining against Ki67. Tumor volume was quantified with pre- and postoperative volumetric magnetic resonance imaging.

Strong fluorescence identified solid tumor with 100% positive predictive value. Invaded tissue beyond the solid tumor mass was identified by vague fluorescence with 97% positive predictive value and 66% negative predictive value, measured against hematoxylin–eosin examination. All the contrast-enhancing volume was resected in 83.3% of the patients, all patients had resection over 98% of the volume and mean volume resected was 99.8%. One month after surgery there was no mortality, and new or increased neurological morbidity was 8.2%.

The fluorescence induced by 5-aminolevulinic can help to achieve near total resection of enhancing tumor volume in most surgical cases of GBM. It is possible during surgery to obtain separate samples of the infiltrating cells from the tumor border.

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Identification of diagnostic serum protein profiles of glioblastoma patients

J Neurooncol (2011) 102:71–80.DOI 10.1007/s11060-010-0284-8

Diagnosis of a glioblastoma (GBM) is triggered by the onset of symptoms and is based on cerebral imaging and histological examination. Serum-based biomarkers may support detection of GBM. Here, we explored serum protein concentrations of GBM patients and used data mining to explore profiles of biomarkers and determine whether these are associated with the clinical status of the patients.

Gene and protein expression data for astrocytoma and GBM were used to identify secreted proteins differently expressed in tumors and in normal brain tissues. Tumor expression and serum concentrations of 14 candidate proteins were analyzed for 23 GBM patients and nine healthy subjects. Datamining methods involving all 14 proteins were used as an initial evaluation step to find clinically informative profiles.

Data mining identified a serum protein profile formed by BMP2, HSP70, and CXCL10 that enabled correct assignment to the GBM group with specificity and sensitivity of 89 and 96%, respectively (p< 0.0001, Fischer’s exact test). Survival for more than 15 months after tumor resection was associated with a profile formed by TSP1, HSP70, and IGFBP3, enabling correct assignment in all cases (p< 0.0001, Fischer’s exact test). No correlation was found with tumor size or age of the patient.

This study shows that robust serum profiles for GBM may be identified by data mining on the basis of a relatively small study cohort. Profiles of more than one biomarker enable more specific assignment to the GBM and survival group than those based on single proteins, confirming earlier attempts to correlate  single markers with cancer. These conceptual findings will be a basis for validation in a larger sample size.

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Patterns of Care and Survival in a Retrospective Analysis of 1059 Patients With Glioblastoma Multiforme Treated Between 2002 and 2007: A Multicenter Study by the Central Nervous System Study Group of Airo (Italian Association of Radiation Oncology)

Neurosurgery 67:446-458, 2010 DOI: 10.1227/01.NEU.0000371990.86656.E8

OBJECTIVE: To investigate the pattern of care and outcomes for newly diagnosed glioblastoma in Italy and compare our results with the previous Italian Patterns of Care study to determine whether significant changes occurred in clinical practice during the past 10 years.

METHODS: Clinical, pathological, therapeutic, and survival data regarding 1059 patients treated in 18 radiotherapy centers between 2002 and 2007 were collected and retrospectively reviewed.

RESULTS:Most patients underwent both computed tomography and magnetic resonance imaging either preoperatively (62.7%) or postoperatively (35.5%). Only 123 patients (11.6%) underwent a biopsy. Radiochemotherapy with temozolomide was the most frequent adjuvant treatment (70.7%). Most patients (88.2%) received 3-dimensional conformal radiotherapy. Median survival was 9.5 months. Two- and 5-year survival rates were 24.8% and 3.9%, respectively. Multivariate analysis showed the statistical significance of age, postoperative Karnofsky Performance Status scale score, surgical extent, use of 3-dimensional conformal radiotherapy, and use of chemotherapy. Use of a more aggressive approach was associated with longer survival in elderly patients. Comparing our results with those of the subgroup of patients included in our previous study who were treated between 1997 and 2001, relevant differences were found: more frequent use of magnetic resonance imaging, surgical removal more common than biopsy, and widespread use of 3-dimensional conformal radiotherapy + temozolomide. Furthermore, a significant improvement in terms of survival was noted (P < .001).

CONCLUSION: Changes in the care of glioblastoma over the past few years are documented. Prognosis of glioblastoma patients has slightly but significantly improved with a small but noteworthy number of relatively long-term survivors.

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Neurological outcome of long-term glioblastoma survivors

J Neurooncol (2009) 95:301–305 DOI 10.1007/s11060-009-9946-9

Extended survival of 3 or more years is rare in patients with glioblastoma (GBM) but is becoming more common. Clinical outcome has not been well studied. We reviewed GBM patients at Memorial Sloan-Kettering Cancer Center between 2001 and 2003 who were seen for two or more visits. Patient characteristics and long-term clinical outcomes were reviewed for patients who had survived 3 or more years following diagnosis. Thirty-nine (11%) of 352 GBM patients were identified as long-term survivors. Median survival was 9.15 years (range: 3–18 years). Median age was 47 years (range: 16–69); 13% were 65 years or older. Median KPS was 90 (range: 50–100). One long-term survivor underwent biopsy alone; 19 patients each had either complete or subtotal resection. All received focal radiotherapy (RT) with a median dose of 5940 cGy; 18% received concurrent temozolomide. Adjuvant chemotherapy was administered to 35 (90%). Twelve patients (31%) remained in continuous remission. Twenty-seven had tumor progression a median of 29.2 months after diagnosis (range: 1.2–167 months); 18 had multiple relapses. Median KPS at last follow-up was 70 (range: 40–100); 85% of long-term survivors had at least one significant neurologic deficit. Eleven (28%) had clinically significant RT-induced leukoencephalopathy, 9 (23%) developed RT necrosis and 9 (23%) treatment-related strokes. Treatment-related complications occurred a median of 2.7 years from diagnosis (range: 0.9–11.5 years).

Long-term survivors remain rare, but are found across all age groups despite multiple recurrences; clinically significant delayed complications of treatment are common.

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Long-term survivors of glioblastoma: clinical features and molecular analysis

Acta Neurochir (2009) 151:1349–1358. DOI 10.1007/s00701-009-0387-1

Glioblastoma is a highly lethal neoplasm with a median survival of 12–14 months; only 2–5% of patients survive >3 years.

Methods At our institute, patients with glioblastoma are initially treated with maximum tumor resection followed by radiation and the intravenous injection of nimustine hydrochloride (ACNU).

Results Using this strategy, 18 of 123 (14.6%) patients treated at our hospital survived >3 years; 7 manifested no recurrence, and the other 11 had early recurrence and received additional therapies. To identify factors associated with prolonged survival, we compared these patients with 21 short-term (<1.5 years) glioblastoma survivors. In the long-term survivors, the MGMT promoter methylation was significantly more frequent. The rate of p53 mutation was lower, and the rate of PTEN mutations and the proliferation index were slightly higher in short-term survivors.

Conclusion By multivariate analysis,  we found that a younger age and MGMT promoter methylation were significant favorable factors in patients with glioblastoma.

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Improving the prognosis for patients with glioblastoma: the rationale for targeting Src

J Neurooncol (2009) 95:151–163 DOI 10.1007/s11060-009-9916-2

Glioblastoma is the most common and aggressive form of primary brain tumor. The prognosis for patients diagnosed with glioblastoma is poor, with a median survival of 12–14 months and a 5-year survival rate of <5%. The upfront standard treatment for patients with newly diagnosed glioblastoma, consisting of surgery followed by chemotherapy combined with radiotherapy, provides only short-term survival benefits. Recurrent glioblastoma is an extremely challenging therapeutic setting because of the aggressive and resistant nature of the tumor. A set of key molecular targets in oncology is the Src family of non-receptor protein kinases. Dysregulated signaling via the Src kinases has been shown to underlie glioma-related proliferation, angiogenesis, migration, and survival. Here we review the biologic role of Src in malignant glioma and discuss key preclinical studies demonstrating the potential utility of inhibiting Src in glioma. Proof of clinical benefit is forthcoming from the first clinical studies involving the newest generation of small molecule Src inhibitors currently in clinical trials for recurrent glioblastoma. Blocking Src alone will likely not translate into a significant clinical benefit; thus, strategies for combining Src inhibitors with potential synergistic therapeutic modalities will be discussed. This review focus on dasatinib, the most advanced Src inhibitor being tested in glioblastoma, which is currently in phase I/II trials in this setting.


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