P14.62 Overall survival from glioblastoma: partial resection versus biopsy

BACKGROUND Maximal safe resection is standard of care in patients with glioblastoma. Partial resection or biopsy are alternative surgical approaches when macroscopic complete resection is unachievable. Survival benefit from partial resection remains uncertain. We aimed to evaluate overall survival from glioblastoma in patients having undergone partial resection compared to biopsy. MATERIAL AND METHODS We retrospectively identified all patients with histologically confirmed glioblastoma having undergone partial resection or biopsy in Western Norway between 1.1.2007 and 31.12.2014. Clinical characteristics and radiology reports were extracted from electronic medical records. Categorical data were compared by chi square test or Fishers exact test, and continuous data by non-parametric tests. Kaplan Meier method and log rank test were used for survival analyses. RESULTS We identified 158 patients diagnosed with glioblastoma and having undergone biopsy or partial resection. Biopsy was performed in 52 patients (32.9%) and partial resection in 106 patients (67.1%). Median age (range) was 62.5 (18.1–82.3) in the biopsy group and 62.2 (27.9–85.1) in the partial resection group (p=0.90). Median Charlson comorbidity score was four in both groups. Multifocality was observed in 46.2% of patients in the biopsy group, compared to 27.4% of patients in the partial resection group (p=0.02). Deep-seated tumour localisation was also more frequent in the biopsy group than in the partial resection group, seen in 17.3% vs 5.7% of the patients (p=0.04). There was no difference in chemoradiotherapy (CRT) treatment between the groups. CRT according to the Stupp protocol, less intensive CRT and best supportive care was performed in 36.5%, 50.0% and 13.5% of patients in the biopsy group, compared to 45.3%, 49.1% and 5.7% in the partial resection group (p=0.20). Median overall survival in the biopsy group was 8.1 months (95% CI 5.2–11.1) compared to 11.1 months (95% CI 9.4–12.8) in the partial resection group (p=0.19). Median survival in the biopsy group was 13.8 months (95% CI 10.1–17.5), 6.5 months (95% CI 3.6–9.4), and 3.5 months (95% CI 0.0–7.7) for patients receiving CRT according to Stupp protocol, less-intensive CRT and best supportive care, respectively (p<0.001). The corresponding numbers in the partial resection group were 15.1 months (95% CI 13.2–16.9), 9.1 months (95% CI 7.5–10.6), and 1.5 month (95% CI 0.0–4.7) (p<0.001). CONCLUSION Median overall survival was slightly longer in patients having undergone partial resection compared to biopsy, however not statistically significant. Prospective studies are needed to evaluate the survival benefit from partial resection.

P14.24 Estimating survival outcomes in elderly (70+ years) patients with primary glioblastoma

BACKGROUND Elderly patients with glioblastoma are perceived to face a poor prognosis, with perceptions around older age and a relative lack of randomized data raising a concern about their undertreatment. The EANO guidelines recommend >70-year-old patients with good performance status to undergo maximal safe resection followed by hypofractionated (40 Gy in 15 fractions, i.e. RT40/15) radiotherapy with or without concurrent and adjuvant Temozolomide (TMZ), depending on MGMT promoter methylation. This study evaluated the relative survival impact of biological, histological, surgical and oncological factors and aimed to devise a scoring system to estimate the survival of elderly glioblastoma patients, with an aim to more accurately guide treatment in this cohort. METHODS The records of 169 elderly (≥70 years) patients with a new diagnosis of IDH-wild type glioblastoma were retrospectively examined for gender, age, WHO performance status (PS), comorbidities, MGMT methylation, surgical intervention and chemoradiation regime. The adjusted survival impact of these factors was determined using Cox proportional hazards model and used to devise a two-stage scoring system to estimate survival of patients at the stage of surgical (Elderly Glioblastoma Surgical Score, EGSS) and oncological management (Elderly Glioblastoma Oncological Score, EGOS). RESULTS The overall median survival (MS) of the cohort was 28.8 weeks. Subtotal resection (MS=27.7 weeks, 95%CI 24.1–31.6 weeks, HR=0.58) and gross-total resection (MS=77.8 weeks, 95%CI 67.0–88.6 weeks, HR=0.36) were associated with significant overall survival benefit compared to biopsy alone (MS=18.2 weeks, 95%CI 15.7–20.7 weeks, HR=5.23), p<0.05. Hypofractionated radiation with Temozolomide (RT40/15+TMZ, MS=60.9 weeks, 95%CI 49.9–71.8 weeks, HR=0.13) was non-inferior to the Stupp protocol (RT60/30+TMZ, MS=50.6 weeks, 95%CI 32.4–66.7 weeks, HR=0.11), p=0.72. Negative prognosticators included age above 75 years, biopsy alone and no chemoradiotherapy. Subgroup analysis revealed that MGMT unmethylated 70–75 year old patients who received the Stupp protocol had significantly improved overall survival (MS=57.6 weeks, 95%CI 27.7–88.1 weeks) compared to standard of care RT40/15 alone (MS=29.7 weeks, 95%CI 7.1–51.6 weeks), p=0.002. EGSS and EGOS scores estimated survival with 65% and 73% accuracy, respectively. CONCLUSION When appropriate and safe, a subgroup of elderly glioblastoma patients may benefit from more aggressive surgical and oncological management. The proposed EGSS and EGOS scores takes into account important prognostic factors to help guide which patients should receive such treatment.

Expression Analysis of α5 Integrin Subunit Reveals Its Upregulation as a Negative Prognostic Biomarker for Glioblastoma

Integrin α5β1 was suggested to be involved in glioblastoma (GBM) aggressiveness and treatment resistance through preclinical studies and genomic analysis in patients. However, further protein expression data are still required to confirm this hypothesis. In the present study, we investigated by immunofluorescence the expression of integrin α5 and its prognostic impact in a glioblastoma series of patients scheduled to undergo the Stupp protocol as first-line treatment for GBM. The integrin α5 protein expression level was estimated in each tumor by the mean fluorescence intensity (MFI) and allowed us to identify two subpopulations showing either a high or low expression level. The distribution of patients in both subpopulations was not significantly different according to age, gender, recursive partitioning analysis (RPA) prognostic score, molecular markers or surgical and medical treatment. A high integrin α5 protein expression level was associated with a high risk of recurrence (HR = 1.696, 95% CI 1.031–2.792, p = 0.0377) and reduced overall survival (OS), even more significant in patients who completed the Stupp protocol (median OS: 15.6 vs. 22.8 months; HR = 2.324; 95% CI 1.168–4.621, p = 0.0162). In multivariate analysis, a high integrin α5 protein expression level was confirmed as an independent prognostic factor in the subpopulation of patients who completed the temozolomide-based first-line treatment for predicting OS over age, extent of surgery, RPA score and O-6-methylguanine-DNA methyltransferase (MGMT) promoter methylation (p = 0.029). In summary, for the first time, our study validates that a high integrin α5 protein expression level is associated with poor prognosis in GBM and confirms its potential as a therapeutic target implicated in the Stupp protocol resistance.

C-methionine-PET-guided Gamma Knife radiosurgery boost as adjuvant treatment for newly diagnosed glioblastomas

Background: The most common glial tumor is the glioblastoma, and the prognosis remains dismal despite a multimodal therapeutic approach. The role of radiosurgery for the treatment of glioblastomas has been evaluated in several studies with some benefit at the recurrent stage. We evaluate the results of the protocol administered at the Gamma Knife unit administering radiosurgery as a boost to metabolic active parts of the tumor after the patient had completed traditional external beam radiotherapy (XBRT) as part of the Stupp protocol for high-grade gliomas. Methods: This is a retrospective analysis of seven patients with newly diagnosed glioblastomas who were treated with Gamma Knife radiosurgery as a boost after receiving XBRT as part of the Stupp protocol. The target of radiation was determined according to the findings of the C-methionine PET scan in relation to magnetic resonance images. The primary end point of this study was to determine the progression-free survival (PFS) from the time of diagnosis. Results: The median age of patients was 48.8 years and the mean Karnofsky performance score was 92.8%. The median PFS was 12.4 months. No radiation adverse effects were documented. Conclusion: Stereotactic radiosurgery is safe to use in the upfront treatment for these patients and appears to have a beneficial role in improving the PFS. This beneficial role seems to be conditioned not only by the time the treatment is administered but also where the radiation dose is targeted to.

Treatment approach and survival from glioblastoma: results from a population-based retrospective cohort study from Western Norway

ObjectivesTo evaluate treatment and survival from glioblastoma in a real-world setting.Design and settingsA population-based retrospective cohort study from Western Norway.Participants363 patients aged 18 years or older diagnosed with glioblastoma between 1 January 2007 and 31 December 2014.Primary and secondary outcome measuresOverall survival and survival rates determined by Kaplan-Meier method, groups compared by log-rank test. Associations between clinical characteristics and treatment approach assessed by logistic regression. Associations between treatment approach and outcome analysed by Cox regression.ResultsMedian overall survival was 10.2 months (95% CI 9.1 to 11.3). Resection was performed in 221 patients (60.9%), and was inversely associated with age over 70 years, higher comorbidity burden, deep-seated tumour localisation and multifocality. Median survival was 13.7 months (95% CI 12.1 to 15.4) in patients undergoing tumour resection, 8.3 months (95% CI 6.6 to 9.9) in patients undergoing biopsy and 4.5 months (95% CI 4.0 to 5.1) in patients where no surgical intervention was performed. Chemoradiotherapy according to the Stupp protocol was given to 157 patients (43%). Age over 70 years, higher comorbidity burden and cognitive impairment were associated with less intensive chemoradiotherapy. Median survival was 16.3 months (95% CI 14.1 to 18.5), 7.9 months (95% CI 6.7 to 9.0) and 2.0 months (95% CI 0.9 to 3.2) in patients treated according to the Stupp protocol, with less intensive chemoradiotherapy and with best supportive care, respectively. Surgical resection (HR 0.61 (95% CI 0.47 to 0.79)) and chemoradiotherapy according to the Stupp protocol (HR 0.09 (95% CI 0.06 to 0.15)) were strongly associated with favourable overall survival, when adjusted for clinical variables.ConclusionsIn a real-world setting, less than half of the patients received full-course chemoradiotherapy, with a median survival comparable to results from clinical trials. Survival was considerably worse in patients receiving less intensive treatment. Our results point out a substantial risk of undertreating glioblastoma, especially in elderly patients.

Reuse of Molecules for Glioblastoma Therapy

Glioblastoma multiforme (GBM) is a highly malignant primary brain tumor. The current standard of care for GBM is the Stupp protocol which includes surgical resection, followed by radiotherapy concomitant with the DNA alkylator temozolomide; however, survival under this treatment regimen is an abysmal 12–18 months. New and emerging treatments include the application of a physical device, non-invasive ‘tumor treating fields’ (TTFs), including its concomitant use with standard of care; and varied vaccines and immunotherapeutics being trialed. Some of these approaches have extended life by a few months over standard of care, but in some cases are only available for a minority of GBM patients. Extensive activity is also underway to repurpose and reposition therapeutics for GBM, either alone or in combination with the standard of care. In this review, we present select molecules that target different pathways and are at various stages of clinical translation as case studies to illustrate the rationale for their repurposing-repositioning and potential clinical use.

Systemic Inflammation Response Index Predicts Survival Outcomes in Glioblastoma Multiforme Patients Treated with Standard Stupp Protocol

Objectives. We endeavored to retrospectively assess the prognostic merit of pretreatment systemic immune response index (SIRI) in glioblastoma multiforme (GBM) patients who underwent postoperative partial brain radiotherapy (RT) and concurrent plus adjuvant temozolomide (TMZ), namely, the Stupp protocol. Methods. The records of 181 newly diagnosed GBM patients who received the postoperative Stupp protocol were retrospectively analyzed. The SIRI value for each eligible patient was calculated by utilizing the platelet, neutrophil, and lymphocyte measures obtained on the first day of treatment: SIRI = Neutrophils × Monocytes / Lymphocytes . The ideal cutoff values for SIRI connected with the progression-free- (PFS) and overall survival (OS) results were methodically searched through using the receiver operating characteristic (ROC) curve analysis. Primary and secondary end-points constituted the potential OS and PFS distinctions among the SIRI groups, respectively. Results. The ROC curve analysis labeled the ideal SIRI cutoffs at 1.74 (Area under the curve (AUC): 74.9%; sensitivity: 74.2%; specificity: 71.4%) and 1.78 (AUC: 73.6%; sensitivity: 73.1%; specificity: 70.8%) for PFS and OS status, individually. The SIRI cutoff of 1.78 of the OS status was chosen as the common cutoff for the stratification of the study population (Group 1: SIRI ≤ 1.78 ( N = 96 ) and SIRI > 1.78 ( N = 85 )) and further comparative PFS and OS analyses. Comparisons between the two SIRI cohorts manifested that the SIRI ≤ 1.78 cohort had altogether significantly superior median PFS (16.2 versus 6.6 months; P < 0.001 ) and OS (22.9 versus 12.2 months; P < 0.001 ) than its SIRI > 1.78 counterparts. The results of multivariate Cox regression analyses ratified the independent and significant alliance between a low SIRI and longer PFS ( P < 0.001 ) and OS ( P < 0.001 ) durations, respectively. Conclusions. Present results firmly counseled the pretreatment SIRI as a novel, sound, and independent predictor of survival outcomes in newly diagnosed GBM patients intended to undergo postoperative Stupp protocol.

Practical Review on Preclinical Human 3D Glioblastoma Models: Advances and Challenges for Clinical Translation

Fifteen years after the establishment of the Stupp protocol as the standard of care to treat glioblastomas, no major clinical advances have been achieved and increasing patient’s overall survival remains a challenge. Nevertheless, crucial molecular and cellular findings revealed the intra-tumoral and inter-tumoral complexities of these incurable brain tumors, and the essential role played by cells of the microenvironment in the lack of treatment efficacy. Taking this knowledge into account, fulfilling gaps between preclinical models and clinical samples is necessary to improve the successful rate of clinical trials. Since the beginning of the characterization of brain tumors initiated by Bailey and Cushing in the 1920s, several glioblastoma models have been developed and improved. In this review, we focused on the most widely used 3D human glioblastoma models, including spheroids, tumorospheres, organotypic slices, explants, tumoroids and glioblastoma-derived from cerebral organoids. We discuss their history, development and especially their usefulness.