Survival In Recurrent Glioblastoma Research Articles

NIMG-50. TOTAL TUMOR CELLULARITY AND CELLULAR GROWTH RATES ESTIMATED USING A RADIO-PATHOMIC AI MODEL PREDICTS PROGNOSIS AND RESPONSE TO CYTOTOXIC THERAPY IN RECURRENT GBM

Abstract PURPOSE A radio-pathomic machine learning model trained with postmortem tissue samples has recently been developed to estimate tumor cellularity from standard anatomic MR images (Bobholz SA et al. AJNR 2022). The aim of this study was to use this externally developed, machine learning-based model to assess the impact of tumor cellularity and changes in cellularity on survival in recurrent glioblastoma (rGBM) treated with standard cytotoxic therapies. METHODS We retrospectively evaluated 22 cases of rGBM treated with chemotherapy. Radio-pathomic maps of predicted tumor cellularity were generated using the radio-pathomic model using pre- and post-contrast T1-weighted MR images, T2-weighted FLAIR images and apparent diffusion coefficient calculated from diffusion-weighted imaging. Total cellularity was estimated by integrating the cellularity measures within a contrast-enhancing tumor volume of interest. Cellularity growth rates (CGRs) were computed using three pre-treatment scans and available post-treatment scans. Tumor cellularity and CGRs were assessed in terms of their impact on overall survival (OS) using log-rank analysis. RESULTS Patients with baseline tumor cellularity < 8.89x108 cells and those with pre-treatment CGR < 7.55x106 cells/day showed significantly longer OS than those with higher cellularity or CGRs (P = 0.001 and 0.008, respectively). Patients with cellularity < 8.90x108 cells at the 1st follow-up (one month after treatment), those with cellularity at 2nd follow-up < 8.89x108 cells (two months after treatment), post-treatment CGR < 1.51x107 cells/day, and change in CGR after treatment < +5.91x106 cells/day showed significantly longer OS than those with higher values (P = 0.03, < 0.001, < 0.001, = 0.02, respectively). CONCLUSION These preliminary results suggest the potential value of estimating total cellularity within the enhancing tumor as a biomarker for prognosis prediction and cytotoxic therapy effect evaluation in rGBM. Additional analyses with more cases and treatments are warranted.

P11.66.A COMBINATION OF TROFOSFAMIDE AND ETOPOSIDE IN RECURRENT GLIOBLASTOMA

Abstract BACKGROUND Standard of care treatment options at glioblastoma relapse are still not well defined. Few studies indicate that the combination of trofosfamide plus etoposide may be feasible in pediatric glioblastoma patients. In this retrospective analysis, we determined tolerability and feasibility of combined trofosfamide plus etoposide treatment at disease recurrence of adult glioblastoma patients. MATERIAL AND METHODS We collected clinicopathological data from adult recurrent glioblastoma patients treated with the combination of trofosfamide and etoposide for more than four weeks (one course). A cohort of patients receiving empiric treatment at the investigators’ discretion balanced for tumor entity and canonical prognostic factors served as control. RESULTS A total of n=22 recurrent glioblastoma patients were eligible for this analysis. Median progression-free survival (3.1 versus 2.3 months, HR: 1.961, 95% CI: 0.9724-3.9560, p=0.0274) and median overall survival (9.0 versus 5.7 months, HR: 4.687, 95% CI: 2.034-10.800, p=0.0003) were significantly prolonged compared to the control cohort (n=17). In a multivariable Cox regression analysis, treatment with trofosfamide plus etoposide emerged as a significant prognostic marker regarding progression-free and overall survival. We observed high-grade adverse events in n=16/22 (73%) patients with hematotoxicity comprising the majority of adverse events (n=15/16, 94%). Lymphopenia was by far the most commonly observed hematotoxic adverse event (n=11/15, 73%). CONCLUSION This study provides first indication that the combination of trofosfamide plus etoposide is safe in adult glioblastoma patients and may be associated with prolonged survival in recurrent glioblastoma. Our data provide a reasonable rationale for follow-up of a larger cohort in a prospective controlled trial.

LMAP-05 BEVACIZUMAB AND GAMMA KNIFE RADIOSURGERY IN THE TREATMENT OF FIRST-RECURRENCE GLIOBLASTOMA

Abstract Glioblastoma is the most common central nervous system malignancy in adults and remains a uniformly fatal disease despite two decades of developments in surgical management, radiation treatment, chemotherapy, and immunotherapy. There is currently no established standard of care for patients with recurrent glioblastoma following failure of initial Stupp protocol management. In this retrospective cohort study, we set out to determine if the use of bevacizumab and/or Gamma Knife radiosurgery in patients with recurrent disease could have an effect on prolonging progression-free survival (PFS) or overall survival (OS). Patients in the combined treatment group demonstrated longer post-recurrence mean PFS (9.1 ± 6.0 months) and OS (13.5 ± 8.6 months) compared to glioblastoma patients previously reported in the literature, and showed improvements in total OS (p=0.021), total PFS (p=0.057), post-recurrence PFS (p=0.034), and post-recurrence OS (p=0.017) compared to patients who received standalone bevacizumab or Gamma Knife treatment. This study demonstrates that the combined use of an antiangiogenic agent with stereotactic radiosurgery can have significant effects on improving patient survival in recurrent glioblastoma.

Depth of Radiographic Response and Time to Tumor Regrowth Predicts Overall Survival Following Anti-VEGF Therapy in Recurrent Glioblastoma.

Antiangiogenic therapies are known to cause high radiographic response rates due to reduction in vascular permeability resulting in a lower degree of contrast extravasation. In this study, we investigate the prognostic ability for model-derived parameters describing enhancing tumor volumetric dynamics to predict survival in recurrent glioblastoma treated with antiangiogenic therapy. N = 276 patients in two phase II trials were used as training data, including bevacizumab ± irinotecan (NCT00345163) and cabozantinib (NCT00704288), and N = 74 patients in the bevacizumab arm of a phase III trial (NCT02511405) were used for validation. Enhancing volumes were estimated using T1 subtraction maps, and a biexponential model was used to estimate regrowth (g) and regression (d) rates, time to tumor regrowth (TTG), and the depth of response (DpR). Response characteristics were compared to diffusion MR phenotypes previously shown to predict survival. Optimized thresholds occurred at g = 0.07 months-1 (phase II: HR = 0.2579, P = 5 × 10-20; phase III: HR = 0.2197, P = 5 × 10-5); d = 0.11 months-1 (HR = 0.3365, P < 0.0001; HR = 0.3675, P = 0.0113); TTG = 3.8 months (HR = 0.2702, P = 6 × 10-17; HR = 0.2061, P = 2 × 10-5); and DpR = 11.3% (HR = 0.6326, P = 0.0028; HR = 0.4785, P = 0.0206). Multivariable Cox regression controlling for age and baseline tumor volume confirmed these factors as significant predictors of survival. Patients with a favorable pretreatment diffusion MRI phenotype had a significantly longer TTG and slower regrowth. Recurrent glioblastoma patients with a large, durable radiographic response to antiangiogenic agents have significantly longer survival. This information is useful for interpreting activity of antiangiogenic agents in recurrent glioblastoma.

Change in volumetric tumor growth rate after cytotoxic therapy is predictive of overall survival in recurrent glioblastoma.

Alterations in tumor growth rate (TGR) in recurrent glioblastoma (rGBM) after treatment may be useful for identifying therapeutic activity. The aim of this study was to assess the impact of volumetric TGR alterations on overall survival (OS) in rGBM treated with chemotherapy with or without radiation therapy (RT). Sixty-one rGBM patients treated with chemotherapy with or without concomitant radiation therapy (RT) at 1st or 2nd recurrence were retrospectively examined. Pre- and post-treatment contrast enhancing volumes were computed. Patients were considered "responders" if they reached progression-free survival at 6 months (PFS6) and showed a decrease in TGR after treatment and "non-responders" if they didn't reach PFS6 or if TGR increased. Stratification by PFS6 and based on TGR resulted in significant differences in OS both for all patients and for patients without RT (P < 0.05). A decrease of TGR (P = 0.009), smaller baseline tumor volume (P = 0.02), O6-methylguanine-DNA methyltransferase promoter methylation (P = 0.048) and fewer number of recurrences (P = 0.048) were significantly associated with longer OS after controlling for age, sex and concomitant RT. A decrease in TGR in patients with PFS6, along with smaller baseline tumor volume, were associated with a significantly longer OS in rGBM treated with chemotherapy with or without radiation. Importantly, all patients that exhibited PFS6 also showed a measurable decrease in TGR.

Impact of prognostic nutritional index on survival in recurrent glioblastoma.

Primary brain tumors are relatively rare malignancy, with high-grade gliomas (glioblastoma multiforme and anaplastic gliomas) are the most common types. We aimed to evaluate the prognostic value of Prognostic Nutritional Index (PNI), which is calculated by lymphocyte count and albumin, in recurrent glioblastoma patients treated with systemic treatment. Data of 64 patients with recurrent glioblastoma who received systemic treatment and followed in our clinic between 2012 and 2018 was retrospectively collected and analyzed. PNI was calculated as: [(10×serum albumin (g/dL))+(0.005×total lymphocyte count)]. Patients were categorized according to the median PNI value. We investigated the prognostic role of PNI groups, and survival outcomes. Median value of PNI was 45.7, and median follow-up duration was 9 months (1-68 months). Median overall survival (OS) was 7.9 months (95%CI: 5.5-10.4). Median OS was significantly longer in patients with PNI>45.7 compared to patients with PNI≤45.7 (13.9 months (95%CI: 10.5-17.4), and 4.6 months (95%CI: 2.5-6.8), p<0.001, respectively). In multivariate analysis, PNI was found to be an independent prognostic factor for OS [HR:0.41 (95%CI:0.22-0.74), p=0.03)]. In our study, the PNI was found to be an independent prognostic biomarker in patients with recurrent glioblastoma, but further prospective trials are necessary to validate its prognostic role.

Impact of prognostic nutritional index on survival in recurrent glioblastoma

BackgroundPrimary brain tumors are relatively rare malignancy, with high-grade gliomas (glioblastoma multiforme and anaplastic gliomas) are the most common types. We aimed to evaluate the prognostic value of Prognostic Nutritional Index (PNI), which is calculated by lymphocyte count and albumin, in recurrent glioblastoma patients treated with systemic treatment. MethodsData of 64 patients with recurrent glioblastoma who received systemic treatment and followed in our clinic between 2012 and 2018 was retrospectively collected and analyzed. PNI was calculated as: [(10×serum albumin (g/dL))+(0.005×total lymphocyte count)]. Patients were categorized according to the median PNI value. We investigated the prognostic role of PNI groups, and survival outcomes. ResultsMedian value of PNI was 45.7, and median follow-up duration was 9 months (1–68 months). Median overall survival (OS) was 7.9 months (95%CI: 5.5–10.4). Median OS was significantly longer in patients with PNI>45.7 compared to patients with PNI≤45.7 (13.9 months (95%CI: 10.5–17.4), and 4.6 months (95%CI: 2.5–6.8), p<0.001, respectively). In multivariate analysis, PNI was found to be an independent prognostic factor for OS [HR:0.41 (95%CI:0.22–0.74), p=0.03)]. ConclusionIn our study, the PNI was found to be an independent prognostic biomarker in patients with recurrent glioblastoma, but further prospective trials are necessary to validate its prognostic role.

Comparison of carbon ion and photon reirradiation for recurrent glioblastoma

PurposePurpose of this study was to investigate overall survival in recurrent glioblastoma treated with either carbon ion reirradiation or photon reirradiation.Materials and methodsIn this retrospective study we evaluated 78 consecutive patients with recurrent IDH (Isocitrate dehydrogenase)-wildtype glioblastoma (38 patients carbon ion re-radiotherapy, 40 patients photon re-radiotherapy) treated with either carbon ion reirradiation or stereotactic photon reirradiation. 45 Gy (RBE; 15 fractions) carbon ion reirradiation (CIRT) or 39 Gy (13 fractions) photon reirradiation (FSRT) was administered, respectively. Overall survival was investigated with respect to histological, clinical, and epidemiological features. Kaplan–Meier and multivariate Cox statistics were calculated. A propensity score-matched analysis of the FSRT and CIRT groups using variables from a validated prognosis score was carried out.ResultsThe type of reirradiation (CIRT vs. FSRT) significantly influenced overall survival—8.0 months vs. 6.5 months (univariate: p = 0.046)—and remained an independent prognostic factor in multivariate analysis (p = 0.017). Propensity score-adjusted analysis with CIRT versus FSRT as the dependent variable yielded a significant overall survival advantage for the CIRT group (median OS 8.9 versus 7.2 months, p = 0.041, 1‑year survival 29 versus 10%). Adverse events (AE) were evaluated for both subgroups. For the FSRT group no toxicity ≥ grade 4 occurred. For the CIRT subgroup no grade 5 AE occurred, but 1 patient developed a grade 4 radionecrosis. We encountered 4 grade 3 toxicities. One patient developed a zoster at the trunk, 2 progressed in their paresis, and 1 featured progressive dysesthesia.ConclusionIn conclusion, carbon ion treatment is a safe and feasible treatment option for recurrent glioblastoma. Due to the retrospective nature of the study and two different dose levels for CIRT or FSRT, the improved outcome in CIRT reirradiation might be an effect of higher biological impact from carbon ions or a simple dose-escalation effect. This hypothesis needs prospective testing in larger patient cohorts. A prospective phase III randomized trial is in preparation at our center.

EXTH-38. ORTHOGONAL IN VIVO MODELS WERE THE SOLE PRECLINICAL PREDICTOR OF CLINICAL EFFICACY IN PHASE 1 TRIALS OF TARGETED THERAPIES FOR GLIOBLASTOMA: RESULTS OF A SYSTEMATIC REVIEW

Abstract INTRODUCTION No drug has improved survival in recurrent glioblastoma despite encouraging activity preclinically. We undertook a systematic review of matched preclinical and Phase 1 trials (P1Ts) of targeted agents to investigate potential preclinical predictors of clinical efficacy. METHODS We identified all adult glioblastoma monotherapy P1Ts of targeted agents &amp; preceding preclinical data published between 2006–2019 via structured searches of EMBASE/MEDLINE/PUBMED. For preclinical studies, data regarding in vitro models, in vivo models (species, implantation site, cell-line type) and efficacy (growth inhibition, regression rate, survival) were extracted. For P1T, response rate (RR) data were collected as absolute (%) and categorical (RR&amp;lt; 5% vs. RR≥ 5%) variables. Associations were compared by chi-square/Fisher’s exact test, Kruskal-Wallis or Mann-Whitney U testing as appropriate with 2-sided p-values. RESULTS We found 28 P1Ts with median RR 2.9% (range 0.0–33.3%) and mOS 8.0mo (range 4.6–13.0mo). Seven (25%) had ‘minimal’ published pre-clinical data (5 missing entirely; 2 in vitro only); 12 (43%) utilised one cell line in vivo (‘single model’ group); and 9 (32%) used 2+ biologically distinct in vivo models (‘orthogonal’ group). There was strong reliance on U87-based cell lines (14/21 (71%)) in the latter groups. None of the variables tested were associated with RR except for use of ‘orthogonal models’. Compared to the ‘orthogonal’ group, the P1T RR rate was lower in ‘single’ and ‘minimal’ groups (6.8% vs 1.2%, p= 0.043 and 6.8% vs 0.0%, p= 0.026 respectively). The frequency of P1T with a RR &amp;gt; 5% was also higher in the ‘orthogonal’ compared to the same two groups (78% vs 20%, p= 0.042 and 78% vs 17%, p= 0.041). CONCLUSION The availability of good quality pre-clinical data, especially the use of orthogonal models in vivo, was significantly associated with P1T response rates and warrants further investigation as a minimal threshold of evidence in future drug development.

Diffusion Magnetic Resonance Imaging Phenotypes Predict Overall Survival Benefit From Bevacizumab or Surgery in Recurrent Glioblastoma With Large Tumor Burden.

Diffusion magnetic resonance (MR) characteristics are a predictive imaging biomarker for survival benefit in recurrent glioblastoma treated with anti-vascular endothelial growth factor (VEGF) therapy; however, its use in large volume recurrence has not been evaluated. To determine if diffusion MR characteristics can predict survival outcomes in patients with large volume recurrent glioblastoma treated with bevacizumab or repeat resection. A total of 32 patients with large volume (>20 cc or > 3.4 cm diameter) recurrent glioblastoma treated with bevacizumab and 35 patients treated with repeat surgery were included. Pretreatment tumor volume and apparent diffusion coefficient (ADC) histogram analysis were used to phenotype patients as having high (>1.24 μm2/ms) or low (<1.24 μm2/ms) ADCL, the mean value of the lower peak in a double Gaussian model of the ADC histogram within the contrast enhancing tumor. In bevacizumab and surgical cohorts, volume was correlated with overall survival (Bevacizumab: P=.009, HR=1.02; Surgical: P=.006, HR=0.96). ADCL was an independent predictor of survival in the bevacizumab cohort (P=.049, HR=0.44), but not the surgical cohort (P=.273, HR=0.67). There was a survival advantage of surgery over bevacizumab in patients with low ADCL (P=.036, HR=0.43) but not in patients with high ADCL (P=.284, HR=0.69). Pretreatment diffusion MR imaging is an independent predictive biomarker for overall survival in recurrent glioblastoma with a large tumor burden. Large tumors with low ADCL have a survival benefit when treated with surgical resection, whereas large tumors with high ADCL may be best managed with bevacizumab.

A phase 0 analysis of ixazomib in patients with glioblastoma.

Improving overall survival in recurrent glioblastoma remains a challenge, and drugs acting by unique mechanisms are urgently required. Ixazomib is an orally-administered proteasome inhibitor used in combination with lenalidomide and dexamethasone to treat patients with multiple myeloma who have received at least one prior therapy. However, ixazomib's ability to reach brain tumors has not been studied during its development. The aim of the present study (ClinicalTrials.gov, NCT02630030) was to establish and quantify ixazomib's presence in glioblastoma. The present study investigated 3 patients with recurrent glioblastoma after administration of oral ixazomib citrate (MLN 9708) at a fixed 4.0 mg dose within a 3-hpreoperative window. A total of 2 blood samples were taken from each patient at the time of incision, tumor sampling and closure. Brain tumor samples were collected during tumor resection. These samples were then used to measure the plasma and brain tumor tissue concentration of the biologically-active form of ixazomib (MLN 2238). Patient 1 had plasma concentrations of ixazomib averaging 26.2, 21.8 and 15.3 ng/ml at incision, tumor sampling and closure, respectively. The brain tumor tissue concentration was 7.88 ng/g. Patient 2 had the same interval and brain tumor tissue measurements of 19.0, 18.0 and 8.93 ng/ml, and 2.03 ng/g. Patient 3 had plasma concentration interval measurements of 25.6, 36.2 and 28.7 ng/ml. Multiple brain tumor tissue samples were taken in patient 3, with an average tissue ixazomib concentration of 3.37 ng/g. Ixazomib was found at plasma concentrations commensurate with its previously established pharmacokinetic profile without clinically relevant drug-related adverse events. Ixazomib reaches glioblastoma tissues at measurable concentrations at the time of tumor resection, confirming target tissue delivery. This justifies the phase I study of ixazomib in recurrent glioblastoma currently in development.

Does reintervention improve survival in recurrent glioblastoma? Facing a temporal bias in the literature.

Glioblastoma (GBM) is the most frequent intraaxial malignant brain tumour, in which recurrence management is a frequent and demanding issue. Recently, reintervention has emerged as a useful tool for treatment. However, some new evidence has shown that most of the articles published could have overestimated its effects. We aimed to analyse the effect on survival of reintervention considering it as a time-dependent variable and to compare it with classic statistical analysis. We performed a retrospective study with GBM patients between 2007 and 2017. We compared the overall survival (OS) between reintervention and non-reintervention groups with time-dependent statistical methods (Simon-Makuch and landmarking methods and time-dependent multivariable Cox analysis) and compared them with those obtained with non-dependent time variable analysis. A total of 183 patients were included in the analysis and 44 of them were reoperated. The standard analysis with Kaplan-Meier and multivariable Cox regression of the cohort showed an OS of 22.2months (95% CI 12.56-16.06) in the reintervention group and 11.8months (95% CI 9.87-13.67) in the non-reintervention group (p< .001); and an HR 0.649 (95% CI 0.434-0.97 p= .035) for reintervention, demonstrating an increase in OS. However, time-dependent analysis with the Simon-Makuch test and the landmarking method showed that the relationship was not consistent, as this increase in OS was not significant. Moreover, time-dependent multivariable Cox analysis did not show that reintervention improved OS in our cohort (HR 0.997 95% CI 0.976-1.018 p= 0.75). There has been a temporal bias in the literature that has led to an overestimation of the positive effect of reintervention in recurrent GBM. However, reintervention could still be useful in some selected patients, who should be individualized according to prognostic factors related to the patient, biology of the tumour, and characteristics of surgical procedure.

MDNA55 survival in recurrent glioblastoma (rGBM) patients expressing the interleukin-4 receptor (IL4R) as compared to a matched synthetic control.

2513 Background: MDNA55 is an engineered IL-4 fused to pseudomonas exotoxin A being developed for GBM, an aggressive, universally fatal disease. No curative therapy exists and 75% of patients are not eligible for resection at recurrence. MDNA55 targets IL4R overexpressed in GBM, the immunosuppressive tumor microenvironment, and high expression is associated with poor survival outcomes in GBM. A Ph 2b trial of MDNA55 was completed in rGBM using convection-enhanced delivery to bypass the BBB. Here we report results from the Ph 2b trial and comparison against a matched Synthetic Control Arm (SCA). Methods: MDNA55-05 is an open-label, single-arm study of intratumoral delivery of ≤ 240 μg MDNA55 as a single treatment via ≤ 4 catheters in de novo GBM without IDH1/2 mutation at 1st or 2nd recurrence not eligible for resection, tumors ≤ 4 cm, KPS ≥ 70. IL4R expression in GBM tissues was determined by H-Score using a validated IHC assay. 1o endpoint is median overall survival (mOS); 2o endpoint includes the impact of IL4R status on mOS. An eligibility-matched SCA was identified retrospectively from patient registries at major neurosurgery centers with access to GBM tumor tissue banks under IRB-approved protocols. Results: 44 subjects comprise the MDNA55 per protocol analysis population: median age 56 (35 - 77); median dose 177 mg (range 18 – 240 mg), 50% had KPS ≤ 80. No systemic toxicities observed, drug-related AEs were primarily neurological and characteristic of GBM, no deaths attributed to MDNA55. Median OS was 11.6 months (95% CI 7.9 – 15.2). When stratified by IL4R expression, mOS in IL4R High (n = 21) was 15 vs. 8.4 months in IL4R Low (n = 19); p = 0.2175. OS12 is 57% vs. 33%. When compared to the SCA (n = 81), MDNA55 subjects survived significantly longer: mOS 12.4 vs. 7.7 months; p = 0.0077. When comparing IL4R High groups, mOS in MDNA55 (n = 21) was 15.8 vs. 6.2 months in the SCA (n = 17); p = 0.0626. Subgroup analysis in unmethylated MGMT subjects also show better survival with MDNA55 (n = 23) than the SCA (n = 31); mOS 12.3 vs. 7.7 months (p = 0.0268), indicating that MDNA55 may be beneficial in patients resistant to temozolomide. Conclusions: MDNA55 subjects represent a difficult to treat population ( de novo GBM, IDH wild-type, not eligible for surgery at recurrence). Single treatment with MDNA55 prolongs survival by nearly 10 months in a subset of rGBM expressing high levels of IL4R when compared to a matched SCA, providing an unprecedented outcome for this highly lethal disease. Clinical trial information: NCT02858895 .

Eosinophil and lymphocyte counts predict bevacizumab response and survival in recurrent glioblastoma.

BackgroundThere is a lack of biomarkers to identify glioblastoma (GBM) patients who may benefit from specific salvage therapies, such as the anti-angiogenic agent bevacizumab. We hypothesized that circulating blood counts may serve as biomarkers for treatment response and clinical outcomes.MethodsComplete blood counts, clinical data, and radiographic information were collected retrospectively from 84 recurrent GBM patients receiving bevacizumab (10 mg/kg every 2 weeks). Significant biomarkers were categorized into quartiles and the association with clinical outcomes was assessed using the Kaplan–Meier method.ResultsThe median treatment duration and survival on bevacizumab (OS-A) was 88 and 192 days, respectively. On multivariate analysis, MGMT promoter methylation (hazard ratio [HR] 0.504, P = .031), increases in red blood cells (HR 0.496, P = .035), and increases in eosinophils (HR 0.048, P = .054) during treatment predicted improved OS-A. Patients in the first and fourth quartiles of eosinophil changes had a 12-month survival probability of 5.6% and 41.2% (P < .0001), respectively. Treatment response was associated with increases in eosinophil counts (P = .009) and improved progression-free survival (P = .013). On multivariate analysis, increases in lymphocyte counts among responders predicted improved OS-A (HR 0.389, P = .044). Responders in the first and fourth quartiles of lymphocyte changes had a 12-month survival probability of 0% and 44.4% (P = .019), respectively. Changes in platelet counts differed before and after radiographic response (P = .014).ConclusionsChanges in circulating eosinophil, lymphocyte, and platelet counts may predict treatment response and clinical outcomes in patients with recurrent GBM receiving bevacizumab.

RDNA-05. RADIOTHERAPY PROMOTES ONCOPROGRESSIVE CROSSTALK BETWEEN GLIOBLASTOMA TUMOR CELLS AND M2 MACROPHAGES VIA THE NLRP3 INFLAMMASOME PATHWAY

Abstract PURPOSE Radiotherapy (RT) is an essential component in the adjuvant treatment of glioblastoma (GBM); however, despite an initial benefit in tumor control, recurrence is nearly universal. The inflammasome is a multimeric cytosolic complex that has been shown to be activated in immune cells following RT. We investigated the relationship of inflammasome activation and disease progression after RT in GBM. METHODS We performed survival analysis for patients with recurrent GBM using the TCGA dataset, stratifying according to expression of inflammasome pathway molecules Caspase 1 (CASP1), IL-1β, and NLRP3. IL-1β expression and colocalization with CD11b+ myeloid cells were analyzed at different time points following RT in a murine glioma GL261 model. We detected the secreted IL-1β, CASP1 activity, and NLRP3 expression in both tumor and infiltrating immune cells, and the downstream effects of their interplay, including cellular apoptosis, proliferation, and viability. RESULTS High expression of CASP1, IL-1β, and NLRP3 are associated with poor survival in recurrent GBM. In a mouse model, recurrent tumors after treatment with RT display higher levels of the inflammasome effector molecule IL-1β, which colocalizes with infiltrating CD11b+ myeloid cells. Using a co-culture system of tumor cell and M2 macrophages, we found that RT enhances inflammasome activation in both cell types, and this interaction restores the proliferative capacity of surviving tumor cells following treatment. RT induces the inflammasome pathway activation in the setting of an associated immune microenvironment rich in tumor-associated macrophages and myeloid-derived suppressor cells (TAM/MDSCs) and not in tumor cells alone. CONCLUSIONS Inhibition of the oncoprogressive crosstalk between GBM tumor cells and M2 macrophages, possibly through disruption of the inflammasome pathway, might be a potential therapeutic strategy with RT.

Safety of nivolumab in combination with dendritic cell vaccines in recurrent high-grade glioma.

e13526 Background: Recurrence of high-grade glioma (HGG) (WHO grade III-IV) is a nearly universal phenomenon and necessitates the development of new therapeutic modalities. Two possible immunotherapeutic modalities are checkpoint blockade with agents such as nivolumab, a blocking antibody against the inhibitory checkpoint programmed cell death-1 (PD-1), and dendritic cell (DC) vaccination. We have shown in phase 1 and 2 trials that DC vaccination against the glioblastoma (GBM)-associated antigen human cytomegalovirus pp65-lysosomal-associated membrane protein (CMVpp65) is safe and possesses potential benefit. We hypothesized that nivolumab-induced immune checkpoint blockade could enhance efficacy of DC vaccination. Therefore, we undertook a phase 1 study to evaluate safety of nivolumab in combination with CMVpp65 mRNA pulsed DC vaccination in subjects with first or second recurrence of resectable HGG. Methods: We performed a phase 1, single-center, randomized study of nivolumab alone versus nivolumab + DC vaccination prior to planned surgical resection for both groups. We administered nivolumab 3 mg/kg IV q2weeks for 8 weeks followed by surgery and planned continuation of nivolumab. For the group receiving nivolumab + DC vaccination, we administered 3 vaccines before surgical resection with both groups receiving 5 planned post-resection DC vaccines. Primary endpoint was safety assessment using NCI-CTCAE 4.03. Results: We enrolled 6 subjects (4: GBM, 1: anaplastic astrocytoma, 1: anaplastic oligodendroglioma) with 3 receiving nivolumab alone and 3 receiving nivolumab + DC vaccination. Age range was 45-63 years subjects. We documented similar adverse events in both groups with most common grade 1-2 toxicities being fatigue (2 subjects, nivolumab alone) and thrombocytopenia (2 subjects, nivolumab + DC vaccine). Grade 4 toxicities included wound infection (2 subjects, nivolumab + DC vaccine) and meningitis (1 subject, nivolumab + DC vaccine). While we designed the study to enroll 66 subjects, we terminated the study early in light of CheckMate 143 phase III data showing nivolumab did not improve overall survival in recurrent GBM. Conclusions: Safety of nivolumab + DC vaccination in recurrent HGG is similar to nivolumab alone. Continued evaluation of new therapeutics including immunotherapy is underway for this patient population. Clinical trial information: NCT02529072.

Impact of resection on overall survival of recurrent Glioblastoma in elderly patients

ObjectivesGlioblastoma multiforme (GBM) mostly affects elderly patients. Adequate therapy especially in case of tumor recurrence is still under discussion, since most studies focus on patients under 65 years. We evaluated the impact of second surgery in regard to progression free survival (PFS) and overall survival (OAS) in elderly patients. Patients and methods59 patients with recurrent glioblastoma multiforme were retrospectively evaluated. Patients were divided into three subgroups: stereotactic biopsy (STX), resection and second resection. Second and third group were pooled as "surgery" after first diagnosis. The median age for all groups was 71 years.The primary endpoint was overall survival. Statistical analysis was calculated using Kaplan-Meier analysis and SPSS. ResultsOAS was significantly longer for patients who had undergone surgery compared to the STX group. For patients who underwent reresection OAS was not significantly longer. Age (over 71) had no significant effect on OAS. PFS was significantly increased in patients who underwent surgery compared to those who underwent STX. PFS was not significantly longer in patients who underwent second resection. Furthermore PFS was not significantly different between patients under 71 and over. ConclusionOAS and PFS were significant increased for patients who underwent surgery compared to only STX.Patients showed prolonged survival of almost 4 months after they underwent reresection (p > 0.05). Therapy of elderly patients with GBM remains an individual decision with priority on quality of life. Clinical status, comorbidities and family background) should be taken into account.

ACTR-27. COMPLIANCE AND TREATMENT DURATION PREDICT SURVIVAL IN A PHASE 3 EF-14 TRIAL OF TUMOR TREATING FIELDS WITH TEMOZOLOMIDE IN PATIENTS WITH NEWLY DIAGNOSED GLIOBLASTOMA

AbstractTumor treating fields (TTFields) are a physical anti-mitotic treatment modality characterized by their immediate mode of action and lack of a half-life. It has been shown previously that average monthly compliance with TTFields is correlated with overall survival in recurrent glioblastoma. A ≥75% compliance, i.e. an average daily use of at least 18h/d, has been suggested as a target for patients with recurrent glioblastoma when receiving TTFields as monotherapy. In the EF-14 phase 3 trial in newly diagnosed glioblastoma, TTFields were applied together with temozolomide (TTFields/TMZ) and led to superior progression free (PFS) and overall survival (OS) compared to TMZ alone. Patients in the TTFields/TMZ arm received TTFields for a median of 8.2 months (95%CI 7.9–9.3), with 13%, 3%, 1% and 90% compliance: PFS HR 0.54 95%CI 0.37–0.79; OS HR 0.52 95%CI 0.35–0.79). A Cox model controlling for gender, extent of resection, MGMT methylation status, age, region and performance status indicated compliance is independent of these factors (HR 0.78; p=0.031; for OS at compliance ≥75% vs <75%). In conclusion, in the EF-14 trial a compliance threshold of 50% with TTFields treatment was correlated with significantly improved outcomes. The results clearly show that the higher patients’ compliance with TTFields, the better their outcomes. This effect was independent of other prognostic factors such as performance status, age and MGMT methylation.

P04.27 Texture feature analysis to predict overall survival in recurrent glioblastoma treated in the DIRECTOR trial

P04.27 Texture feature analysis to predict overall survival in recurrent glioblastoma treated in the DIRECTOR trial

Multimodal imaging patterns predict survival in recurrent glioblastoma patients treated with bevacizumab.

Bevacizumab is a humanized antibody against vascular endothelial growth factor approved for treatment of recurrent glioblastoma. There is a need to discover imaging biomarkers that can aid in the selection of patients who will likely derive the most survival benefit from bevacizumab. The aim of the study was to examine if pre- and posttherapy multimodal MRI features could predict progression-free survival and overall survival (OS) for patients with recurrent glioblastoma treated with bevacizumab. The patient population included 84 patients in a training cohort and 42 patients in a testing cohort, separated based on pretherapy imaging date. Tumor volumes of interest were segmented from contrast-enhanced T1-weighted and fluid attenuated inversion recovery images and were used to derive volumetric, shape, texture, parametric, and histogram features. A total of 2293 pretherapy and 9811 posttherapy features were used to generate the model. Using standard radiographic assessment criteria, the hazard ratio for predicting OS was 3.38 (P < .001). The hazard ratios for pre- and posttherapy features predicting OS were 5.10 (P < .001) and 3.64 (P < .005) for the training and testing cohorts, respectively. With the use of machine learning techniques to analyze imaging features derived from pre- and posttherapy multimodal MRI, we were able to develop a predictive model for patient OS that could potentially assist clinical decision making.