Radiation Therapy For Glioblastoma Research Articles

TMOD-33. DOES PRE-CLINICAL DRUG ACTIVITY PREDICT PHASE II CLINICAL EFFICACY IN GLIOBLASTOMA? A DETAILED ANALYSIS

Abstract Despite decades of research, there are fewer than six FDA-approved therapies for glioblastoma (GBM). The drug approval process relies on studies establishing pre-clinical activity, most commonly using murine models, followed by in human studies establishing safety and then efficacy. Although murine models for GBM have allowed for insights into tumor biology, their utility in assessing the efficacy of novel anti-cancer therapies remains highly debated. Here, we sought to establish whether there was any relationship between drug activity in preclinical models and phase 2 clinical trial outcomes. Using ClinicalTrials.gov (NIH), all phase 2 trials in glioblastoma up to December 2023 were queried and downloaded. Trials that were never started, had not yet started, were withdrawn, not completed, or contained indications beyond glioblastoma were excluded. Studies examining anti-tumor effects of an investigational agent with or without bevacizumab, temozolomide, or radiation therapy in glioblastoma were included, and studies examining alternative dosing strategies, various medical devices, or drug combinations, were excluded. The corresponding preclinical studies were identified via literature review for each clinical trial. Data including the progression free and overall survival benefit, mouse models used, and sample sizes were extracted from each study. 659 trials between 1994 and 2023 were included for analysis. Of these, 272 (41%) were for monotherapies, examining 90 unique small molecules. Preclinical endpoints included murine survival and tumor weight. In comparing mouse survival and tumor size to progression free and overall survival in humans, our preliminary analysis did not reveal any clear correlation. The correlation between preclinical and clinical drug response in GBM remains uncertain. Future work will examine whether mouse genotype, immune status, or GBM cell line used affected the degree of concordance with human clinical trial data. Our analysis suggests that further investigation into preclinical models of GBM, and standardized reporting of preclinical models, are needed.

Abstract 2827: Application of AZD2281 combine with radiation therapy in glioblastoma

Abstract Glioblastoma (GBM), can be divided into primary tumors from brain tissue (>90% of all cases) and secondary tumors that progress from low-grade gliomas. The current GBM treatment strategy is chemotherapy drug temozolomide (TMZ) combined with radiotherapy (RT), which has limited treatment effect, poor prognosis, high recurrence rate, and short prognosis survival time. Recently, studies indicated that breast cancer susceptibility gene 1/2 (BRCA1/2) mutations are frequently occur in GBM, while few studies have explored this pathway in depth. At present, AZD2281 (PARP Inhibitor) has been used to treat breast cancer and ovarian cancer patients with BRCA1/2 mutation...etc. Whether AZD2281 can play a role in affecting the relevant pathways after BRCA1/2 mutate GBM patients, and the possible mechanism and benefit of combined RT are the focus of this study. AZD2281 is the first Poly (ADP-ribose) polymerase (PARP) inhibitor approved by the U.S. Food and Drug Administration (FDA) for the treatment of germline BRCA mutation-associated ovarian cancer. AZD2281 is a targeted therapy that used to block DNA Damage Response (DDR) in cells/tumors deficient in homologous recombination repair (HRR). After RT, there may be a phenomenon of DNA repair; therefore, AZD2281 can be used to disrupt the repair process. At the beginning, we used RSI analysis to confirm that patient with higher expression level of BRCA1 may relatively resistance to RT. To overcome this issue, we identified the effect of AZD2281 combined with RT on GBM cells (BRCA1/2 higher and lower expression cells) by (3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT assay), and colony formation. The internal/external apoptosis pathways (Caspase-3/Caspase-8/Caspase-9) and TUNEL assay were used to prove the superior apoptosis effect of AZD2281 combined with RT as compared to single treatment. Additionally, cells lower BRCA1 expression level (U87 and U251 siBRCA1) may sensitive to RT treatment. In our DNA damage, DNA fragmentation, and transwell invasion/migration results, we showed that the combination of AZD2281 and RT may effective induce DNA damage. In our animal data, we proved that combination therapy can effective suppression tumor growth and apoptosis-related protein signaling increased in DNA damage by IHC (p-ATM/p-CHK2/Caspase-3/Caspase-8/Caspase-9). In conclude, we suggested that AZD2281 can be used as a radiosensitizer to sensitize GBM patient to RT, which is dependent to BRCA1 expression. Citation Format: Tsal-Lan Liao, I-Tsang Chiang, Yuan Chang, Fei-Ting Hsu. Application of AZD2281 combine with radiation therapy in glioblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2827.

Radiation therapy of glioblastoma: experience of a Moroccan center

Radiation therapy of glioblastoma: experience of a Moroccan center

Effects of platinum-coexisting dopamine with X-ray irradiation upon human glioblastoma cell proliferation.

In brain tumors, neurotransmitters and platinum drugs may have some interaction, but their role in radiation therapy remains unclear. We investigated the effects of dopamine in combination with platinum on human glioblastoma U-251MG cells upon X-ray irradiation, comparing with L-DOPA, 2-phenylethylamine and temozolomide. Cell proliferation of U-251MG cells was prominently decreased by dopamine in combination with 10μM platinum upon 4Gy of X-ray irradiation, accompanied with intracellular reactive oxygen species generation and mitotic catastrophe. Platinum alone did not increase intracellular reactive oxygen species. On the other hand, L-DOPA in combination with platinum did not decrease cell proliferation regardless of X-ray irradiation. It was clearly shown that 2-phenylethylamine did not suppress cell proliferation as compared to dopamine. Temozolomide decreased cell proliferation in a dose-dependent manner upon X-ray irradiation. However, the combined administration of temozolomide and platinum did not further decrease cell proliferation. The platinum nanoparticles were gradually taken up by cells after administration as determined by ICP analysis. Our results suggest that platinum-coexisting dopamine led cells to mitotic catastrophe due to increased production of intracellular reactive oxygen species which was boosted by X-ray and platinum-catalyzed auto-oxidation of dopamine, and thereby cell proliferation was suppressed. In addition, normal human fibroblast OUMS-36T-1 cells were subjected to experiments. Regarding the effect of the combined administration of dopamine and platinum on each cell which was exposed to X-ray, cell proliferation was decreased in U-251MG cells by the combined administration of platinum, whereas that was not decreased in OUMS-36T-1 cells. This provides one basic insight into the effects of dopamine in combined with platinum on radiation therapy for glioblastoma.

The dopamine receptor antagonist trifluoperazine prevents phenotype conversion and improves survival in mouse models of glioblastoma

Glioblastoma (GBM) is the deadliest adult brain cancer, and all patients ultimately succumb to the disease. Radiation therapy (RT) provides survival benefit of 6 mo over surgery alone, but these results have not improved in decades. We report that radiation induces a glioma-initiating cell phenotype, and we have identified trifluoperazine (TFP) as a compound that interferes with this phenotype conversion. TFP causes loss of radiation-induced Nanog mRNA expression, and activation of GSK3 with consecutive posttranslational reduction in p-Akt, Sox2, and β-catenin protein levels. TFP did not alter the intrinsic radiation sensitivity of glioma-initiating cells (GICs). Continuous treatment with TFP and a single dose of radiation reduced the number of GICs in vivo and prolonged survival in syngeneic and patient-derived orthotopic xenograft (PDOX) mouse models of GBM. Our findings suggest that the combination of a dopamine receptor antagonist with radiation enhances the efficacy of RT in GBM by preventing radiation-induced phenotype conversion of radiosensitive non-GICs into treatment-resistant, induced GICs (iGICs).

Phase I trial of dimethyl fumarate, temozolomide, and radiation therapy in glioblastoma.

BackgroundDimethyl fumarate (DMF), an oral agent approved for the treatment of relapsing–remitting multiple sclerosis (RRMS), has promising preclinical activity against glioblastoma (GBM). This phase I study sought to determine the recommended phase 2 dose (RP2D) of DMF and evaluate its safety and toxicity when combined with standard concurrent radiotherapy (RT) and temozolomide (TMZ) followed by maintenance TMZ in patients with newly diagnosed GBM.MethodsUsing a standard 3 + 3 dose-escalation design with 3 dose levels, patients received daily DMF with 60 Gy RT and concurrent TMZ 75 mg/m2 daily, followed by maintenance DMF (continuously) and TMZ 150–200 mg/m2 on days 1–5 of each 28-day cycle for up to 6 cycles. The maximum tolerated dose (MTD) was determined by evaluation of dose-limiting toxicity (DLT) during the first 6 weeks of therapy.ResultsTwelve patients were treated at the 3 dose levels, and no DLTs were observed. There were no unexpected toxicities. The most common grade 3/4 treatment related adverse events (AEs) were lymphopenia (58%), decreased CD4 count (17%), and thrombocytopenia (17%). Four patients completed all planned treatment; seven patients had progression on treatment. One patient chose to withdraw from the study during maintenance. The median progression-free survival (PFS) for all patients was 8.7 months with no difference in PFS between those with stable disease or a partial response; median overall survival was 13.8 months.ConclusionsDMF may be safely combined with RT and TMZ in patients with newly diagnosed GBM. The RP2D for DMF is 240 mg three times daily.

Therapeutic targeting of tumor-associated myeloid cells synergizes with radiation therapy for glioblastoma

Tumor-associated myeloid cells (TAMCs) are key drivers of immunosuppression in the tumor microenvironment, which profoundly impedes the clinical response to immune-dependent and conventional therapeutic modalities. As a hallmark of glioblastoma (GBM), TAMCs are massively recruited to reach up to 50% of the brain tumor mass. Therefore, they have recently been recognized as an appealing therapeutic target to blunt immunosuppression in GBM with the hope of maximizing the clinical outcome of antitumor therapies. Here we report a nano-immunotherapy approach capable of actively targeting TAMCs in vivo. As we found that programmed death-ligand 1 (PD-L1) is highly expressed on glioma-associated TAMCs, we rationally designed a lipid nanoparticle (LNP) formulation surface-functionalized with an anti-PD-L1 therapeutic antibody (αPD-L1). We demonstrated that this system (αPD-L1-LNP) enabled effective and specific delivery of therapeutic payload to TAMCs. Specifically, encapsulation of dinaciclib, a cyclin-dependent kinase inhibitor, into PD-L1-targeted LNPs led to a robust depletion of TAMCs and an attenuation of their immunosuppressive functions. Importantly, the delivery efficiency of PD-L1-targeted LNPs was robustly enhanced in the context of radiation therapy (RT) owing to the RT-induced up-regulation of PD-L1 on glioma-infiltrating TAMCs. Accordingly, RT combined with our nano-immunotherapy led to dramatically extended survival of mice in 2 syngeneic glioma models, GL261 and CT2A. The high targeting efficiency of αPD-L1-LNP to human TAMCs from GBM patients further validated the clinical relevance. Thus, this study establishes a therapeutic approach with immense potential to improve the clinical response in the treatment of GBM and warrants a rapid translation into clinical practice.

Delta-6-desaturase inhibitor enhances radiation therapy in glioblastoma in vitro and in vivo.

BackgroundIt has been reported that cell inflammation pathways contribute to the development of prostaglandin E2 (PGE2)-inhibitor of DNA-binding protein-1 (ID1)-dependent radio-resistance in glioblastoma. Here, we proposed that inhibiting delta-6-desaturase (D6D) could block arachidonic acid synthesis and PGE2 production, thereby reversing PGE2-ID1-dependent radioresistance in glioblastoma cells and xenograft tumor models.Materials and methodsTwo glioblastoma cell lines, namely, U-87 MG and LN-229, were used for the in vitro study. The combination effects of SC-26196 (a D6D inhibitor) and radiation were assessed by the MTS assay, colony formation assay, and cell apoptosis analysis. HPLC/MS analysis was performed to quantify the production of arachidonic acid and PGE2. For the in vivo study, 6-week-old nude mice, each bearing a U-87 MG xenograft tumor, were subjected to 4-week treatments of vehicle, SC-26196, radiation, or the combination of both. Tumor growth was monitored during the treatment, and the tumor tissues were collected at the end for further analysis.ResultsTreatment with SC-26196 significantly improved radiosensitivity in both glioblastoma cell lines in vitro, and radiosensitivity was associated with inhibited synthesis of arachidonic acid and PGE2. The combination of SC-26196 and radiation synergistically inhibited U-87 MG xenograft tumor growth, in association with the induction of tumor apoptosis and suppressed tumor proliferation. SC-26196 also inhibited arachidonic acid and PGE2 production in vivo and limited expression of ID1.ConclusionThese data suggested that the D6D inhibitor could reverse PGE2-ID1-dependent radioresistance in glioblastoma cells and xenograft tumor models by blocking the synthesis of arachidonic acid and PGE2. Although further investigation is required, the outcomes from this study may guide us in developing a potentially novel combination strategy for current glioblastoma therapy.

Daily Tracking with MRI-Guided Radiation Therapy of Glioblastoma Resection Cavity and Cerebral Edema Volumes

Radiation therapy (RT) plays a critical role in the treatment of glioblastoma. Studies of brain imaging during RT for glioblastoma have demonstrated changes in the brain during RT. However, feasibility has limited frequent or daily utilization of standalone MRI scans during RT. The recent release of the Tri-Cobalt-60 MRI-Guided RT (MR-IGRT) device allows for daily brain MRI for RT setup. Findings from daily brain MRIs during RT have not been previously reported. Under an institutional review board approved protocol, resection cavities, edema, and visible tumor were measured from daily MRI of three post-operative patients undergoing RT (60 Gy) and temozolomide for glioblastoma over a six week course. Simulation and daily MRIs were obtained by the MR-IGRT system. Scans were performed with the balanced steady state free precession sequence included with the scanner, which has significant T2-weighting (128 sec acquisition, 0.15 × 0.15 × 0.15 cm resolution, 40 × 43 × 40 cm field of view). The volumes and dimensions of the cavity, edema, and visible tumor were generated from manual contours. Changes to the cavity and edema could be visualized on a daily basis. A general trend of daily decreases in cavity measurements was observed in all patients. Table 1 displays the measurements taken at fraction 1, fraction 15 and fraction 30. For the patient with edema, the edema volume increased until fraction 13 and then began to decrease, though the patient never required steroids during RT. Two other patients had no or minimal edema even on diagnostic scans. The measurements of a second, unresected tumor seen in one patient did not change during RT.Abstract MO_26_2712; Table 1Fraction 1Fraction 15Fraction 30PatientStructureVolume (cc)Size (cm)Volume (cc)Size (cm)Volume (cc)Size (cm)Total Days1Cavity2.33.0 × 0.8 × 1.10.82.6 × 0.6 × 0.70.61.7 × 0.4 × 0.5452Cavity82.67.2 × 3.3 × 8.077.67.1 × 3.1 × 7.672.06.9 × 3.0 × 7.5393Cavity3.62.4 × 1.0 × 2.72.32.7 × 0.6 × 1.61.92.3 × 0.6 × 1.3413Secondary Tumor0.81.2 × 0.6 × 1.10.71.3 × 0.7 × 1.10.71.3 × 0.7 × 1.2413Edema55.25.7 × 3.6 × 7.468.16.2 × 3.6 × 6.851.45.8 × 2.8 × 5.841 Open table in a new tab In this preliminary analysis of daily MR-IGRT of glioblastoma, we observed and quantified changes in tumor cavities, edema, and visible tumor in three patients. This suggests that daily MRI could be used for onboard re-simulation and adaptive radiotherapy for future fluctuations in sizes of tumors, cavities, or cystic components. This would ensure proper targeting and reduced RT of healthy brain tissue. Additional MRI pulse sequences could provide further information about the tumor microenvironment for adaptation of therapy during the course of RT.

Predictors for and Clinical Impact of Time between Surgical Resection and Radiation Therapy in Glioblastoma: Analysis of the National Cancer Database

Predictors for and Clinical Impact of Time between Surgical Resection and Radiation Therapy in Glioblastoma: Analysis of the National Cancer Database

Daily Tracking of Glioblastoma Resection Cavity, Cerebral Edema, and Tumor Volume with MRI-Guided Radiation Therapy

Radiation therapy (RT) plays a critical role in the treatment of glioblastoma. Studies of brain imaging during RT for glioblastoma have demonstrated changes in the brain during RT. However, frequent or daily utilization of standalone magnetic resonance imaging (MRI) scans during RT have limited feasibility. The recent release of the tri-cobalt-60 MRI-guided RT (MR-IGRT) device (ViewRay MRIdian, Cleveland, OH) allows for daily brain MRI for the RT setup. Daily MRI of three postoperative patients undergoing RT and temozolomide for glioblastoma over a six-week course allowed for the identification of changes to the cavity, edema, and visible tumor on a daily basis. The volumes and dimensions of the resection cavities, edema, and T2-hyperintense tumor were measured. A general trend of daily decreases in cavity measurements was observed in all patients. For the one patient with edema, a trend of daily increases followed by a trend of daily decreases were observed. These results suggest that daily MRI could be used for onboard resimulation and adaptive RT for future fluctuations in the sizes of brain tumors, cavities, or cystic components. This could improve tumor targeting and reduce RT of healthy brain tissue.

Application of Diffusion Weighted MRI for Target Delineation in Radiation Therapy for Glioblastoma

Although the predominant pattern of failure after radiotherapy for glioblastoma (GBM) has historically been within the high-dose region, recent studies of patients with MGMT methylated tumors receiving concurrent chemoradiotherapy reveal a 30-40% rate of marginal or distant failure. Thus, current radiotherapy target volumes may not adequately encompass regions at risk for tumor spread. It has long been recognized that GBM invades predominantly along large white matter pathways within the brain, but this information has not been systematically incorporated into radiotherapy planning. We investigate the use of diffusion-weighted MRI (dwMRI), which non-invasively measures the orientation of major white matter tracts, to inform target delineation for GBM. 31 patients were retrospectively identified who had undergone 55-direction, high angular resolution dwMRI (HARDI) at the time of radiotherapy treatment planning. Diffusion tractography was performed using the physician contoured GTV as a seed, and used to automatically generate an anisotropic CTV expansion (CTVdwMRI), encompassing all surrounding white matter up to a threshold tract length from the GTV. All CTV expansions were performed in the planning system (RayStation V5) using python scripting. For all patients who experienced disease recurrence, the progression MRI was registered to the treatment planning MRI, and the recurrence was characterized as encompassed within the CTV (in-field) or at least partially outside CTV (marginal/distant) for both the CTVdwMRI and the clinically used isotropic CTV. Simulated replanning was also performed using the CTVdwMRIto determine the effect of anisotropic expansion on dosimetric parameters. Results : At the time of submission, a pilot set of 5 patients had been analyzed, all of whom experienced disease recurrence. All recurrences were encompassed within the CTVdwMRI, while the conventional CTV encompassed the recurrence in only 80% of the cases. Furthermore, the target volume for radiotherapy was significantly reduced in a majority of patients using the dwMRI-based CTV (median CTV volume change of -26.7%, range [-35.4, +9.0]%). Critical structures such as the hippocampus and the fornix had significant reduction in mean and maximum doses for the 5 cases analyzed. The results for all 31 patients will be available at the time of presentation. We have demonstrated the feasibility of incorporating white matter track information in the target delineation process for GBM patients. Our preliminary data demonstrates that our dwMRI-based approach can be used to define target volumes that may provide superior coverage of areas at highest risk of tumor spread, without increased risk for long-term toxicity from treatment. Further analysis is needed to determine whether this personalized approach to target delineation yields improves disease control and quality of life of patients with GBM.

Radiation Therapy for Glioblastoma: American Society of Clinical Oncology Clinical Practice Guideline Endorsement of the American Society for Radiation Oncology Guideline.

Radiation Therapy for Glioblastoma: American Society of Clinical Oncology Clinical Practice Guideline Endorsement of the American Society for Radiation Oncology Guideline.

Radiation Therapy for Glioblastoma: American Society of Clinical Oncology Clinical Practice Guideline Endorsement of the American Society for Radiation Oncology Guideline.

Purpose The American Society for Radiation Oncology (ASTRO) produced an evidence-based guideline on radiation therapy for glioblastoma. Because of its relevance to the ASCO membership, ASCO reviewed the guideline and applied a set of procedures and policies used to critically examine guidelines developed by other organizations. Methods The ASTRO guideline on radiation therapy for glioblastoma was reviewed for developmental rigor by methodologists. An ASCO endorsement panel updated the literature search and reviewed the content and recommendations. Results The ASCO endorsement panel determined that the recommendations from the ASTRO guideline, published in 2016, are clear, thorough, and based on current scientific evidence. ASCO endorsed the ASTRO guideline on radiation therapy for glioblastoma and added qualifying statements. Recommendations Partial-brain fractionated radiotherapy with concurrent and adjuvant temozolomide is the standard of care after biopsy or resection of newly diagnosed glioblastoma in patients up to 70 years of age. Hypofractionated radiotherapy for elderly patients with fair to good performance status is appropriate. The addition of concurrent and adjuvant temozolomide to hypofractionated radiotherapy seems to be safe and efficacious without impairing quality of life for elderly patients with good performance status. Reasonable options for patients with poor performance status include hypofractionated radiotherapy alone, temozolomide alone, or best supportive care. Focal reirradiation represents an option for select patients with recurrent glioblastoma, although this is not supported by prospective randomized evidence. Additional information is available at www.asco.org/glioblastoma-radiotherapy-endorsement and www.asco.org/guidelineswiki .

Impact of timing of radiotherapy in patients with newly diagnosed glioblastoma

ObjectiveTo further evaluate if a delay in the start of radiation therapy (RT) affects patient outcomes for glioblastoma (GBM). Patients and methodsFrom May 1999 to May 2010, a total of 161 patients underwent surgery followed by RT for GBM. We assessed overall survival (OS) and progression free survival (PFS), stratified by extent of surgical resection. Included in the analysis were genomic predictors of progression. ResultsMedian time from surgery to start of RT was 20days for biopsy alone, 28days for subtotal resection (STR) and 28days for gross total resection (GTR). For all patients, a delay >28days did not result in a difference in PFS when compared to no delay (6.7 vs. 6.9 months, p=0.07). PFS was improved in biopsy or STR patients with a >28day delay to start of RT (4.2 vs. 6.7 months, p=0.006). OS was also improved in patients receiving biopsy or STR with a >28day delay to start of RT (12.3 vs. 7.8 months, p=0.005). Multivariable analysis (MVA) demonstrated an improvement in OS and PFS with time to RT >28days for biopsy or STR patients (HR 0.52 p=0.008 and HR 0.48 p=0.02, respectively). ConclusionIn this retrospective review of GBM patients treated at a single institution, OS and PFS were not different between time to RT >28days compared to <28 days. There was a modest improvement in both PFS and OS in patients who received biopsy or STR with time to RT >28 days.

Radiation therapy for glioblastoma: Executive summary of an American Society for Radiation Oncology Evidence-Based Clinical Practice Guideline

PurposeTo present evidence-based guidelines for radiation therapy in treating glioblastoma not arising from the brainstem. Methods and materialsThe American Society for Radiation Oncology (ASTRO) convened the Glioblastoma Guideline Panel to perform a systematic literature review investigating the following: (1) Is radiation therapy indicated after biopsy/resection of glioblastoma and how does systemic therapy modify its effects? (2) What is the optimal dose-fractionation schedule for external beam radiation therapy after biopsy/resection of glioblastoma and how might treatment vary based on pretreatment characteristics such as age or performance status? (3) What are ideal target volumes for curative-intent external beam radiation therapy of glioblastoma? (4) What is the role of reirradiation among glioblastoma patients whose disease recurs following completion of standard first-line therapy? Guideline recommendations were created using predefined consensus-building methodology supported by ASTRO-approved tools for grading evidence quality and recommendation strength. ResultsFollowing biopsy or resection, glioblastoma patients with reasonable performance status up to 70 years of age should receive conventionally fractionated radiation therapy (eg, 60 Gy in 2-Gy fractions) with concurrent and adjuvant temozolomide. Routine addition of bevacizumab to this regimen is not recommended. Elderly patients (≥70 years of age) with reasonable performance status should receive hypofractionated radiation therapy (eg, 40 Gy in 2.66-Gy fractions); preliminary evidence may support adding concurrent and adjuvant temozolomide to this regimen. Partial brain irradiation is the standard paradigm for radiation delivery. A variety of acceptable strategies exist for target volume definition, generally involving 2 phases (primary and boost volumes) or 1 phase (single volume). For recurrent glioblastoma, focal reirradiation can be considered in younger patients with good performance status. ConclusionsRadiation therapy occupies an integral role in treating glioblastoma. Whether and how radiation therapy should be applied depends on characteristics specific to tumor and patient, including age and performance status.

Roles of Valproic Acid in Improving Radiation Therapy for Glioblastoma: a Review of Literature Focusing on Clinical Evidence.

Glioblastoma (GBM) is the most common and aggressive type of primary brain neoplasm. The current standard therapy for GBM consists of maximal surgical resection within safe limits, followed by radiation therapy (RT) and chemotherapy with temozolomide. Despite advances in treatment, the prognosis of GBM remains poor. Epileptic seizure is one of the most common symptoms in patients with GBM. Valproic acid (VPA), a histone deacetylase inhibitor, is often used as an anti-epileptic drug in patients with brain neoplasms due to its effectiveness and low toxicity profile. Several in vivo and in vitro studies have indicated that VPA has radiosensitizing effects for gliomas and radioprotective influence on normal brain tissue or hippocampal neurons. The results of several retrospective studies have also indicated potential benefit to improve survival of patients with GBM. Moreover, the promising treatment results of a phase 2 trial of concurrent radiation therapy, temozolomide, and VPA for patients with GBM have been recently reported. The use of VPA in patients with GBM has thus recently receiving more attention. In this article, we review the role of VPA in radiation therapy for GBM, focusing on the clinical evidence.

Safety analysis of Intensity-modulated radiation therapy of glioblastoma with simultaneous integrated boost technique

Objective To investigate clinical efficacy of simultaneous integrate boost for glioblastoma with intensity-modulated radiotherapy(SIB-IMRT). Methods A total of 46 patients with glioblastoma who underwents SIB-IMRT from January 2013 to August 2014, were retrospectively analyzed. Toxicity after completion of SIB-IMRT were assessed. Kaplan-Meier method was used to analyze survival and progression-free survival. Multivariate analyses were performed to determine significant prognostic factors. Results There was no patients delayed by more than grade 3 radiation toxicity. The median overall survival and 1-year survival rates was 69 weeks and 73%, respectively. The progression free survival and 1-year progression-free survival rate were 43 weeks and 39%, respectively. The pattern of failure was identical(9 Local, 7 distant and 0 marginal recurrence). Multivariate analyses show that temozolomide concurrent chemoradiotherapy were independent factors correlated to prognosis. Conclusions The preliminary results demonstrate that SIB-IMRT for glioblastoma appear to be effective and safe. With the limted number of patients in this group, SIB-IMRT could be used for treating glioblastoma with caution, which deserves further study. Key words: Glioblastoma/intensity modulated radiotherapy; Intensity modulated radiotherapy, simultaneous integrate boost; Safety analysis

72. Enhancement of Immune Responses to Measles Virotherapy with aPD-1 Therapy for Improved Efficacy in Glioblastoma Therapy

Glioblastoma (GBM) is one of the most lethal malignancies with a median survival of 12-16 months. There is urgent need for improved therapies. Use of the measles virus (MV) Edmonston vaccine strain lineage for GBM virotherapy is a promising direction due to the excellent safety record and demonstrated pre-clinical efficacy in multiple patient derived orthotopic models. GBM have been shown to be immune suppressive, subverting both the innate (da Fonseca et.al. 2013) and adaptive immune systems (Wei et.al. 2010). GBM have been shown to express PD-L1, MHC-1, and down regulate MHC-II compared to non-neoplastic tissue, thereby aiding in immune evasion and suppression. Furthermore GBM can induce PD-L1 expression on tumor associated macrophages and increase PD-1 expression on peripheral blood T cells, further bolstering an immune suppressive environment. Anti PD-1 therapy with mAB (aPD-1) blocks the binding of PD-1 to its ligands, thereby preventing T cell inactivation, and was previously reported to have synergistic effects in combination with radiation therapy in GBM (Zeng et.al. 2013). We therefore sought to combine aPD-1 therapy and MV therapy of GBM to enhance immune responses and improve therapeutic outcome. Herein we present our preliminary findings. We first sought to characterize PD-L1 expression on our primary patient derived GBM and murine GBM cells and found a significant up regulation of PD-L1 and HLA-ABC upon IFN-γ stimulation, indicating functionality of these immune evading mechanisms. Next we determined if T cells trafficked to GBM following MV therapy and whether aPD-1 therapy could affect T cell influx as assessed by MRI. Briefly, C57/Blk6 mice bearing GL261 syngeneic orthotopic GBM were treated with MV-EGFR, UV-MV-EGFR, or MV-EGFR+aPD-1 on days 5 and 9 post tumor implantation. Day 11 post tumor implantation mice received tail-vein injections of monocrystalline iron oxide particles conjugated to CD4 and CD8 mAB. MRI 24 hrs later demonstrated a significant influx of T cells into the brains of mice treated with MV-EGFR+aPD-1. To examine the effect of aPD-1 on the immune system in vitro, we established co-cultures of patient derived primary GBM39 or murine GL261 GBM cells, overlaid with BV2 microglia. GBM39 cells were infected with MV-GFP and murine GL261 cells were infected with MV-EGFR (MOI=3). Cultures were treated with either 1 or 20mg/ml of aPD-1 and overlaid with BV2. Twenty four hours later the co-cultures were harvested and rtQPCR performed: results showed a significant increase in mRNA for IFN-α, IFN-β in both GBM39 and GL261 co-culture models when aPD-1 was present at 1μg/mL. aPD-1 also increased BV2 migration towards MV-GFP infected GBM39 and MV-EGFR infected GL261 cells (MOI=3) in a transwell system. Lastly, survival analysis of mice bearing orthotopic syngeneic GL261 GBM treated with MV-EGFR (2×105 TCID50 × 4 doses), aPD-1 (10mg/kg × 3 doses), MV-EGFR+ aPD-1 or untreated showed a significant prolongation of survival for mice treated with MV-EGFR+aPD-1 compared to the other treatment groups (P=0.009, 0.038, and 0.003 respectively). Additional in vitro and in vivo experiments are ongoing. Funding by: Brain SPORE (P50 CA108961), R01 CA154348, T32 NS 07494.

Radiation therapy of glioblastoma.

Glioblastoma multiforme (GBM) is the most common malignant brain tumor that affects approximately 17,000 patients annually. Clear survival advantages have been demonstrated with postoperative radiation therapy (RT) to doses of 5,000-6,000 cGy but dose-escalation attempts beyond 6,000 cGy have resulted in increased toxicity but no additional survival benefit. To improve local control and limit toxicity to normal brain tissue with these infiltrating tumors, novel imaging techniques are actively being explored to better define tumor extent and associated RT treatment fields. Hyperfractionated RT has been associated with a survival detriment. Current standard-of-care treatment involves concurrent use of temozolomide and RT to 6,000 cGy over 30 days followed by adjuvant temozolomide treatment for 6 months. Brachytherapy and stereotactic radiosurgery are effective therapies for relapsed GBM but tend to be associated with notable toxicity. More recently, re-irradiation strategies employ concurrent use of bevacizumab to limit treatment-related injury while still permitting delivery of meaningful doses. These clinical trials are ongoing and merits of these strategies are not yet clear but appear promising.