Recurrent High-grade Glioma Research Articles

Dose-dense temozolomide for recurrent high-grade gliomas: a single-center retrospective study.

There are limited treatment modalities after high-grade gliomas recurrence. MGMT depletion modulated by dose-dense temozolomide (ddTMZ) remains a debated therapy for initial TMZ responders. Patients were selected retrospectively from our practice with diagnosis of high-grade gliomas (WHO grade III or IV), and were followed since the start of ddTMZ until death or change of therapy. Twenty-one patients were reviewed, with a median age of 47 (25-61) years and a median of 5.8 (1.5-38.8) cycles of ddTMZ. The majority were males (71.4%). Sixty-six percent received 21 on/28 off ddTMZ schedule, 28.6% daily, and 1 patient received a 7days on/7days off schedule. IDH mutation status was available for 18 (85.7%) patients, with 7 (33.3%) IDH mutant and 11 (52.5%) IDH wild type. MGMT methylation was assessed in 6 (28.6%) of the patients, being MGMT methylated in 3 (14.3%) patients, and non-methylated in 3 (14.3%) patients. The majority of patients (57.1%) were receiving ddTMZ in addition to other forms of therapy, including either bevacizumab (38.1%) or tumor-treating fields (TTFields) (19.1%). Overall ddTMZ was well tolerated, with few adverse events reported. The estimated median overall survival after ddTMZ start was 11months. Median progression-free survival (PFS) was 6months. Outcomes did not vary between patients receiving ddTMZ alone or those using TTFields or bevacizumab as concomitant therapy, but there was a trend to longer survival with the use of concomitant TTFields. Our results demonstrate benefit of ddTMZ after previous treatment with standard TMZ dosing with no apparent increase in treatment-related toxicities. In summary, ddTMZ should be considered in TMZ responsive patients and warrants further investigation.

The roles of PKCs in regulating autophagy.

Autophagy, as a highly conserved cellular degradation and recycling process, plays an important part in maintaining cellular homeostasis. PKC signaling is involved in multiple pathways including cell cycle progression, tumorigenesis, migration and autophagy. Literatures about PKC and autophagy from PubMed databases were reviewed in this study. Studies regarding the association of PKC and autophagy remain debatable. Different duration of the stimulation of autophagy and distinct cell contexts result in different function of PKC in regulating autophagy. The subcellular localization of PKCs and their downstream regulators may influence the autophagy regulation as well. As important intracellular components, the mitochondria play an important role in regulating autophagy, by metabolic modulation and structural derangement. Phase II studies regarding PKC-β inhibitor, enzastaurin, showed promising results in MCL, DLBCL and recurrent high-grade gliomas. However, the detailed mechanism is still in need. The mechanism of PKC-β in mediating autophagy in lymphoma and high-grade gliomas remains elusive as well. Moreover, several studies were in agreement that rottlerin enhanced autophagy in breast cancer cells, which warrants further clinical studies to verify PKC-δ as a therapeutic target. Thus, identifying the function of PKC in modulating autophagy and conducting related clinical studies help find novel target for chemotherapy.

5-Aminolevulinic acid fluorescence guided surgery for recurrent high-grade gliomas.

Fluorescence guided surgery (FGS) with five-aminolevulinic acid (5-ALA) is expected to revolutionize neurosurgical care of patients with high-grade gliomas (HGG). After the recent landmark FDA approval, this optical agent is now available to neurosurgeons in the United States. This review is designed to highlight the evidence for the use of 5-ALA in recurrent HGG surgery for the neurosurgical community. The manuscript was prepared in accordance with the PRISMA guidelines. Intra-operatively, a strong fluorescent signal is highly correlated with the presence of cellular tumor in recurrent HGG, giving it a high positive predictive value (PPV). Similar to what is observed in primary HGG surgery, false-negative results can occur if tumor cells do not emit fluorescence. In addition, false-positive fluorescence signals in tissues devoid of tumor cells can be observed more frequently in recurrent HGG compared to the primary setting. However, these areas overwhelmingly contain reactive/regressive tissue, resection of which is unlikely to cause functional deficits. The safety profile of 5-ALA is similarly favorable in primary and recurrent HGG. 5-ALA FGS is a powerful adjunct in the resection of recurrent HGG with a high PPV and favorable safety profile. It is therefore the authors' opinion to routinely employ this fluorescent agent as a standard of care.

Comparative effect of immunotherapy and standard therapy in patients with high grade glioma: a meta-analysis of published clinical trials

Immunotherapy holds great promise in the treatment of high grade glioma (HGG). We performed a comprehensive meta-analysis of clinical trials involving dendritic cell (DC) therapy and viral therapy (VT) for the treatment of HGG, in order to assess their clinical impact in comparison to standard treatments in terms of overall survival (OS) and progression-free survival (PFS). To our knowledge, this is the first meta-analysis to evaluate VT for the treatment of HGG, allowing comparison of different immunotherapeutic approaches. Thirteen eligible studies of 1043 cases were included in the meta-analysis. For DC vaccination, in terms of OS, both newly diagnosed patients (HR, 0.65) and patients who suffered from recurrent HGGs (HR = 0.63) presented markedly improved results compared to the control groups. PFS was also improved (HR = 0.49) but was not statistically significant (p = 0.1). A slight improvement was observed for newly diagnosed patients receiving VT in terms of OS (HR = 0.88) while PFS was inferior for patients in the experimental arm (HR = 1.16). Our results show that DC therapy greatly improves OS for patients with both newly diagnosed and recurrent HGGs. VT, however, did not provide any statistically significant improvements in terms of OS and PFS for patients with newly diagnosed HGGs.

Re-irradiation for malignant glioma: Toward patient selection and defining treatment parameters for salvage

PurposeReirradiation for recurrent glioma remains controversial without knowledge of optimal patient selection, dose, fractionation, and normal tissue tolerances. We retrospectively evaluated outcomes and toxicity after conventionally fractionated reirradiation for recurrent high-grade glioma, along with the impact of concurrent chemotherapy. Methods and materialsWe conducted a retrospective review of patients reirradiated for high-grade glioma recurrence between 2007 and 2016 (including patients with initial low-grade glioma). Outcome metrics included overall survival (OS), prognostic factors for survival, and treatment-related toxicity. ResultsPatients (n = 118; median age 47 years; median Karnofsky performance status score: 80) were re-treated at a median of 28 months (range, 5-214 months) after initial radiation therapy. The median reirradiation dose was 41.4 Gy (range, 12.6-54.0 Gy) to a median lesion volume of 202 cm3 (range, 20-901 cm3). The median cumulative (initial radiation and reirradiation combined) potential maximum brainstem dose was 76.9 Gy (range, 5.0-108.3 Gy) and optic apparatus dose was 56.0 Gy (range, 4.5-90.9 Gy). Of the patients, 56% received concurrent temozolomide, 14%, bevacizumab, and 11%, temozolomide plus bevacizumab; 19% had no chemotherapy. The planned reirradiation was completed by 90% of patients. Median OS from the completion of reirradiation was 9.6 months (95% confidence interval [CI], 7.5-11.7 months) for all patients and 14.0, 11.5, and 6.7 months for patients with initial grade 2, 3, and 4 glioma, respectively. On multivariate analysis, better OS was observed with a >24-month interval between radiation treatments (hazard ratio [HR]: 0.3; 95% CI, 0.2-0.5; P < .001), reirradiation dose >41.4 Gy (HR: 0.6; 95% CI, 0.4-0.9; P = .03), and gross total resection before reirradiation (HR: 0.6, 95% CI, 0.3-0.9; P = .02). Radiation necrosis and grade ≥3 late neurotoxicity were both minimal (<5%). No symptomatic persistent brainstem or optic nerve/chiasm injury was identified. ConclusionsSalvage reirradiation, even at doses >41.4 Gy in conventional fractionation, along with chemotherapy, was safe and well tolerated with meaningful survival duration. These data provide information that may be useful in implementing safe reirradiation treatments for appropriately selected patients and guiding future studies to define optimal reirradiation doses, maximal safe doses to critical structures, and the role of systemic therapy.

Efficacy of Gamma Knife Radiosurgery for Recurrent High-Grade Gliomas with Limited Tumor Volume.

ObjectiveThis study aims to determine whether gamma knife radiosurgery (GKR) improves survival in patients with recurrent highgrade gliomas.MethodsTwenty nine patients with recurrent high-grade glioma underwent 38 GKR. The male-to-female ratio was 10 : 19, and the median age was 53.8 years (range, 20–75). GKR was performed in 11 cases of recurrent anaplastic oligodendrogliomas, five anaplastic astrocytomas, and 22 glioblastomas. The median prescription dose was 16 Gy (range, 10–24), and the median target volume was 7.0 mL (range, 1.1–15.7). Of the 29 patients, 13 (44.8%) received concurrent chemotherapy. We retrospectively analyzed the progression-free survival (PFS) and overall survival (OS) after GKR depending on the Eastern Cooperative Oncology Group (ECOG) performance status (PS), pathology, concurrent chemotherapy, radiation dose, and target tumor volume.ResultsStarting from when the patients underwent GKR, the median PFS and OS were 5.0 months (range, 1.1–28.1) and 13.0 months (range, 1.1–75.1), respectively. On univariate analysis, the median PFS was significantly long in patients with anaplastic oligodendroglioma, ECOG PS 1, and target tumor volume less than 10 mL (p<0.05). Meanwhile, on multivariate analysis, patients with ECOG PS 1 and target tumor volume less than 10 mL showed improved PFS (p=0.043 and p=0.007, respectively). The median OS was significantly increased in patients with ECOG PS 1 and tumor volume less than 10 mL on univariate and multivariate analyses (p<0.05).ConclusionGKR could be an additional treatment option in recurrent high-grade glioma, particularly in patients with good PS and limited tumor volume.

Abstract 5630: Immune profile of tumor microenvironment helps predict response in patients treated with an investigational immunotherapeutic consisting of a retroviral replicating vector (Toca 511) and an extended-release formulation of 5-fluorocytosine (Toca FC)

Abstract Toca 511 (vocimagene amiretrorepvec) is an investigational, conditionally lytic, retroviral replicating vector (RRV). RRVs selectively infect cancer cells due to defects in innate and adaptive immune responses found in cancers that support virus replication, and cell division requirements for virus integration into the genome. Toca 511 spreads through cancer cells, stably delivering an optimized cytosine deaminase (CD) gene that converts the prodrug Toca FC (investigational, extended-release 5-fluorocytosine) into 5-fluorouracil (5-FU), a canonical chemotherapeutic. In preclinical tumor models, as infected cancer cells are killed, diffusible 5-FU also kills nearby susceptible cells, including uninfected cancer cells, and myeloid derived suppressor cells (MDSC) that contribute to immune-suppression in the tumor microenvironment. This action by Toca 511 and Toca FC has been shown in animal models to generate a durable anti-tumor immune response that can be transferred to naïve, untreated animals. The Toca 511 and Toca FC immunotherapeutic are proposed to remodel the tumor microenvironment to break tumor tolerance resulting in induction of antitumor activity by the patient's immune system and durable complete responses. In a phase 1 clinical study for recurrent high grade glioma (NCT01470794), Toca 511 was injected into resection cavity walls at time of resection followed by multiple courses of oral Toca FC. We observed multi-year durable and objective responses; including 5 ongoing complete responses in a group of 23 patients in the higher dose single agent treatment cohorts given approximately the same Toca 511 doses and having the same entry criteria as an ongoing Phase 3 study in recurrent high grade glioma (NCT02414165). Patient tumors at time of resection were analyzed by exome sequencing, RNA sequencing, IHC, and TCR sequencing, before Toca 511 treatment. In this study, we report higher levels of tumor infiltrating T cells by TCR sequencing, before the start of treatment, were significantly associated with responding patients compared to patients whose disease progressed. The significance of this data is supported by the preclinical mechanism of action reported previously. Additionally, we plan to report on T cell, B cell, and myeloid populations in the tumor as measured by IHC and RNA sequencing and their relationship to clinical response. Data reported here will provide mechanistic context to the immunotherapeutic mode of action proposed to account for durable responses seen in treatment of brain tumors with Toca 511 and Toca FC. Citation Format: Derek Ostertag, William Accomando, Leah Mitchell, Maria Rodriguez-Aguirre, Daniel Hogan, Oscar Diago, Dawn Gammon, Ali Haghighi, Harry Gruber, Asha Das, Douglas Jolly. Immune profile of tumor microenvironment helps predict response in patients treated with an investigational immunotherapeutic consisting of a retroviral replicating vector (Toca 511) and an extended-release formulation of 5-fluorocytosine (Toca FC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5630.

Abstract CT092: Effect of tumor treating fields in children with recurrent or progressive high-grade glioma and ependymoma; Pediatric Brain Tumor Consortium PBTC048

Abstract Background: Current treatment regimens show poor prognosis in recurrent or progressive pediatric CNS tumors. Children with high-grade gliomas (HGG) after progression cannot be cured, with reported median survival &amp;lt;1-2 years. Overall survival (OS) of pediatric recurrent/progressive ependymoma is also poor. Tumor Treating Fields (TTFields) is an anti-mitotic cancer therapy for the treatment of recurrent (supratentorial) glioblastoma (GB). A phase 3 clinical trial in adults with newly-diagnosed GB was stopped early due to significant improvements of event-free (EFS) and OS in patients receiving TTFields in conjunction with temozolomide. A separate phase 3 trial comparing TTFields monotherapy with physician's choice chemotherapy in adults with recurrent GB demonstrated comparable OS and improved quality-of-life (QoL). Methods: This multicenter feasibility trial [NCT03033992] will examine the feasibility and device-related toxicity of TTFields in children aged 5-21 years with supratentorial HGG and ependymoma. The secondary objectives include: response rate, event-free survival, compliance and QoL. To establish feasibility Optune device will need to be worn ≥18 hours/day for at least 23/28 days of cycle one. Patients will have a brain MRI with/without contrast performed prior to therapy, after cycles 2, 4, 6, 9, then every 3 cycles thereafter until time of progression or completion of treatment. Treatment may continue up to 26 cycles based on observed benefit and safety. A sample size of 20 patients is planned with an interim analysis after the first 11 patients. Kaplan-Meier estimates of EFS for all eligible patients will be provided separately for the HGG and ependymoma cohorts. The rates of confirmed sustained objective responses (CR+PR) observed during treatment will be estimated. All PROMIS and Neuro-QoL scores will be reported using T-score matrix (mean=50; SD=10). The projected accrual rate is 1.5-2.5 patients per month with a follow-up for 2 years. The study is currently accruing patients. Citation Format: Stewart Goldman, Arzu Onar-Thomas, Ira Dunkel, Eugene Hwang. Effect of tumor treating fields in children with recurrent or progressive high-grade glioma and ependymoma; Pediatric Brain Tumor Consortium PBTC048 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr CT092.

Abstract 5927: Assessing the efficacy of a novel gene therapy approach for treating ovarian cancer: Combination RRV-mediated prodrug activated suicide gene therapy

Abstract Introduction/Aim: Retroviral replicating vectors (RRVs) afford a unique strategy for gene therapy targeting cancer cells. By “activating” RRVs with prodrug activator suicide genes, these RRVs become strong gene delivery vehicles that replicate selectively in cancer cells, and stably persist through proviral genomic integration, leading to inducible cell death upon prodrug administration. This strategy has shown highly promising clinical results in early phase trials (published), and is currently being evaluated in an international Phase III clinical trial for patients with recurrent high-grade glioma. Recently, we have also applied RRV-mediated gene therapy to preclinical models of ovarian cancer. The aim of this current study was to evaluate feasibility and efficacy of combination suicide gene therapy using two RRVs encoated (‘pseudotyped') with different envelope proteins and delivering different prodrug activators for the treatment of ovarian cancer. Methods: Viral spread was monitored in established and primary patient-derived ovarian cancer cell lines (SKOV3, OCI-P5X, OCI-C5X) over the course of ≥27 days using amphotropic murine leukemia virus (AMLV) envelope- and gibbon ape leukemia virus (GALV) envelope-pseudotyped RRVs delivering either fluorescent protein reporter genes (GFP, mStrawberry) or prodrug activator genes (yeast cytosine deaminase, E. coli nitroreductase), either individually or in combination, at various multiplicities of infection (MOI). Flow cytometry for GFP, mStrawberry, and Gag viral protein was used to determine transduction levels and transgene expression levels of RRVs at serial time points. Each therapeutic RRV was tested by MTS assay for its ability to induce cytotoxicity upon exposure to different concentrations prodrug. To determine viral integration and vector stability, PCR of genomic DNA extracted from infected cells was performed using RRV specific primers, and qRT-PCR was performed to determine vector copy number per cell. Results: All ovarian cancer cell lines tested could be &amp;gt;80% transduced by AMLV- and GALV-pseudotyped RRVs, both individually and in combination, within 6-24 days even after initial inoculation at MOI 0.001, with replication kinetics varying between different cell lines. Both RRVs could stably integrate into the target cell genome without evidence of transgene deletion. MTS assays demonstrated that prodrug activated cytotoxicity led to efficient killing of RRV-transduced ovarian cancer cells in vitro, with synergistic cytotoxicity observed at lower prodrug concentrations after combined treatment. Conclusion: RRV-mediated prodrug activator gene therapy may be an effective approach for efficiently and selectively inducing cytotoxicity in ovarian cancer cells. These data support further evaluation of this strategy through translational studies in vivo. Citation Format: James Grosso, Sara Collins, Aki Inagaki, Brian Slomovitz, Noriyuki Kasahara. Assessing the efficacy of a novel gene therapy approach for treating ovarian cancer: Combination RRV-mediated prodrug activated suicide gene therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5927.

Abstract 3857: Selective targeting of dopamine receptor dysregulation in high grade gliomas with imipridone ONC201

Abstract D2-like dopamine receptors (DRD2/3/4) are G protein-coupled receptors (GPCRs) that are overexpressed in glioblastoma (GBM) and their antagonism induces tumor cell apoptosis. We describe the first selective DRD2/3 antagonist for neuro-oncology using computational, receptor pharmacology, biochemical and clinical studies. Consistent with an in-silico prediction and in contrast to antipsychotics that target several dopamine receptors and other GPCRs, β-arrestin recruitment and cAMP assays determined that ONC201 is a selective DRD2/3 antagonist. Schild analyses and radioligand competition assays revealed competitive and non-competitive DRD2 antagonism with a potency (2-3 µM) that is consistent with anticancer activity and driven by an unusually slow association rate. Proof-of-concept studies show that selective DRD2 inhibition induces superior anti-cancer efficacy relative to pan-targeting of the dopamine receptor family. In accordance with superior selectivity, ONC201 also exhibited a wider therapeutic window compared to antipsychotics. Shotgun mutagenesis across 350 amino acids of DRD2 identified 8 residues that are critical for ONC201-mediated DRD2 antagonism. Consistent with competitive inhibition, several mutated residues were within the orthosteric binding site. However, distal residues were identified that were not involved in DRD2 antagonism by antipsychotics and may explain the selectivity and non-competitive antagonism of ONC201. In vitro and in vivo studies have previously demonstrated single agent ONC201 efficacy in GBM models (Allen et al 2013). Analyses of The Cancer Genome Atlas and tissue microarrays revealed high DRD2 expression relative to other dopamine receptors, correlation with poor prognosis and high DRD2 expression in primary rather than secondary GBM. A linear correlation between DRD2 mRNA and ONC201 GI50 was observed among GBM cell lines in the NCI60 panel. Interestingly expression of DRD5, a D1-like dopamine receptor that counteracts DRD2 signaling, was significantly inversely correlated with ONC201 potency in the NCI60 dataset (P &amp;lt;.05). Furthermore, a de novo missense DRD5 mutation was identified in cancer cells with acquired resistance to ONC201, and overexpression of the mutant construct could recapitulate resistance. ONC201 exhibited biological activity in a phase II recurrent GBM study, including tumor regressions (Arrillaga et al, 2017). Among the 15 available archival patient tumor specimens from the first cohort of this trial, all had DRD2 expression and 8 had low DRD5 expression that was associated with superior progression-free and overall survival, with 4/8 DRD5- and 0/7 DRD5+ patients alive after 15 months (P=0.012). Thus, ONC201 possesses unique receptor pharmacology as the first selective DRD2/3 antagonist for clinical neuro-oncology that has exhibited clinical activity in biomarker-defined recurrent high grade glioma patients. Citation Format: Varun Vijay Prabhu, Neel Madhukar, C. Leah B. Kline, Rohinton Tarapore, Wafik S. El-Deiry, Joseph Rucker, Benjamin Doranz, Faye Doherty, Alexander VanEngelenburg, Jessica Durrant, Cyril Benes, Sean Deacon, Neil Charter, R. Benjamin Free, Wolfgang Oster, David Sibley, Isabel Arrillaga, Olivier Elemento, Joshua E. Allen. Selective targeting of dopamine receptor dysregulation in high grade gliomas with imipridone ONC201 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3857.

Survival gain with re-Op/RT for recurred high-grade gliomas depends upon risk groups

IntroductionA majority of high-grade gliomas relapse despite combined surgery, radiotherapy and chemotherapy. There is no consensus on standard treatment for recurrent high-grade gliomas, or defined efficacy of adjuvant re-RT after re-Op. This retrospective study evaluated the benefit and safety of re-RT after re-Op (re-Op/RT). Materials and methodsA total of 84 patients with recurrent high-grade gliomas who underwent reoperation from 2009 to 2015 were analyzed. All patients received neurosurgical intervention and adjuvant radiotherapy previously before recurrence. At recurrence and after reoperation, treatment options were discussed in multidisciplinary clinic or brain tumor joint conference. For re-RT, cumulative EQD2 (equivalent dose in 2 Gy fractions at α/β = 2) was below 106.9 Gy. ResultMedian progression free survival (PFS) was 6.5 months; 3.5 months with re-Op, 9.0 months with re-Op/RT (p = 0.025). Age <50, time interval to recur ≥12 months, WHO pathologic grade III, methylated MGMT promotor, and re-RT were factors enhancing PFS in the multivariate analysis. Median overall survival (OS) was 18.3 months: 12.7 months with re-Op, and 28.1 months with re-Op/RT (p = 0.066). Three risk factors (age >50, WHO grade IV, and unmethylated promoter of MGMT) were significantly associated with poor OS in multivariate analysis. Benefit of re-RT in both OS and PFS was established in patients carrying 2 or more risk factors. During re-RT, 4 patients (8%) had grade 2 or higher toxicity, and 3 patients (6%) did not complete re-RT. No radionecrosis was observed. ConclusionRe-RT after re-Op was tolerable with a cumulative median EQD2 of 99.3 Gy and resulted in clear benefit in PFS and marginal gain in OS. Survival gain with re-Op/RT was more prominent in patients with two or more risk factors (age ≥50, WHO pathologic grade IV, unmethylated MGMT promoter), and needs to be validated.

A Retrospective Review of Re-irradiating Patients' Recurrent High-grade Gliomas

AimsAfter radical treatment, most high-grade gliomas (HGG) recur locally. Upon recurrence, no standard treatment exists. Options include re-resection, salvage systemic therapy and re-irradiation. This retrospective study evaluated patients who underwent re-irradiation for recurrent HGGs and assessed prognostic factors and their influence on management. Materials and methodsEighty-two patients who underwent re-irradiation for HGG from 2009 to 2014 were retrospectively identified. Re-irradiation consisted of either standard three-dimensional conformal, intensity-modulated radiotherapy or highly conformal stereotactic radiotherapy using mostly volumetric modulated arc therapy. Patient survival from re-irradiation was the primary end point. Survival was estimated via the Kaplan–Meier method with differences assessed using the Log-rank test; hazard ratios were estimated using Cox regression analysis. ResultsThe median overall survival from re-irradiation was 9.5 months. Re-irradiation, to a median dose of 35 Gy in 10 fractions, was well tolerated: 4% developed grade 3 toxicity, no patients experienced grade ≥4 or radionecrosis. In the multivariate analysis, factors significantly associated with increased survival included: longer duration from initial radiotherapy, better performance status at re-irradiation of 0–1 versus ≥2, unifocal versus multifocal recurrence and higher total re-irradiation dose (≥35 Gy versus <35 Gy). Re-resection, salvage systemic therapy and age were unrelated to survival. ConclusionPatients with recurrent HGG tolerated re-irradiation well with minimal toxicity. Those patients in good prognostic groups, including good performance status can achieve durable control, suggesting managing patients with regular magnetic resonance imaging surveillance post-radical treatment, identifying early radiological progression and instituting salvage therapy when performance status is best.

Surgery for recurrent high-grade gliomas: the dilemma of debate

Abstract Background: Treating recurrent gliomas is a big dilemma in the literature and no uniform protocol is approved to treat such disappointing problem. Although improvement in the RT techniques, new CTX techniques and new techniques including targeted therapy and gene therapy; all fail to dramatically improve the outcome and solve the problem of significant mass effect when the recurrent tumor is big So resurgery play a role in treating such challenging problem. The aim of the study: to assess the goal and outcome of surgery in treatment of recurrent malignant glioma. Methods: We retrospectively analyzed the data of 56 patients who were operated upon for recurrent or progressed high grade gliomas in the Mansoura neurosurgery department allover 2007 to 2016. We have excluded patients with recurrent thalamic gliomas and patients with Kps score less than 70. Results: 12 patient underwent sterotactic biopsy for their tumor and were sent for adjuvant radiotherapy, 29 patients underwent partial tumor resection and gross total resection was done in 15 patients. The median time to progression was 5 months. All patients were sent after surgery for poster radiotherapy and chemotherapy. The median overall survival was 4 months. Conclusion: Recurrent high grade glioma is one of unsolved problem and optimal management is no longer available. Redo surgery is quiet challenging with higher minorities and no add to overall survival. Surgery is indicated to relieve significant mass effect. Outcome of surgery is better for those who did aggressive surgical resection at initial surgery than those who did only partial resection.

25 Durable complete responses observed in patients with recurrent high grade glioma treated with Toca 511 &amp; Toca FC

Toca 511 (vocimagene amiretrorepvec) is an investigational retroviral replicating vector that selectively infects dividing cancer cells, integrates into the genome and replicates due to immune defects in tumors. Toca 511 spreads through tumors and stably delivers the gene encoding an optimized yeast cytosine deaminase that converts the prodrug Toca FC (investigational, extended-release of 5-fluorocytosine) into 5-fluorouracil. In preclinical models, 5-fluorouracil kills infected dividing cancer cells, myeloid derived suppressor cells and tumor associated macrophages, enabling immune activation against the tumor. In this dose ascending Ph1 trial (NCT01470794), Toca 511 was injected into the resection cavity wall of patients with rHGG, followed by courses of oral Toca FC. Additional cohorts included combination with bevacizumab or lomustine. Across the Ph1 program, the safety profile remains favorable. Objective responses (ORs) were assessed by IRR using MRI scans prior to Toca FC treatment as baseline. ORs occurred 6-19 months after Toca 511 administration, suggesting an immunologic mechanism. The ORs were observed in 4 patients with IDH1-wildtype and 2 patients with IDH1-mutant tumors, including 5 complete responses (CRs) with the investigational therapy alone, and 1 CR in combination with bevacizumab. The median duration of response (mDoR) was 35.1+ months. As of AUG2017, all responders were CR and remain alive. In a 23-patient subgroup who received high doses of Toca 511 and met Ph3 trial criteria, mOS was 14.4 months, 3-year survival rate was 26.1%, and mDoR was 35.7+ months with a durable response rate of 21.7%. Data suggest a positive association of durable response with OS.

First in human phase I study of chlorogenic acid injection in recurrent high grade glioma.

e14081Background: Chlorogenic acid (CHA) is a natural product with good antitumor activity in preclinical study. A phase I clinical trial of CHA injection was conducted to determine tolerance, safe...

A phase I expansion study of pegargiminase, cisplatin, and pemetrexed in argininosuccinate synthetase 1-negative recurrent high grade gliomas (HGGs).

e14085Background: Patients (pts) with recurrent HGGs are usually managed with alkylating chemotherapy +/- bevacizumab. However, prognosis remains poor with an overall survival (OS) of 7-9 months. P...

Retrospective study of nivolumab for patients with recurrent high grade gliomas.

Patients with recurrent high-grade gliomas (HGG) have limited treatment options. HGG utilize the PD-1 pathway to evade immune responses. Checkpoint inhibitors have demonstrated safety and clinical activity in patients with recurrent glioblastoma. We explored the efficacy of nivolumab in recurrent HGG with a primary objective of progression free survival (PFS) and overall survival (OS). We retrospectively analyzed HGG patients treated with nivolumab in our institution. We included patients with advanced HGG who received nivolumab at their oncologist's decision. Patients received nivolumab 3mg/kg every 2 weeks until confirmed progression, intolerable toxicity, death, or physician decision. Radiographic assessments were performed every 8 weeks. Between April 2015 and October 2017, 50 HGG patients received nivolumab. 43 patients received nivolumab with bevacizumab. 44 patients were bevacizumab refractory and 7 patients received nivolumab monotherapy. All had received prior radiation and chemotherapy. 39 adverse events (AEs) were noted [most commonly fatigue (16%) and constipation (10%)]. 4 (8%) patients experienced grade 3-4 AEs. 36 (72%) patients experienced stable disease (SD) at the 2-month assessment. Median duration of SD was 4.3 months (5.1 months in the bevacizumab naïve, 3.8 months in the bevacizumab refractory). Median PFS was 4.3 months (95% CI 3.5-5.3); median OS was 6.5 months (95% CI 6.0-8.8). Treatment with nivolumab therapy was associated with a manageable safety profile. In a subset of patients, there was disease stabilization in heavily pre-treated recurrent HGG.

Impact of 18F-FET PET on Target Volume Definition and Tumor Progression of Recurrent High Grade Glioma Treated with Carbon-Ion Radiotherapy

High-precision radiotherapy (HPR) of recurrent high grade glioma (HGG) requires accurate spatial allocation of these infiltrative tumors. We investigated the impact of 18F-FET PET on tumor delineation and progression of recurrent HGG after HPR with carbon ions. T1 contrast enhanced MRI and 18F-FET-PET scans of 26 HGG patients were fused with radiotherapy planning volumes. PET-positive (PET+) tumor volumes using different isocontours (I%) were systematically investigated and compared with MRI-derived gross tumor volumes (GTV). Standardized uptake ratios (SUR) were further correlated with GTV and tumor progression patterns. In grade IV glioma, SUR > 2.92 significantly correlated with poor median overall survival (6.5 vs 13.1 months, p = 0.00016). We found no reliable SUR cut-off criteria for definition of PET+ volumes. Overall conformity between PET and MRI-based contours was low, with maximum conformities between 0.42–0.51 at I40%. The maximum sensitivity and specificity for PET+ volumes outside of GTV predicting tumor progression were 0.16 (I40%) and 0.52 (I50%), respectively. In 75% of cases, FLAIR hyperintense area covered over 80% of PET+ volumes. 18F-FET-PET derived SUR has a prognostic impact in grade IV glioma. The value of substantial mismatches between MRI-based GTV and PET+ volumes to improve tumor delineation in radiotherapy awaits further validation in randomized prospective trials.

Policies for reirradiation of recurrent high-grade gliomas: a survey among Italian radiation oncologists.

To assess the contribution of Italian radiation oncologists in the current management of recurrent high-grade gliomas (HGG), focusing on a reirradiation (reRT) approach. In 2015, the Reirradiation and the Central Nervous System Study Groups on behalf of the Italian Association of Radiation Oncology (AIRO) proposed a survey. All Italian radiation oncologists were individually invited to complete an online questionnaire regarding their clinical management of recurrent HGG, focusing on a reRT approach. A total of 37 of 210 questionnaires were returned (18% of all centers): 16 (43%) from nonacademic hospitals, 14 (38%) from academic hospitals, 5 (13%) from private institutions, and 2 (6%) from hadron therapy centers. The majority of responding centers (59%) treated ≤5 cases per year. Performance status at the time of recurrence, along with a target diameter <5 cm and an interval from primary radiation ≥6 months, were the prevalent predictive factors considered for reRT. Sixty percent of reirradiated patients had already received a salvage therapy, either chemotherapy (40%) or reoperation (20%). The most common approach for reRT was fractionated stereotactic radiotherapy to a mean (photon) dose of 41.6 Gy. Although there were wide variations in the clinical practice of reRT across the 37 centers, the core activities were reasonably consistent. These findings provide a basis for encouraging a national collaborative study to develop, implement, and monitor the use of reRT in this challenging clinical setting.

Quantitative dynamic susceptibility contrast perfusion-weighted imaging-guided customized gamma knife re-irradiation of recurrent high-grade gliomas

Treatment of recurrent high-grade gliomas (rHGG) has always been challenging. This study aimed to explore the treatment effect of quantitative dynamic susceptibility contrast perfusion-weighted imaging (DSC-PWI)-guided gamma knife radiosurgery (GKRS) on rHGG. Between April 2014 and July 2016, 26 consecutive patients were treated by quantitative DSC-PWI-guided GKRS as salvage treatment for rHGG. The gross tumor volume (GTV) was defined as the high perfusion area on absolute cerebral blood volume maps, with a cutoff value of 22ml/100g. The clinical target volume (CTV) encompassed the GTV by 3mm. Overall survival (OS) and progression-free survival (PFS) were calculated by the Kaplan-Meier method. Prognostic factors were tested by the log-rank (Mantel-Cox) test. With a median follow-up of 32 months, the median PFS after GKRS was 8months (95% CI [6, 12]); the 1- and 2-year survival rates were 30.8 and 11.5%, respectively. The median OS was 25.5months (95% CI [18, 40]); the 1- and 2-year survival rates were 96.2 and 57.7%, respectively. Pathology grade and CTV were identified as prognostic factors for PFS. However, none of the parameters tested were independent prognostic factors for OS among these selected patients. No severe radiotoxicity was observed among all patients. Quantitative DSC-PWI-guided GKRS is feasible for the treatment of rHGG and that these outcomes remain to be validated. Despite this, we think that carefully selected patients can benefit from this treatment method.