scholarly journals DIPG-77. TREATMENT EXTENT AND THE EFFECT ON SURVIVAL IN DIFFUSE INTRINSIC PONTINE GLIOMA

2020 ◽  
Vol 22 (Supplement_3) ◽  
pp. iii302-iii302
Author(s):  
Joshua Baugh ◽  
Niclas Colditz ◽  
Geert Janssens ◽  
Stefan Dietzsch ◽  
Darren Hargrave ◽  
...  
Keyword(s):  
Progression Free Survival ◽  
Standard Of Care ◽  
Diffuse Intrinsic Pontine Glioma ◽  
Treatment Modalities ◽  
Front Line ◽  
Pontine Glioma ◽  
Treatment Groups ◽  
Respective Treatment ◽  
Radiotherapy Alone ◽  
Radio Chemotherapy

Abstract BACKGROUND Front line radiotherapy for diffuse intrinsic pontine glioma (DIPG) remains the only standard of care. Is this still appropriate? PATIENTS AND METHODS We examined survival outcomes across six treatment modalities including I) no treatment (n=19), II) radiotherapy alone (n=38), III) radio-chemotherapy (n=101), IV) radiotherapy and relapse chemotherapy (n=35), V) radio-chemotherapy and relapse chemotherapy (n=163), and VI) radio-chemotherapy and relapse chemotherapy, plus reirradiation (n=54). Data were collected retrospectively using the Society of Pediatric Oncology and Hematology (GPOH) and the SIOPE DIPG Registry. 410 patients were included with radiologically centrally reviewed DIPG, mostly unbiopsied. Of note, the untreated patients and radiotherapy only cohorts chose limited treatment voluntarily. RESULTS Median overall survival (MOS) of the whole cohort was 11 months and progression free survival (PFS) 7 months. PFS was not significantly different between the treatment groups. OS and post-progression survival (PPS) were significantly different between cohorts. For the respective treatment groups, median OS was 3 months (I), 7 months (II), 8 months (III), 13 months (IV), 13 months (V), and 15 months (VI). For only front line vs at least one second line therapy, MOS was 8 months vs 14 months and PPS 2 months vs 5 months. CONCLUSIONS Although subject to biases to some extent, it seems that additional therapies beyond radiation therapy are of benefit to extending survival in DIPG patients. This is at least partially caused by the introduction of reirradiation regimens. To what extent other therapies contribute to survival and quality of life is subject to further investigation.

scholarly journals DIPG-55. PATTERNS OF CEREBROSPINAL FLUID DIVERSION AND SURVIVAL IN CHILDREN WITH DIFFUSE INTRINSIC PONTINE GLIOMA: A REPORT FROM THE INTERNATIONAL DIPG REGISTRY

2020 ◽  
Vol 22 (Supplement_3) ◽  
pp. iii297-iii298
Author(s):  
Tabitha Cooney ◽  
Mariko DeWire-Schottmiller ◽  
Adam Lane ◽  
Raya Saab ◽  
Pratiti Bandopadhayay ◽  
...  
Keyword(s):  
Overall Survival ◽  
Survival Data ◽  
Clinical Symptoms ◽  
Progression Free Survival ◽  
Standard Of Care ◽  
Diffuse Intrinsic Pontine Glioma ◽  
Pontine Glioma ◽  
Exact Test ◽  
Significant Difference ◽  
Csf Diversion

Abstract There is no standard of care for cerebrospinal (CSF) diversion in children with diffuse intrinsic pontine glioma (DIPG), nor understanding of survival impact. We evaluated CSF diversion characteristics in children with DIPG to determine incidence, indications and potential impact on survival. Data was extracted from subjects registered in the International DIPG registry (IDIPGR). IDIPGR team personnel obtained clinical and radiographic data from the registry database and when appropriate, abstracted additional data from individual medical records. Univariable analyses were performed using the Fisher’s exact test or Wilcoxon rank sum test. Survival was estimated using the Kaplan-Meier method. Evaluable patients (n=457) met criteria for DIPG diagnosis by central radiology review. Ninety-two patients (20%) had permanent CSF diversion. Indications for permanent diversion were hydrocephalus (41%), hydrocephalus and clinical symptoms (35%), and clinical symptoms alone (3%). Those with permanent diversion were significantly younger at diagnosis than those without diversion (median 5.3 years vs 6.9 years, p=0.0002), otherwise no significant differences in gender, race, or treatment were found. The progression-free and overall survival of those with permanent CSF diversion compared to those without permanent diversion was 4.5 and 10.9 months vs 6.9 and 11.2 months, respectively (p=0.001, p= 0.4). There was no significant difference in overall survival in patients with or without permanent CSF diversion among a large cohort of DIPG patients. Patients without permanent diversion had significantly prolonged progression free survival compared to those with permanent diversion. The qualitative risks and benefits of permanent CSF diversion need to be further evaluated.

scholarly journals HG-45PSEUDOPROGRESSION AFTER RADIO-CHEMOTHERAPY IN CHILDREN WITH DIFFUSE INTRINSIC PONTINE GLIOMA (DIPG):IMPACT ON SURVIVAL IN PATIENTS TREATED WITH ERLOTINIB OR TEMOZOLOMIDE

2016 ◽  
Vol 18 (suppl 3) ◽  
pp. iii57.3-iii57
Author(s):  
Marion Gilbert-Yvert ◽  
Frederic Dhermain ◽  
Stephanie Bolle ◽  
Sandra Canale ◽  
Christelle Dufour ◽  
...  
Keyword(s):  
Diffuse Intrinsic Pontine Glioma ◽  
Pontine Glioma ◽  
Impact On Survival ◽  
Radio Chemotherapy

Bevacizumab plus radiotherapy for elderly patients with glioblastoma (ARTE).

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. TPS2105-TPS2105 ◽  
Author(s):  
Ghazaleh Tabatabai ◽  
Michael Weller
Keyword(s):  
Overall Survival ◽  
Elderly Patients ◽  
Progression Free Survival ◽  
Standard Of Care ◽  
Combined Modality Treatment ◽  
Newly Diagnosed ◽  
Free Survival ◽  
Biomarker Analysis ◽  
Radiotherapy Alone ◽  
Temozolomide Chemotherapy

TPS2105 Background: The standard of care for patients with newly diagnosed glioblastomas after surgical resection is radiotherapy with concomitant and adjuvant temozolomide chemotherapy. Yet, inclusion into the pivotal trial was limited to patients up to the age of 70, and subgroup analyses suggested that older patients did not gain benefit from combined modality treatment. Further, the efficacy of radiotherapy has been confirmed in a randomized trial comparing best supportive care versus radiotherapy alone. Of note, hypofractionated radiotherapy is equieffective in patients aged 65-70 years and more. Two randomized trials in elderly patients (NOA-08, Nordic Trial) indicated smilar efficacy of primary temozolomide chemotherapy alone compared with radiotherapy alone. Combined radiochemotherapy is compared with radiotherapy alone in an ongoing NCIC-CTG EORTC TROG Japanese group trial 26062-22061. Thus, radiotherapy alone is the standard of care for newly diagnosed glioblastoma of elderly patients. These clinical data justify the exploration of new, temozolomide-free first-line treatment strategies in elderly patients. Methods: The ARTE trial will therefore investigate bevacizumab when added to a short course of radiotherapy and bevacizumab maintenance therapy until progression. The translational research program shall include blood and urine biomarker analysis and FET-PET in addition to MRI for monitoring the course of the disease. This trial is an explorative randomized, non-comparative phase II trial aiming at recruiting 60 patients in Switzerland. Elderly patients (> 65) will be randomized 2:1 either to the experimental arm (bevacizumab plus radiotherapy) or the standard arm (radiotherapy). The primary endpoint is median overall survival. Secondary endpoints include overall survival at 6 months, overall survival at 12 months, median progression-free survival, progression-free survival at 6 months, median time to treatment failure.

scholarly journals Progress in diffuse intrinsic pontine glioma: advocating for stereotactic biopsy in the standard of care

2020 ◽  
Vol 48 (1) ◽  
pp. E4 ◽  
Author(s):  
John R. Williams ◽  
Christopher C. Young ◽  
Nicholas A. Vitanza ◽  
Margaret McGrath ◽  
Abdullah H. Feroze ◽  
...  
Keyword(s):  
Stereotactic Biopsy ◽  
Standard Of Care ◽  
Diffuse Intrinsic Pontine Glioma ◽  
Pontine Glioma ◽  
Brainstem Tumor ◽  
T Cell Therapy ◽  
The Us ◽  
Brainstem Tumors ◽  
Prospective Trials ◽  
Brainstem Biopsy

Diffuse intrinsic pontine glioma (DIPG) is a universally fatal pediatric brainstem tumor affecting approximately 300 children in the US annually. Median survival is less than 1 year, and radiation therapy has been the mainstay of treatment for decades. Recent advances in the biological understanding of the disease have identified the H3K27M mutation in nearly 80% of DIPGs, leading to the 2016 WHO classification of diffuse midline glioma H3K27M-mutant, a grade IV brainstem tumor. Developments in epigenetic targeting of transcriptional tendencies have yielded potential molecular targets for clinical trials. Chimeric antigen receptor T cell therapy has also shown preclinical promise. Recent clinical studies, including prospective trials, have demonstrated the safety and feasibility of pediatric brainstem biopsy in the setting of DIPG and other brainstem tumors. Given developments in the ability to analyze DIPG tumor tissue to deepen biological understanding of this disease and develop new therapies for treatment, together with the increased safety of stereotactic brainstem biopsy, the authors present a case for offering biopsy to all children with suspected DIPG. They also present their standard operative techniques for image-guided, frameless stereotactic biopsy.

Diffuse Intrinsic Pontine Glioma (DIPG): breakthrough and clinical perspective

2020 ◽  
Vol 27 ◽  
Author(s):  
Maria Grazia Perrone ◽  
Antonio Ruggiero ◽  
Antonella Centonze ◽  
Antonio Carrieri ◽  
Savina Ferorelli ◽  
...  
Keyword(s):  
High Throughput Screening ◽  
Antitumor Agents ◽  
Public Libraries ◽  
Suppressor Gene ◽  
Diffuse Intrinsic Pontine Glioma ◽  
New Drugs ◽  
Pontine Glioma ◽  
Radiotherapy Alone ◽  
Apoptotic Activity ◽  
Necrosis Factor

: Diffuse intrinsic pontine glioma (DIPG) mainly affects children with a median age of 6-7 years old. It accounts for 10% of all pediatric tumors. Unfortunately, DIPG has a poor prognosis, and the median survival is generally less than 16-24 months independently from the treatment received. Up to now, children with DIPG are treated with focal radiotherapy alone or in combination with antitumor agents. In the last decade, ONC201 known as dopamine receptor antagonist was uncovered, by a high throughput screening of public libraries of compounds, to be endowed with cytotoxic activity against several cancer cell lines. Efforts were made to identify the real ONC201 target, responsible for its antiproliferative effect. The hypothesized targets were the Tumor necrosis factor-Related Apoptosis-Inducing Ligand stimulation (TRAIL), two oncogenic kinases (ERK/AKT system) that target the same tumor-suppressor gene (FOXO3a), dopamine receptors (DRD2 and DRD3 subtypes) and finally the mitochondrial Caseynolitic Protease P (ClpP). Carried out ONC201 structure-activity relationship is extensively discussed in this review, together with other two classes of compounds, namely ADEPs and D9, already known for their antibiotic activity but noteworthy to be commented as potential “leads” for the development of new drugs to be used in the treatment of DIPG. In this review, a detailed and critical description of ONC201, ADEPs, and D9 pro-apoptotic activity is made, with particular attention to the specific interactions established with its targets that also are intimately described. Pubmed, published patents and clinical trial reports of the last ten years was the bibliographic source.

scholarly journals Cutting Edge Therapeutic Insights Derived from Molecular Biology of Pediatric High-Grade Glioma and Diffuse Intrinsic Pontine Glioma (DIPG)

2018 ◽  
Vol 5 (4) ◽  
pp. 88 ◽  
Author(s):  
Cavan Bailey ◽  
Mary Figueroa ◽  
Sana Mohiuddin ◽  
Wafik Zaky ◽  
Joya Chandra
Keyword(s):  
Clinical Trial Data ◽  
Standard Of Care ◽  
High Grade Glioma ◽  
Diffuse Intrinsic Pontine Glioma ◽  
High Grade ◽  
Pontine Glioma ◽  
Clinical Models ◽  
Malignant Glioma Cells ◽  
Epigenetic Disruption ◽  
Pediatric High Grade Glioma

Pediatric high-grade glioma (pHGG) and brainstem gliomas are some of the most challenging cancers to treat in children, with no effective therapies and 5-year survival at ~2% for diffuse intrinsic pontine glioma (DIPG) patients. The standard of care for pHGG as a whole remains surgery and radiation combined with chemotherapy, while radiation alone is standard treatment for DIPG. Unfortunately, these therapies lack specificity for malignant glioma cells and have few to no reliable biomarkers of efficacy. Recent discoveries have revealed that epigenetic disruption by highly conserved mutations in DNA-packaging histone proteins in pHGG, especially DIPG, contribute to the aggressive nature of these cancers. In this review we pose unanswered questions and address unexplored mechanisms in pre-clinical models and clinical trial data from pHGG patients. Particular focus will be paid towards therapeutics targeting chromatin modifiers and other epigenetic vulnerabilities that can be exploited for pHGG therapy. Further delineation of rational therapeutic combinations has strong potential to drive development of safe and efficacious treatments for pHGG patients.

scholarly journals A phase I/II study of bevacizumab, irinotecan and erlotinib in children with progressive diffuse intrinsic pontine glioma

2021 ◽  
Author(s):  
Fatma E. El-Khouly ◽  
Sophie E. M. Veldhuijzen van Zanten ◽  
Marc H. A. Jansen ◽  
Dewi P. Bakker ◽  
Esther Sanchez Aliaga ◽  
...  
Keyword(s):  
Disease Progression ◽  
Topoisomerase I ◽  
Combined Treatment ◽  
Progression Free Survival ◽  
Diffuse Intrinsic Pontine Glioma ◽  
Pontine Glioma ◽  
Vegf Inhibitor ◽  
Radiological Response ◽  
One Year

Abstract Introduction This study investigates the safety, tolerability, and preliminary efficacy of combined treatment with VEGF inhibitor bevacizumab, topoisomerase I inhibitor irinotecan, and EGFR inhibitor erlotinib in children with progressive diffuse intrinsic pontine glioma (DIPG). Methods Biweekly bevacizumab (10 mg/kg) and irinotecan (125 mg/m2) were combined with daily erlotinib. Two cohorts received increasing doses of erlotinib (65 and 85 mg/m2) following a 3 + 3 dose-escalation schedule, until disease progression with a maximum of one year. Dose-limiting toxicities (DLT) were monitored biweekly. Secondary progression free survival (sPFS) and overall survival (OS) were determined based on clinical and radiological response measurements. Quality of life (QoL) during treatment was also assessed. Results Between November 2011 and March 2018, nine patients with disease progression after initial radiotherapy were enrolled. Median PFS at start of the study was 7.3 months (range 3.5–10.0). In the first dose cohort, one patient experienced a DLT (grade III acute diarrhea), resulting in enrollment of three additional patients in this cohort. No additional DLTs were observed in consecutive patients receiving up to a maximum dose of 85 mg/m2. Median sPFS was 3.2 months (range 1.0–10.9), and median OS was 13.8 months (range 9.3–33.0). Overall QoL was stable during treatment. Conclusions Daily erlotinib is safe and well tolerated in doses up to 85 mg/m2 when combined with biweekly bevacizumab and irinotecan in children with progressive DIPG. Median OS of the study patients was longer than known form literature.

scholarly journals IMMU-22. PHASE IB IMMUNOTHERAPY CLINICAL TRIAL WITH THE USE OF AUTOLOGOUS DENDRITIC CELLS PULSED WITH AN ALLOGENIC TUMORAL CELL LINES LYSATE IN PATIENTS WITH NEWLY DIAGNOSED DIFFUSE INTRINSIC PONTINE GLIOMA (DIPG)

2020 ◽  
Vol 22 (Supplement_3) ◽  
pp. iii364-iii364
Author(s):  
Andres Morales La Madrid ◽  
Jaume Mora ◽  
Ofelia Cruz ◽  
Vicente Santa-Maria Lopez ◽  
Sara Perez-Jaume ◽  
...  
Keyword(s):  
Immune Response ◽  
Dendritic Cells ◽  
Mononuclear Cells ◽  
Tumor Antigens ◽  
Progression Free Survival ◽  
Diffuse Intrinsic Pontine Glioma ◽  
Newly Diagnosed ◽  
Tumor Lysate ◽  
Pontine Glioma ◽  
Peripheral Blood Mononuclear

Abstract BACKGROUND Diffuse intrinsic pontine glioma (DIPG) is a lethal condition, and therefore novel approaches are needed. Monocyte-derived dendritic cells (mDCs) pulsed with tumor antigens, as professional antigen-presenting cells, are a promising strategy for immunotherapy of invasive brain tumors. METHODS Our Ib pilot study explored the use of immunotherapy with mDCs for the treatment of newly diagnosed DIPG. Patient′s mDCs were extracted after irradiation and were primed with an allogenic tumor lysate from five patients with K27M-mutated DIPGs. The principal goal of this study was to establish the feasibility and safety of the intradermic administration of these mDC vaccines in patients with DIPG. In the absence of progression, patients received maintenance boosts of tumor lysate. Additionally, we evaluated the non-specific and antitumoral immune response generated in peripheral blood mononuclear cells (PBMC) and in cerebrospinal fluid (CSF) cells. RESULTS Nine patients were included in the study (2016–2018). Vaccines fabrication was feasible and administered in all cases without grade 3 or 4 toxicities. KLH (9/9 patients) and antitumor (8/9 patients) specific responses were identified in PBMC. Immunological responses were also confirmed in T-lymphocytes from the CSF of two patients. Twenty-four month overall survival and progression free survival was 33.3% (95 % CI 13.2% to 84.0 %) and zero, respectively. DISCUSSION These results demonstrate that mDC vaccination is feasible, safe, and generates a DIPG-specific immune response detected in PBMC and CSF. There was a trend in improved OS when compared to historic controls. This strategy shows a promising immunotherapy backbone for future combination schemas.

CTIM-08. SAFETY, EFFICACY, AND SURVIVAL RESULTS FROM A PHASE 1 STUDY OF THE ONCOLYTIC ADENOVIRUS DNX-2401 FOLLOWED BY STANDARD OF CARE RADIOTHERAPY FOR NEWLY DIAGNOSED DIFFUSE INTRINSIC PONTINE GLIOMA (DIPG)

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi50-vi51
Author(s):  
Jaime Gállego Pérez-Larraya ◽  
Marc Garcia-Moure ◽  
Ana Patiño-García ◽  
Marisol González-Huarriz ◽  
Jasper Van der Lugt ◽  
...  
Keyword(s):  
Adverse Events ◽  
Phase 1 ◽  
Standard Of Care ◽  
Diffuse Intrinsic Pontine Glioma ◽  
Oncolytic Adenovirus ◽  
Newly Diagnosed ◽  
Pontine Glioma ◽  
Serious Adverse Events ◽  
Tumor Biopsy ◽  
Grade 3

Abstract BACKGROUND Diffuse intrinsic pontine glioma (DIPG) is the most lethal pediatric brain tumor. Median overall survival (OS) with standard of care radiation therapy (RT) is approximately 8-10 months and 2-year survival is < 10%. A Phase 1 single-center study was conducted to evaluate the oncolytic adenovirus, DNX-2401 (tasadenoturev), followed by RT for DIPG. METHODS Newly-diagnosed DIPG patients 1-18 years old received a tumor biopsy through the cerebellar peduncle followed by intratumoral injection of 1e10 – 5e10 vp DNX-2401 and conventional RT 1-3 weeks later. RESULTS Subjects were enrolled (n=12) from December 2017 to January 2020 and had a median age of 9 years (range 3-18) and Lansky/Karnofsky performance scores of 90-100 (n=4; 33%) or 70-80 (n=8; 67%). Genetic assessment was completed for 11 subjects (92%) and histone 3 K27M mutations were identified in 10 subjects, including H3F3A (n=8), HIST2H3C (n=1), and HIST1H3B (n=1); 1 subject was H3 wildtype (n=1). TP53 mutations were identified in 5 subjects (42%). DNX-2401 was administered followed by RT (n=11; 92%). No dose-limiting toxicities were observed and the treatment regimen was well-tolerated. The most commonly reported adverse events (≥ 5 subjects), regardless of study drug relationship, include asthenia, headache, vomiting, pyrexia, and neurological deterioration. Three serious adverse events were reported including grade 3 abdominal pain, grade 3 lymphopenia, and grade 3 clinical deterioration. Tumor reductions were reported for 9 subjects (75%), including 2 confirmed (17%) and 2 unconfirmed (17%) responses per RAPNO criteria. As of the data cutoff, median OS is 19.7 months and OS-24 is 32% with follow-up ongoing for 3 subjects (26.9, 25.6, 13.7 months). CONCLUSIONS DNX-2401 followed by RT can be safely administered to DIPG. Survival outcomes are encouraging, thus warranting further evaluation in a Phase 2 study.

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