NCOG-27. STATUS AS A CLINICAL TRIAL PARTICIPANT AND OUTCOME IN IDH-WILDTYPE GLIOBLASTOMA

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi157-vi158
Author(s):  
Peter Pan ◽  
Adela Joanta-Gomez ◽  
Fabio Iwamoto ◽  
Mary Welch ◽  
Aya Haggiagi ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Clinical Study ◽  
Promoter Methylation ◽  
Parietal Lobe ◽  
Strong Predictor ◽  
Standard Of Care ◽  
Mgmt Promoter Methylation ◽  
Study Patient ◽  
Trial Participant ◽  
Mgmt Promoter

Abstract INTRODUCTION Standard of care for glioblastoma consists of surgery, followed by combined chemoradiation and adjuvant chemotherapy, as per the seminal EORTC study from 2005. Clinical trial patients, being a population selected for functional status, hepatic function, renal function, and lack of other malignancies, may have improved outcome over the general treated population. METHOD Single center retrospective analysis of status as a clinical trial patient in the upfront setting and other clinical factors/biomarkers, analyzed for correlation with outcomes (PFS/OS) in IDH-wildtype glioblastomas. RESULTS 82 patients with IDH-wildtype glioblastoma were identified between 2014 and 2020, treated with standard of care or with an upfront clinical study (43% women; median age 66 years, range 35-91 years of age). 22 patients (27%) were treated with upfront clinical study. Status as a patient treated in an upfront clinical study did not correlate with outcome (hazard ratio HR PFS 0.99, CI 0.57-1.7, p=0.97; HR OS 1.09, CI 0.56-2.1, p=0.81). Frontal lobe was most frequently involved (n=36, 44%), followed by parietal lobe (n=33, 40%). Age was not a strong predictor of survival (R2 0.01). No statistically significant correlation was observed between outcome and laterality or location. MGMT promoter methylation was associated with improved PFS (HR 0.56, CI 0.33-0.94, p=0.03) and OS (HR 0.40, CI 0.19-0.85, p=0.02), with mPFS 6 months vs 9 months and mOS 16 months vs 20 months (unmethylated vs methylated respectively). CONCLUSION In this retrospective cohort of IDH-wildtype glioblastomas, age, tumor laterality, and tumor location were not significant predictors of outcome. MGMT promoter methylation predicted for superior PFS/OS. Patient selection for clinical studies are influenced by entry criteria, however at least in this retrospective review, status as a clinical study patient in the upfront setting did not correlate with outcome compared to patients treated with upfront standard of care.

MGMT methylation testing in RTOG 0525: A phase III trial of newly diagnosed glioblastoma

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 2051-2051
Author(s):  
K. D. Aldape ◽  
G. Jones ◽  
M. Wang ◽  
M. Hegi ◽  
R. C. Janzer ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Real Time ◽  
Promoter Methylation ◽  
Mgmt Promoter Methylation ◽  
Phase Iii ◽  
Major Advance ◽  
Newly Diagnosed ◽  
Mgmt Methylation ◽  
Mgmt Promoter ◽  
Central Pathology

2051 Background: MGMT promoter methylation has been described as a prognostic marker in glioblastoma (GBM) and may be associated with chemosensitivity to alkylating agents. This study determined the feasibility of real-time determination of MGMT promoter methylation testing in a large international phase III clinical trial. Methods: Paraffin tumor blocks were obtained from patients registered onto RTOG 0525 then distributed to one of two central pathology labs: MD Anderson (Houston TX, K. Aldape) or CHUV (Lausanne, CH, R. Janzer). After histologic confirmation of GBM, unstained slides (40 microns of tumor tissue) were sent to the testing laboratories. Results were used for randomization into a treatment arm. MGMT methylation was assessed using methylation specific real-time PCR (MSP). The assay determined the number of copies of both methylated MGMT and of beta-actin (ACTB) in the sample. The ACTB copy number was used to assess the quality and quantity of the sample DNA. Results: Results were available for 995 samples. Following MSP samples were categorized into one of five possible results: failed (2, 0.2%), methylated (302, 30.2%), non-methylated (602, 60.2%), indeterminate (62, 6.2%), and invalid (27, 2.7%). Among cases that were evaluable as either methylated or unmethylated (n = 904) the MGMT promoter methylation rate in newly diagnosed GBM was approximately 1/3 (33.4%), a rate that is somewhat lower than prior reports. The average time from receipt of sample at the central pathology laboratory to reporting of results was 9.3 days. The time required decreased over the course of the clinical trial. This was due, in part, to training of the sites to deliver samples just before the start of runs. Conclusions: The results demonstrate the feasibility of performing real-time MGMT methylation testing, a tumor based assay, as a stratification factor in a multinational clinical trial. This study confirms that treatment decisions based on the molecular characteristics of the tumor are feasible, thereby providing opportunities to develop more molecularly-based tumor stratification or selection, a major advance in developing personalized treatment regimens. No significant financial relationships to disclose.

Phase II trial of bevacizumab and temozolomide for treatment of elderly patients with newly diagnosed glioblastoma.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 2540-2540
Author(s):  
Donna Molaie ◽  
Albert Lai ◽  
Benjamin M. Ellingson ◽  
Thien Nguyen ◽  
Hye Hyun Bahng ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Elderly Patients ◽  
Phase Ii ◽  
Promoter Methylation ◽  
Tumor Volume ◽  
Mgmt Promoter Methylation ◽  
Control Group ◽  
Newly Diagnosed ◽  
Treatment Type ◽  
Mgmt Promoter

2540 Background: Glioblastoma (GBM) in elderly patients differ molecularly as compared to younger patients, and may have increased angiogenic activity. Bevacizumab (BV) is an anti-angiogenic monoclonal antibody against vascular endothelial growth factor. We conducted a clinical trial to evaluate the efficacy and safety of BV and temozolomide (TMZ) for elderly patients with a new diagnosis of GBM, while deferring radiotherapy. Methods: This is a phase II, single-arm, multicenter, open label trial. Eligible patients have a tissue diagnosis of GBM with no treatment other than surgery, age ≥ 70, KPS ≥ 60, and adequate organ function. TMZ was initiated within 2 weeks of surgery and BV was initiated within 4 weeks thereafter. TMZ was administered at 150-200 mg/m2/day for 5 days every 4 weeks and BV at 10mg/kg every 2 weeks. A historical control group of 42 patients with similar criteria who received concurrent TMZ and RT followed by adjuvant TMZ, was derived for comparison from an institutional patient database. The primary endpoint is overall survival (OS) and secondary endpoints are progression-free-survival and safety. Results: 50 patients were enrolled from June 2010 to January 2016. Median age is 75 (range 70-87), and median KPS is 80 (range 60-100). 17 patients had a biopsy only, 26 patients have MGMT promoter methylation, and all patients are IDH wildtype. The study and control group are well matched in terms of age and molecular markers, however, the study patients had worse initial KPS and higher baseline tumor volume. At time of analysis, all but 2 patients were deceased. The median OS was 12.6 months for study patients (95% CI, 10.9-15.9 months) and 16.3 months for control patients (95% CI, 12.9-22.4 months). In a multivariate Cox analysis, baseline tumor volume (HR = 2.6, p = 0.0001) and MGMT promoter methylation (HR = 0.49, p = 0.004) were significant prognostic markers. Treatment type did not have a significant impact on OS (HR = 1.5, p = 0.14). Treatment-related serious adverse events included: pulmonary embolism (5), cerebral hemorrhage (3), pneumonia (1), intestinal perforation (1), deep venous thrombosis (6), hypertension (2), atrial fibrillation (1), congestive heart failure (1), cardio-respiratory arrest (1), lymphopenia (2), thrombocytopenia (8), and neutropenia (5). Conclusions: The results of this study suggest for patients with newly diagnosed GBM age ≥70 and KPS ≥60, treatment with BV and TMZ is equivalent to standard chemoradiotherapy, and has tolerable side effects. Complete endpoint analysis will be presented with the poster. Clinical trial information: NCT01149850 .

scholarly journals Prognostic significance of MGMT promoter methylation in diffuse glioma patients

2019 ◽  
Vol 33 (1) ◽  
pp. 639-644
Author(s):  
Nikola Jovanović ◽  
Tatjana Mitrović ◽  
Vladimir J. Cvetković ◽  
Svetlana Tošić ◽  
Jelena Vitorović ◽  
...  
Keyword(s):  
Promoter Methylation ◽  
Prognostic Significance ◽  
Mgmt Promoter Methylation ◽  
Diffuse Glioma ◽  
Mgmt Promoter

scholarly journals Fast Routine Assessment of MGMT Promoter Methylation

2020 ◽  
Author(s):  
Ivana Bratic Hench ◽  
Rosa Della Monica ◽  
Lorenzo Chiariotti ◽  
Michel Bihl ◽  
Markus Tolnay ◽  
...  
Keyword(s):  
Promoter Methylation ◽  
Mgmt Promoter Methylation ◽  
Mgmt Promoter ◽  
Routine Assessment

scholarly journals MGMT-Methylation in Non-Neoplastic Diseases of the Central Nervous System

2021 ◽  
Vol 22 (8) ◽  
pp. 3845
Author(s):  
Sarah Teuber-Hanselmann ◽  
Karl Worm ◽  
Nicole Macha ◽  
Andreas Junker
Keyword(s):  
Promoter Methylation ◽  
Dna Methyltransferase ◽  
Alkylating Agents ◽  
Malignant Gliomas ◽  
Mgmt Promoter Methylation ◽  
Demyelinating Diseases ◽  
Brain Diseases ◽  
Tumor Biomarker ◽  
Mgmt Promoter ◽  
First Time

Quantifying O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation plays an essential role in assessing the potential efficacy of alkylating agents in the chemotherapy of malignant gliomas. MGMT promoter methylation is considered to be a characteristic of subgroups of certain malignancies but has also been described in various peripheral inflammatory diseases. However, MGMT promoter methylation levels have not yet been investigated in non-neoplastic brain diseases. This study demonstrates for the first time that one can indeed detect slightly enhanced MGMT promoter methylation in individual cases of inflammatory demyelinating CNS diseases such as multiple sclerosis and progressive multifocal leucencephalopathy (PML), as well as in other demyelinating diseases such as central pontine and exptrapontine myelinolysis, and diseases with myelin damage such as Wallerian degeneration. In this context, we identified a reduction in the expression of the demethylase TET1 as a possible cause for the enhanced MGMT promoter methylation. Hence, we show for the first time that MGMT hypermethylation occurs in chronic diseases that are not strictly associated to distinct pathogens, oncogenic viruses or neoplasms but that lead to damage of the myelin sheath in various ways. While this gives new insights into epigenetic and pathophysiological processes involved in de- and remyelination, which might offer new therapeutic opportunities for demyelinating diseases in the future, it also reduces the specificity of MGMT hypermethylation as a tumor biomarker.

scholarly journals Treatment of recurrent malignant gliomas with fotemustine monotherapy: impact of dose and correlation with MGMT promoter methylation

BMC Cancer ◽  
2009 ◽  
Vol 9 (1) ◽  
Author(s):  
Alessandra Fabi ◽  
Giulio Metro ◽  
Michelangelo Russillo ◽  
Antonello Vidiri ◽  
Carmine Maria Carapella ◽  
...  
Keyword(s):  
Promoter Methylation ◽  
Malignant Gliomas ◽  
Mgmt Promoter Methylation ◽  
Mgmt Promoter

OC-0322: 4-miRNA signature and MGMT promoter methylation improve risk stratification in glioblastoma.

2020 ◽  
Vol 152 ◽  
pp. S169-S170
Author(s):  
K. Unger ◽  
D.F. Fleischmann ◽  
V. Ruf ◽  
J. Felsberg ◽  
D. Piehlmaier ◽  
...  
Keyword(s):  
Risk Stratification ◽  
Promoter Methylation ◽  
Mgmt Promoter Methylation ◽  
Mirna Signature ◽  
Improve Risk Stratification ◽  
Mgmt Promoter
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