scholarly journals Characteristics of glioblastoma long-term survivors

2021 ◽  
Vol 23 (Supplement_4) ◽  
pp. iv15-iv15
Author(s):  
Tamara Ali ◽  
Farouk Olubajo ◽  
Nitika Rathi ◽  
Piyali Pal ◽  
Michael Jenkinson ◽  
...  
Keyword(s):  
Promoter Methylation ◽  
Performance Status ◽  
Outcome Data ◽  
Mgmt Promoter Methylation ◽  
Small Subset ◽  
Who Grade ◽  
Number Of Patients ◽  
Mgmt Promoter ◽  
Long Term Survivors

Abstract Aims Glioblastoma (GBM) is the commonest and most aggressive primary malignant brain tumour in adults. A small number of patients survive for >5 years and are referred to as long-term survivors (LTS). This study aimed to quantify and characterise GBM LTS in a single large UK centre. Method A retrospective observational cohort study was performed. Patients diagnosed with GBM in a single UK centre between 2000–2011 (inclusive) who survived >5 years from diagnosis were included. Histopathological samples were re-examined as per the WHO 2016 classification criteria and tested for molecular biomarkers including MGMT promoter methylation, IDH1/2 mutations, 1p19q codeletion and ATRX. Demographic, imaging, treatment and outcome data were collected. Results 1130 patients diagnosed with GBM were identified, 30 of whom survived for >5 years. Twenty-three were re-confirmed as GBM histologically and seven were reclassified as anaplastic oligodendroglioma or anaplastic astroctyoma. Median overall survival for this cohort was 6.2 years. We report a 2% 5-year survival, and a 0.7% 7-year survival. LTS-associated factors were younger age (<65 years old), frontal unilateral tumours, maximal management (surgery and chemoradiotherapy), good post-operative performance status (WHO <2), MGMT promoter methylation and IDH1/2 mutation. Conclusion A small subset of GBM patients survive for >5 years. Most still succumb to the disease, implying 5-year survival is not indicative of a cure. On applying current molecular markers, a quarter of previously diagnosed glioblastoma in this LTS population were revised to be WHO grade III gliomas.

Long-term survival in primary glioblastoma revisited: The contribution of isocitrate dehydrogenase mutations.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 2027-2027
Author(s):  
Michael Weller ◽  
Bettina Hentschel ◽  
Matthias Simon ◽  
Manfred Westphal ◽  
Gabriele Schackert ◽  
...  
Keyword(s):  
Promoter Methylation ◽  
Mgmt Promoter Methylation ◽  
Molecular Characteristics ◽  
Wild Type ◽  
Who Grade ◽  
Term Survival ◽  
Long Term Survival ◽  
Tp53 Mutations ◽  
Mgmt Promoter

2027 Background: The determinants of long-term survival in glioblastoma have remained largely obscure. Isocitrate dehydrogenase (IDH) 1 or 2 mutations are common in WHO grade 2/3 gliomas, but rare in primary glioblastomas, and associated with longer survival. Methods: We compared clinical and molecular characteristics of 69 patients with centrally confirmed glioblastoma and survival > 36 months (LTS-36), including 33 patients surviving > 60 months (LTS-60), with 259 patients surviving < 36 months. MGMT promoter methylation, 1p/19q codeletions, EGFR amplification, TP53 mutations and IDH1/2mutations were determined by standard techniques. Results: The rate of IDH1/2 mutations in LTS-36 patients was 34% (23/67 patients) as opposed to 4.3% in controls (11/257 patients). Long-term survivors with IDH1/2 -mutant glioblastomas were younger, had almost no EGFR amplifications, but exhibited more often 1p/19q codeletions and TP53 mutations than LTS patients with IDH1/2 wild-type glioblastomas. Among LTS-36 patients, wild-type TP53 status, MGMT promoter methylation, and absence of EGFR amplification, but not IDH1/2 mutation, were associated with prolonged survival. Among 11 patients with IDH1/2-mutant glioblastomas without long-term survival, the only difference to IDH1/2-mutant long-term survivors was less frequent MGMT promoter methylation. Compared with LTS-36 patients, LTS-60 patients had been treated initially with radiotherapy alone and had TP53 mutations less frequently. Conclusions: IDH1/2 mutations define a subgroup of tumors of LTS patients that exhibit molecular characteristics of WHO grade 2/3 gliomas and secondary glioblastomas. Determinants of LTS with IDH1/2 wild-type glioblastomas, which exhibit typical molecular features of primary glioblastomas, beyond MGMT promoter methylation, remain to be identified.

scholarly journals Superiority of temozolomide over radiotherapy for elderly patients with RTK II methylation class, MGMT promoter methylated malignant astrocytoma

2020 ◽  
Vol 22 (8) ◽  
pp. 1162-1172 ◽  
Author(s):  
Antje Wick ◽  
Tobias Kessler ◽  
Michael Platten ◽  
Christoph Meisner ◽  
Michael Bamberg ◽  
...  
Keyword(s):  
Promoter Methylation ◽  
Methylation Status ◽  
Predictive Biomarker ◽  
Copy Number Variations ◽  
Mgmt Promoter Methylation ◽  
Prognostic Impact ◽  
Term Outcome ◽  
Long Term Outcome ◽  
Mgmt Promoter

Abstract Background O6-methylguanine DNA-methyl transferase (MGMT) promoter methylation status is predictive for alkylating chemotherapy, but there are non-benefiting subgroups. Methods This is the long-term update of NOA-08 (NCT01502241), which compared efficacy and safety of radiotherapy (RT, n = 176) and temozolomide (TMZ, n = 193) at 7/14 days in patients &gt;65 years old with anaplastic astrocytoma or glioblastoma. DNA methylation patterns and copy number variations were assessed in the biomarker cohort of 104 patients and in an independent cohort of 188 patients treated with RT+TMZ-containing regimens in Heidelberg. Results In the full NOA-08 cohort, median overall survival (OS) was 8.2 [7.0–10.0] months for TMZ treatment versus 9.4 [8.1–10.4] months for RT; hazard ratio (HR) = 0.93 (95% CI: 0.76–1.15) of TMZ versus RT. Median event-free survival (EFS) [3.4 (3.2–4.1) months vs 4.6 (4.2–5.0) months] did not differ, with HR = 1.02 (0.83–1.25). Patients with MGMT methylated tumors had markedly longer OS and EFS when treated with TMZ (18.4 [13.9–24.4] mo and 8.5 [6.9–13.3] mo) versus RT (9.6 [6.4–13.7] mo and 4.8 [4.3–6.2] mo, HR 0.44 [0.27–0.70], P &lt; 0.001 for OS and 0.46 [0.29–0.73], P = 0.001 for EFS). Patients with glioblastomas of the methylation classes receptor tyrosine kinase I (RTK I) and mesenchymal subgroups lacked a prognostic impact of MGMT in both cohorts. Conclusion MGMT promoter methylation is a strong predictive biomarker for the choice between RT and TMZ. It indicates favorable long-term outcome with initial TMZ monotherapy in patients with MGMT promoter-methylated tumors primarily in the RTK II subgroup.

Impact of predictive impact of MGMT promoter methylation in malignant astrocytomas depends on the methylation subgroup.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 2013-2013
Author(s):  
Wolfgang Wick ◽  
Tobias Kessler ◽  
Michael Platten ◽  
Christoph Meisner ◽  
Michael Bamberg ◽  
...  
Keyword(s):  
Promoter Methylation ◽  
Malignant Gliomas ◽  
Predictive Biomarker ◽  
Copy Number Variations ◽  
Mgmt Promoter Methylation ◽  
Published Data ◽  
Global Methylation ◽  
Methyl Transferase ◽  
Mgmt Promoter

2013 Background: O6-methylguanine DNA-methyl transferase (MGMT) status is predictive for alkylating chemotherapy in most series, but there are non-benefitting subgroups. Despite multiple attempts, MGMT has not been unambiguously established as a predictive biomarker for patients with malignant gliomas. Further, these tumors are to be better classified according to global methylation profiles. Methods: Long-term efficacy data of the NOA-08 trial (NCT01502241) that compared efficacy and safety of radiotherapy (RT, n= 176) to temozolomide (TMZ, n= 193) in patients > 65 years with anaplastic astrocytoma (AA) or GB as well as genome-wide DNA methylation patterns and copy number variations assessed by methylation arrays in a biomarker subset ( n= 104) and an independent cohort ( n= 380) have been used to assess the interaction between MGMT status and methylation subgroups. Results: In the long-term update of NOA-08 patients with MGMT methylated tumors had longer OS and EFS when treated with TMZ (18.4 [13.9-24.4] months and 8.5 [6.9-13.3] months) versus RT (9.6 [6.4-13.7] months and 4.8 [4.3-6.2] months, HR 0.44 [0.27-0.70], p < 0.001 for OS and 0.46 [0.29-0.73], p = 0.001 for EFS). These data compared favorably with recently published data from patients treated with chemoradiation (Perry et al. NEJM 2017). Importantly, only patients with glioblastomas of the methylation class receptor tyrosine kinase II (RTKII) and mesenchymal but not RTK I demonstrated the predictive impact of MGMT in the NOA and the independent validation cohort. Conclusions: MGMT promoter methylation as a strong but methylation subclass-dependent predictive biomarker for the use of alkylating chemotherapy in malignant gliomas. The data call for embedding of MGMT tests into global methylation analyses for all patients with malignant gliomas potentially treated with alkylating chemotherapy.

“Long extended” temozolomide in a selected population  with  not radically resected high-grade gliomas.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. e12510-e12510
Author(s):  
Gian Paolo Spinelli ◽  
Giuseppe Lo Russo ◽  
Evelina Miele ◽  
Antonio Maria Alberti ◽  
Martina Strudel ◽  
...  
Keyword(s):  
Promoter Methylation ◽  
Methylation Status ◽  
Haematological Toxicity ◽  
Mgmt Promoter Methylation ◽  
Response To Treatment ◽  
High Grade ◽  
Number Of Patients ◽  
Mgmt Promoter ◽  
High Grade Gliomas ◽  
Ecog Ps

e12510 Background: Despite the important progress in the treatment of solid tumors, high grade gliomas (HGGs) remain neoplasm with poor prognosis, especially when are not radically resected. Here we report the results of a selected population treated with standard schedule of Radiotherapy (RT) + Temozolomide (TMZ) followed by TMZ until progression. Methods: From January 2008 to January 2010, 14 newly diagnosed HGG patients, with median age of 50.6 years (range 27-75 yrs), were enrolled at Oncology Unit of S. Maria Goretti Hospital in Latina (University of Rome “Sapienza”). All patients were not radically resected and with ECOG PS=O. Furthermore patients were selected according to O6 Methyl-Guanine-DNA-Methyl Transferase (MGMT) promoter methylation status. Only methylated patients were included in our study. After surgery, patients received standard treatment with TMZ (75 mg/m2) concomitant with RT (60 Gy total dose). After a break of six weeks, Magnetic Resonance Imaging (MRI) was performed and all patients with stable or responsive disease received TMZ (150mg/200mg/m2/d x 5dq 28d) until progression. The response to treatment was evaluated according to RANO criteria Results: In our study the results showed one year overall survival (OS) and progression free survival (PFS) rates of 85,7% and 71,4% respectively. Moreover we observed two years OS rate of 70% and two years PFS rate of 10%. A total of 108 cycles of adjuvant TMZ were administered with average number of 9 per patient (range 1-16). The most frequent side effects observed were haematological toxicity and fatigue. Thrombocytopenia (G2-G3) was observed in 42% of patients, neutropenia (G2-G3), fatigue (G2-G3) and nausea (G2-G3) in 30%, 32% and 25% of patients respectively. Conclusions: Despite the small number of patients, our experience suggests a manageable safety profile and a good efficacy of TMZ until progression in a selected population of patients (HGGs not radically resected, with a good ECOG PS). These data also confirms the literature knowledge, underlining the prognostic positive impact of MGMT promoter methylation in patients with HGG.

Survival in Patients with Newly Diagnosed Conventional Glioblastoma: A Modified Prognostic Score Based on a Single-Institution Series

2012 ◽  
Vol 98 (6) ◽  
pp. 756-761 ◽  
Author(s):  
Federica Bertolini ◽  
Elena Zunarelli ◽  
Caterina Baraldi ◽  
Antonella Valentini ◽  
Cinzia Del Giovane ◽  
...  
Keyword(s):  
Promoter Methylation ◽  
Prognostic Score ◽  
Performance Status ◽  
Methylation Status ◽  
Mgmt Promoter Methylation ◽  
Class I ◽  
Survival Times ◽  
Promoter Methylation Status ◽  
Mgmt Promoter ◽  
Mgmt Promoter Methylation Status

Aims and background Recursive partioning analysis (RPA) is commonly used to define the stratification of patients with glioblastoma. Epigenetic silencing of the O6-methylguanine methyltransferase (MGMT) gene by promoter methylation plays an important role in regulating MGMT expression in gliomas and this is an established independent prognostic factor. We tested a prognostic scoring system including all clinical variables used by RPA classification (age, ECOG performance status and type of surgery) and MGMT gene promoter methylation status. Methods Seventy-eight consecutive patients with newly diagnosed, histopathologically confirmed conventional glioblastoma were included. Information about MGMT promoter methylation status was available for all of them. Based on the patients' age (<50 vs ≥50 years), ECOG performance status (0 vs ≥1), type of surgery (gross tumor resection versus partial resection/biopsy) and MGMT promoter methylation status (methylated versus unmethylated), three classes of risk were generated where the prognostic score was defined assigning 1 point to every favorable parameter (Class I: ≥3; Class II: 2; Class III: 0–1). All classes were correlated with overall survival. Results The median survival times were 32.4, 8.6 and 8.8 months for Class I, II and III, respectively, corresponding to 2-year survival rates of 69%, 13.5% and <1%. The same analysis was performed on 54 patients treated with postoperative concomitant chemoradiotherapy. The median survival times were 32.5, 13.4 and 8.9 months for Class I, II and III, respectively, corresponding to 2-year survival rates of 68.6%, 26.9% and <1%. In both groups of 78 and 54 patients the differences in survival between Class I and III were statistically significant (P <0.0001). Conclusions The proposed prognostic scoring system including clinical variables and MGMT promoter methylation status proved valuable in patients with primary conventional glioblastoma, especially those treated with postoperative chemoradiotherapy.

scholarly journals ACT-10 TREATMENT FOR GLIOBLASTOMA RECURRED AFTER CONCOMITANT CHEMORADIATION THERAPY WITH TEMOZOLOMIDE AND THEIR PROGNOSIS

2019 ◽  
Vol 1 (Supplement_2) ◽  
pp. ii14-ii14
Author(s):  
Kanji Mori ◽  
Tomoko Shofuda ◽  
Masayuki Mano ◽  
Yoshinori Kodama ◽  
Manabu Kinoshita ◽  
...  
Keyword(s):  
Promoter Methylation ◽  
Performance Status ◽  
Univariate Analysis ◽  
Young Patients ◽  
Clinical Information ◽  
Primary Diagnosis ◽  
Chemoradiation Therapy ◽  
Mgmt Promoter Methylation ◽  
Mgmt Promoter ◽  
Concomitant Chemoradiation

Abstract There are few data about treatment for glioblastoma recurred after concomitant chemoradiation therapy with temozolomide (TMZ). We retrospectively examined treatment and prognosis of recurred glioblastoma patients who registered Kansai molecular diagnosis network for central nervous system tumors, and whose clinical information were available. One hundred and fifty-seven patients that were clinically diagnosed as recurrence between November 2007 and April 2019 were included. Their median age at primary diagnosis was 52 years old and median KPS was 80%. Proportion of methylated MGMT promoter was 43.3% (65 patients), and mutated IDH was 5.4% (8 patients). Median overall survival after recurrence (mSAR) was 8.2 months. One hundred and sixteen patients (73.9%) were received any anticancer treatment and their mSAR was 10.5m. Combination of TMZ and bevacizumab (Bev) were most frequently used for 33 patients, followed by Bev monotherapy for 17 patients, surgery + TMZ + Bev for 15 patients, surgery + TMZ for 12 patients, and TMZ monotherapy for ten. Their mSAR were 8.0m, 7.5m, 10.5m, 13.0m, and 8.0m, respectively. Using univariate analysis, MGMT promoter methylation (p=0.0007), TMZ (p=0.00933), surgery (p=0.0126), re-radiation (p=0.0367), and surgery+TMZ+Bev (p=0.0493) significantly affected prognosis. By multivariate analysis, MGMT promoter methylation, TMZ, and re-radiation were statistically significant (p=0.000138, 0.00161, 0.00403, respectively). These data showed that relatively young patients with good performance status would receive anti-cancer treatment beyond progression and MGMT promoter methylation might be one of prognostic factor for longer survival. In this cohort, re-radiation was performed for few patients and nitrosourea such as nimustine was almost not used. Further study would be needed whether these treatments have any positive effect or not.

scholarly journals Does positive MGMT methylation outbalance the limitation of subtotal resection in glioblastoma IDH-wildtype patients?

2021 ◽  
Author(s):  
Müller Mareike ◽  
Staub-Bartelt Franziska ◽  
Ehrmann Julia ◽  
Hänggi Daniel ◽  
Sabel Michael ◽  
...  
Keyword(s):  
Promoter Methylation ◽  
Tumor Tissue ◽  
Tumor Volume ◽  
Residual Tumor ◽  
Mgmt Promoter Methylation ◽  
Subtotal Resection ◽  
Mgmt Methylation ◽  
Who Grade ◽  
Mgmt Promoter ◽  
Methylated Mgmt Promoter

Abstract Background The impact on survival of complete resection (CR) in patients with malignant glioma and MGMT promoter methylation on adjuvant therapy strategies has been proven in the past. However, it is not known whether a MGMT promoter methylation can compensate a subtotal resection. Therefore, we analyzed the progress of postoperative residual tumor tissue depending on the molecular tumor status. Methods We included all glioblastoma, IDH-wildtype (WHO grade IV) patients with postoperative residual tumor tissue, who were treated at our neurooncological department between 2010 and 2018. Correlation of molecular patterns with clinical data and survival times was performed. The results were compared to patients following CR. Results 267 patients with glioblastoma, IDH-wildtype (WHO grade IV) received surgery of whom 81 patients with residual tumor were included in the analysis. MGMT promoter was methylated in 31 patients (38.27%). Median OS and PFS were significantly increased in patients with methylated MGMT promoter (mOS: 16 M vs. 13 M, p = 0.009; mPFS: 13 M vs. 5 M, p = 0.003). In comparison to survival of patients following CR, OS was decreased in patients with residual tumor regardless MGMT methylation. Conclusion Our data confirm impact of MGMT promoter methylation in patients with glioblastoma, IDH-wildtype on OS and PFS. However, in comparison to patients after CR, a methylated MGMT promoter cannot compensate the disadvantage due to residual tumor volume. In terms of personalized medicine and quality of life as major goal in oncology, neuro-oncologists have to thoroughly discuss advantages and disadvantages of residual tumor volume versus possible neurological deficits in CR.

scholarly journals Long-term survival in glioblastoma: methyl guanine methyl transferase (MGMT) promoter methylation as independent favourable prognostic factor

2016 ◽  
Vol 50 (4) ◽  
pp. 394-401 ◽  
Author(s):  
Uros Smrdel ◽  
Mara Popovic ◽  
Matjaz Zwitter ◽  
Emanuela Bostjancic ◽  
Andrej Zupan ◽  
...  
Keyword(s):  
Prognostic Factors ◽  
Promoter Methylation ◽  
Mgmt Promoter Methylation ◽  
Term Survival ◽  
Long Term Survival ◽  
Survivor Group ◽  
Significant Difference ◽  
Mgmt Promoter ◽  
Term Survivor

Abstract Background In spite of significant improvement after multi-modality treatment, prognosis of most patients with glioblastoma remains poor. Standard clinical prognostic factors (age, gender, extent of surgery and performance status) do not clearly predict long-term survival. The aim of this case-control study was to evaluate immuno-histochemical and genetic characteristics of the tumour as additional prognostic factors in glioblastoma. Patients and methods Long-term survivor group were 40 patients with glioblastoma with survival longer than 30 months. Control group were 40 patients with shorter survival and matched to the long-term survivor group according to the clinical prognostic factors. All patients underwent multimodality treatment with surgery, postoperative conformal radiotherapy and temozolomide during and after radiotherapy. Biopsy samples were tested for the methylation of MGMT promoter (with methylation specific polymerase chain reaction), IDH1 (with immunohistochemistry), IDH2, CDKN2A and CDKN2B (with multiplex ligation-dependent probe amplification), and 1p and 19q mutations (with fluorescent in situ hybridization). Results Methylation of MGMT promoter was found in 95% and in 36% in the long-term survivor and control groups, respectively (p < 0.001). IDH1 R132H mutated patients had a non-significant lower risk of dying from glioblastoma (p = 0.437), in comparison to patients without this mutation. Other mutations were rare, with no significant difference between the two groups. Conclusions Molecular and genetic testing offers additional prognostic and predictive information for patients with glioblastoma. The most important finding of our analysis is that in the absence of MGMT promoter methylation, longterm survival is very rare. For patients without this mutation, alternative treatments should be explored.

Long-term therapy with temozolomide is a feasible option for newly diagnosed glioblastoma: a single-institution experience with as many as 101 temozolomide cycles

2014 ◽  
Vol 37 (6) ◽  
pp. E4 ◽  
Author(s):  
Giuseppe M. V. Barbagallo ◽  
Sabrina Paratore ◽  
Rosario Caltabiano ◽  
Stefano Palmucci ◽  
Hector Soto Parra ◽  
...  
Keyword(s):  
Promoter Methylation ◽  
Methylation Status ◽  
Mgmt Promoter Methylation ◽  
Newly Diagnosed ◽  
Mgmt Promoter ◽  
Newly Diagnosed Glioblastoma ◽  
Group A ◽  
Group B ◽  
Mgmt Promoter Methylation Status

Object The objective of this study was to report the authors' experience with the long-term administration of temozolomide (TMZ; > 6 cycles, up to 101) in patients with newly diagnosed glioblastoma and to analyze its feasibility and safety as well as its impact on survival. The authors also compared data obtained from the group of patients undergoing long-term TMZ treatment with data from patients treated with a standard TMZ protocol. Methods A retrospective analysis was conducted of 37 patients who underwent operations for glioblastoma between 2004 and 2012. Volumetric analysis of postoperative Gd-enhanced MR images, obtained within 48 hours, confirmed tumor gross-total resection (GTR) in all but 2 patients. All patients received the first cycle of TMZ at a dosage of 150 mg/m2 starting on the second or third postsurgical day. Afterward, patients received concomitant radiochemotherapy according to the Stupp protocol. With regard to adjuvant TMZ therapy, the 19 patients in Group A, aged 30–72 years (mean 56.1 years), received 150 mg/m2 for 5 days every 28 days for more than 6 cycles (range 7–101 cycles). The 18 patients in Group B, aged 46–82 years (mean 64.8 years), received the same dose, but for no more than 6 cycles. O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation status was analyzed for both groups and correlated with overall survival (OS) and progression-free survival (PFS). The impact of age, sex, Karnofsky Performance Scale score, and Ki 67 staining were also considered. Results All patients but 1 in Group A survived at least 18 months (range 18–101 months), and patients in Group B survived no more than 17 months (range 2–17 months). The long-term survivors (Group A), defined as patients who survived at least 12 months after diagnosis, were 51.3% of the total (19/37). Kaplan-Meier curve analysis showed that patients treated with more than 6 TMZ cycles had OS and PFS that was significantly longer than patients receiving standard treatment (median OS 28 months vs 8 months, respectively; p = 0.0001; median PFS 20 months vs 4 months, respectively; p = 0.0002). By univariate and multivariate Cox proportional hazard regression analysis, MGMT methylation status and number of TMZ cycles appeared to be survival prognostic factors in patients with glioblastoma. After controlling for MGMT status, highly significant differences related to OS and PFS between patients with standard and long-term TMZ treatment were still detected. Furthermore, in Group A and B, the statistical correlation of MGMT status to the number of TMZ cycles showed a significant difference only in Group A patients, suggesting that MGMT promoter methylation was predictive of response for long-term TMZ treatment. Prolonged therapy did not confer hematological toxicity or opportunistic infections in either patient group. Conclusions This study describes the longest experience so far reported with TMZ in patients with newly diagnosed glioblastomas, with as many as 101 cycles, who were treated using GTR. Statistically significant data confirm that median survival correlates with MGMT promoter methylation status as well as with the number of TMZ cycles administered. Long-term TMZ therapy appears feasible and safe.

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