Chemoradiotherapy of Newly Diagnosed Glioblastoma With Intensified Temozolomide

Weiler, Markus; Hartmann, Christian; Wiewrodt, Dorothee; Herrlinger, Ulrich; Gorlia, Thierry; Bähr, Oliver; Meyermann, Richard; Bamberg, M.; Tatagiba, Marcos; Deimling, Andreas von; Weller, Michael; Wick, Wolfgang

doi:10.1016/j.ijrobp.2009.05.031

Cited by 50 publications

(31 citation statements)

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“…This foremost predictive value of MGMT promoter methylation has since been confirmed [4]. In the absence of non-chemotherapy arms, older studies cannot separate prognostic from predictive properties of MGMT promoter methylation, and even the most recent RTOG-0525 trial only confirms a prognostic impact, as there was no TMZ-free treatment arm in this trial [5][6][7][8][9] (Table 1).…”

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confidence: 68%

MGMT testing—the challenges for biomarker-based glioma treatment

et al. 2014

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Many patients with malignant gliomas do not respond to alkylating agent chemotherapy. Alkylator resistance of glioma cells is mainly mediated by the DNA repair enzyme O(6)-methylguanine-DNA methyltransferase (MGMT). Epigenetic silencing of the MGMT gene by promoter methylation in glioma cells compromises this DNA repair mechanism and increases chemosensitivity. MGMT promoter methylation is, therefore, a strong prognostic biomarker in paediatric and adult patients with glioblastoma treated with temozolomide. Notably, elderly patients (>65-70 years) with glioblastoma whose tumours lack MGMT promoter methylation derive minimal benefit from such chemotherapy. Thus, MGMT promoter methylation status has become a frequently requested laboratory test in neuro-oncology. This Review presents current data on the prognostic and predictive relevance of MGMT testing, discusses clinical trials that have used MGMT status to select participants, evaluates known issues concerning the molecular testing procedure, and addresses the necessity for molecular-context-dependent interpretation of MGMT test results. Whether MGMT promoter methylation testing should be offered to all individuals with glioblastoma, or only to elderly patients and those in clinical trials, is also discussed. Justifications for withholding alkylating agent chemotherapy in patients with MGMT-unmethylated glioblastomas outside clinical trials, and the potential role for MGMT testing in other gliomas, are also discussed. What is the role for MGMT testing in other gliomas? The answers to these issues depend not only on data from controlled clinical trials, but also on the availability of alternative treatment options to alkylating agents treatment, as well as on the access to molecular testing and its sensitivity and specificity.

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confidence: 68%

MGMT testing—the challenges for biomarker-based glioma treatment

et al. 2014

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“…MGMT status was determined using methylation-specific polymerase chain reaction [6]. Details are described elsewhere [17]. …”

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confidence: 99%

Prognostic significance of IDH-1 and MGMT in patients with glioblastoma: One step forward, and one step back?

et al. 2011

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A group of 160 patients with primary glioblastoma treated with radiotherapy and temozolomide was analyzed for the impact of O6-methly-guanly-methyl-transferase (MGMT)-promoter methylation as well as isocitrate dehydrogenase (IDH)1-mutational status. Unexpectedly, overall survival or progression-free survival were not longer in the group with methylated MGMT-promoter as compared to patients without that methylation. IDH-1 mutations were significantly associated with increased overall survival.

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“…In 2009, a large prospective phase III clinical study conducted by the European Organization for Research and Treatment of Cancer and the National Cancer Institute of Canada confirmed that newly diagnosed patients with glioblastoma accompanied by MGMT gene promoter methylation could benefit from radiotherapy with concomitant adjuvant temozolomide (TMZ) treatment (3). Subsequently, at the 2011 American Society of Clinical Oncology annual meeting, the Radiation Therapy Oncology Group (RTOG) reported the results of a phase III randomized controlled trial (RTOG 0525), which included 833 cases of malignant glioma; the survival time of patients with MGMT gene promoter methylation was significantly longer than that of patients without MGMT gene promoter methylation after receiving standard TMZ treatment (4). These findings support an independent role for MGMT gene promoter methylation in predicting prognosis.…”

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confidence: 99%

MGMT promoter methylation in serum and cerebrospinal fluid as a tumor-specific biomarker of glioma

et al. 2015

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O-methylguanine-DNA methyltransferase () promoter methylation is a conventional technique to predict the prognosis or individualized treatment of glioma in tumor tissue following surgery or biopsy. However, the technique cannot be applied in those glioma patients with concomitant neurological dysfunctions or advanced age. The present study aimed to find a new minimally invasive and efficient alternative method for the detection of promoter methylation. The expression of promoter methylation was assessed in peripheral blood and cerebrospinal fluid (CSF), and compared to the corresponding tumor tissue from glioma patients. The 89 patients in the study [32 World Health Organization (WHO) grade II, 19 WHO grade III and 38 WHO grade IV) were pathologically-diagnosed glioma and received radiation therapy following sample collection. The resected glioma tumor tissue (89), corresponding serum (89) and CSF (78) samples were collected for the detection of promoter methylation using methylation-specific polymerase chain reaction. The sensitivity and specificity of detecting promoter methylation in CSF and serum were compared. Among the tumor tissue samples, 51/89 (57.3%) showed promoter methylation. The specificity of the detection in the CSF and serum samples reached 100%. The sensitivity of promoter methylation detection in CSF and serum were 26/40 (65.0%) and 19/51 (37.3%), respectively (P<0.05). In the WHO II, III and IV subgroups, the sensitivities of promoter methylation detection using CSF were 8/12 (66.7%), 11/18 (61.1%) and 7/10 (70.0%), respectively, which were significantly higher than the sensitivities using serum (7/21, 33.3%; 7/19, 36.8%; and 5/11, 45.5%, respectively P<0.05). Among patients with residual postoperative tumors, the sensitivities of detecting promoter methylation using CSF and serum were 18/25 (72.0%) and 10/24 (41.7%), respectively, both of which were significantly higher than the corresponding values for patients without residual tumors (8/15, 53.3% and 6/19, 31.6%, respectively; P<0.05). The detection of promoter methylation in CSF specimens shows higher sensitivity compared to the serum for glioma patients. Assessment of promoter methylation in CSF may provide a promising clinical methodology for early diagnosis, individual treatment, monitoring of recurrence and prognosis for glioma patients.

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Chemoradiotherapy of Newly Diagnosed Glioblastoma With Intensified Temozolomide

Abstract: MGMT gene promoter appeared not to benefit from intensifying the TMZ schedule regarding median PFS and overall survival, whereas data are promising for patients with methylated MGMT promoter.

Cited by 50 publications

References 20 publications

MGMT testing—the challenges for biomarker-based glioma treatment

MGMT testing—the challenges for biomarker-based glioma treatment

Prognostic significance of IDH-1 and MGMT in patients with glioblastoma: One step forward, and one step back?

MGMT promoter methylation in serum and cerebrospinal fluid as a tumor-specific biomarker of glioma

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