Phase II Trial of Lomustine Plus Temozolomide Chemotherapy in Addition to Radiotherapy in Newly Diagnosed Glioblastoma: UKT-03

Herrlinger, Ulrich; Rieger, Johannes; Koch, Dorothee; Loeser, Simon; Blaschke, Britta; Kortmann, Rolf Dieter; Steinbach, Joachim P.; Hundsberger, Thomas; Wick, Wolfgang; Meyermann, Richard; Tan, Ta Chih; Sommer, Clemens; Bamberg, M.; Reifenberger, Guido; Weller, Michael

doi:10.1200/jco.2006.06.9104

Cited by 148 publications

(93 citation statements)

References 24 publications

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“…In line with previous studies following other approaches (3,18,19), MGMT gene promoter methylation was highly predictive for survival in glioblastoma patients receiving alkylating chemotherapy.…”

Section: Discussionsupporting

confidence: 88%

“…The PFS-6 of 65.2% suggests that, in the first-line treatment situation, patients with MGMT-expressing tumors might benefit from the intensified TMZ schedule. In contrast, this translates not into a relevant overall improvement regarding median PFS and OS, similar to other trials for patients with MGMT-active glioblastoma (1,3,18,19). Conversely, the comparative statistical analysis with the current standard therapy documented a possible effect on PFS but failed to show an effect on OS in Weiler et al 15 patients with a methylated MGMT gene promoter ( Table 4) …”

Section: Discussionsupporting

confidence: 51%

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Chemoradiotherapy of Newly Diagnosed Glioblastoma With Intensified Temozolomide

Weiler

Hartmann

Wiewrodt³

et al. 2010

International Journal of Radiation Oncology*Biology*Physics

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Section: Discussionsupporting

confidence: 88%

Section: Discussionsupporting

confidence: 51%

Chemoradiotherapy of Newly Diagnosed Glioblastoma With Intensified Temozolomide

Weiler

Hartmann

Wiewrodt³

et al. 2010

International Journal of Radiation Oncology*Biology*Physics

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“…11,38 At present, qMSP 31 is being used for patient selection in the CENTRIC trial (http://clinicaltrials.gov, NCT00689221).…”

Section: Mrna Expressionmentioning

confidence: 99%

“…10,11,13,38,40,41 The 2 year and 5 year survival rates in patients with a methylated MGMT promoter treated with concomitant and adjuvant temozolomide were 49% and 14%, respectively, while the corresponding figures for patients initially treated with radiotherapy only were 24% and 5%. Of patients with an unmethylated MGMT promoter, 15% and 8% were alive at 2 years and 5 years, respectively, after treatment with combined chemoradiotherapy, compared with 2% and 0% in those initially treated with radiotherapy alone.…”

Section: The Role Of Mgmt In Glioma Subtypes Glioblastomamentioning

confidence: 99%

MGMT promoter methylation in malignant gliomas: ready for personalized medicine?

et al. 2009

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The DNA repair enzyme O 6 -methylguanine-DNA methyltransferase (MGMT) antagonizes the genotoxic effects of alkylating agents. MGMT promoter methylation is the key mechanism of MGMT gene silencing and predicts a favorable outcome in patients with glioblastoma who are exposed to alkylating agent chemotherapy. This biomarker is on the verge of entering clinical decision-making and is currently used to stratify or even select glioblastoma patients for clinical trials. In other subtypes of glioma, such as anaplastic gliomas, the relevance of MGMT promoter methylation might extend beyond the prediction of chemosensitivity, and could reflect a distinct molecular profile.Here, we review the most commonly used assays for evaluation of MGMT status, outline the prerequisites for standardized tests, and evaluate reasons for difficulties in reproducibility. We critically discuss the prognostic and predictive value of MGMT silencing, reviewing trials in which patients with different types of glioma were treated with various chemotherapy schedules, either upfront or at recurrence. Standardization of MGMT testing requires comparison of different technologies across laboratories, and prospectively validated cut-off values for prognostic or predictive effects. Moreover, future clinical trials will need to determine, for each subtype of glioma, the degree to which MGMT promoter methylation is predictive or prognostic, and whether testing should become routine clinical practice.

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“…44 Therefore, determining MGMT activity in GBM may provide an additional source of information supporting individualized cancer therapy. To overcome MGMT-related chemotherapy resistance in gliomas, a wide range of therapeutic strategies are currently under trial such as intensified and continuous TMZ regiments [47][48][49] and treatment with MGMT inhibitors. 8,50,51 It is conceivable that knowledge on MGMT level of a given tumor will be guiding therapy as to dose and time course of administration of O 6 -alkylating drugs as well as MGMT inhibitors.…”

Section: Therapeutic Response Of Patientsmentioning

confidence: 99%

MGMT in primary and recurrent human glioblastomas after radiation and chemotherapy and comparison with p53 status and clinical outcome

Wiewrodt

Nagel²,

Dreimüller

et al. 2007

Intl Journal of Cancer

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The DNA repair protein O 6 -methylguanine-DNA methyltransferase (MGMT) plays a pivotal role in alkylating drug resistance. Here, we determined MGMT activity in primary and recurrent glioblastomas (GBM, WHO grade IV) of patients who received radiation therapy (RT) or RT plus chemotherapy with alkylating agents (temozolomide, chloroethylnitrosoureas). The mean MGMT activity of untreated GBM was 37 6 45 (range 0-205) fmol/mg proteins. In the 1st, 2nd and 3rd recurrences, MGMT activity increased from 66 6 50 (13-194) to 68 6 44 (14-143) and 182 6 163 (64-423) fmol/mg protein, respectively. Comparing patients who received RT only with RT plus chemotherapy, a significant increase of MGMT in 1st recurrences was only found after treatment with RT plus chemotherapy, indicating either selection of MGMT expressing cells or induction of the MGMT gene by alkylating agents. The p53 status was not significantly related to the MGMT expression level, although a trend for lower MGMT activity in p53 positively stained tumors was observed. Patients expressing MGMT activity of 30 fmol/mg protein in the pretreatment tumor had a significant better therapeutic response than patients expressing MGMT above this level, which was shown by Kaplan-Meyer curves and the recurrence free interval after primary tumor resection. In patients who received RT only, this correlation was not found. The data revealed a threshold of MGMT expression (30 fmol/mg protein) below which patients respond better to alkylating agents. Therefore, determination of MGMT activity in the primary tumor appears to be useful in predicting the outcome of GBM therapy. ' 2007 Wiley-Liss, Inc.Key words: DNA repair; alkyltransferase; MGMT; glioblastomas; drug resistance; temozolomide Despite the enormous progress in the treatment of various types of tumors, human gliomas still have a low curative response. In the therapy of gliomas, notably the most severe form glioblastoma multiforme (GBM, WHO grade IV), radiation therapy (RT) or RT concomitant with methylating agents such as temozolomide 1 is applied. Methylating and chloroethylating agents such as BCNU (carmustine), CCNU (lomustine) or ACNU (nimustine) are also administered during adjuvant therapy. 2 Unfortunately, only a minority of glioblastoma patients respond to temozolomide and chloroethylating nitrosoureas. A likely explanation for this is the development of either primary or acquired glioblastoma cell resistance that leads to protection of the tumor against alkylating drugs.Methylating and chloroethylating agents attack DNA at nucleophilic sites like the O 6 position of guanine, forming O 6 -alkylguanine. 3 This lesion is considered to be the major cause of mutations and malignant transformation induced by O 6 -alkylating agents. 4 It also provokes cell death by inducing apoptosis 5,6 and, therefore, is considered to be mainly responsible for the antineoplastic effect of O 6 -alkylating agents. O 6 -alkylguanine is repaired by the suicide DNA repair protein O 6 -methylguanine-DNA methyltransferase (MGMT) that transf...

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Phase II Trial of Lomustine Plus Temozolomide Chemotherapy in Addition to Radiotherapy in Newly Diagnosed Glioblastoma: UKT-03

Abstract: The combination of lomustine, TMZ, and radiotherapy had acceptable toxicity and yielded promising survival data in patients with newly diagnosed GBM. MGMT gene-promoter methylation was a strong predictor of survival.

Cited by 148 publications

References 24 publications

Chemoradiotherapy of Newly Diagnosed Glioblastoma With Intensified Temozolomide

Chemoradiotherapy of Newly Diagnosed Glioblastoma With Intensified Temozolomide

MGMT promoter methylation in malignant gliomas: ready for personalized medicine?

MGMT in primary and recurrent human glioblastomas after radiation and chemotherapy and comparison with p53 status and clinical outcome

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