Dorothee Wiewrodt

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

The DNA repair protein O6‐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 ± 45 (range 0–205) fmol/mg proteins. In the 1st, 2nd and 3rd recurrences, MGMT activity increased from 66 ± 50 (13–194) to 68 ± 44 (14–143) and 182 ± 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.

MGMT activity, promoter methylation and immunohistochemistry of pretreatment and recurrent malignant gliomas: a comparative study on astrocytoma and glioblastoma

The DNA repair protein O6‐methylguanine‐DNA methyltransferase (MGMT) is a key player in tumor cell resistance. Promoter methylation, MGMT activity and immunohistochemistry are used for determining the MGMT status. However, it is unclear whether MGMT promoter methylation correlates with MGMT activity and whether MGMT promoter methylation of the pretreatment tumor predicts the MGMT status of recurrences. To address these questions, we determined MGMT activity promoter methylation and immunoreactivity in pretreatment and recurrent glioblastomas (GB, WHO Grade IV), and in astrocytomas (WHO Grade III). We show that GB that were promoter methylated display a range of 0–62 fmol/mg MGMT and tumors that were nonmethylated 0–423 fmol/mg protein. For astrocytomas, promoter‐methylated samples displayed 0–28 fmol/mg and, nonmethylated samples, 23–107 fmol/mg. No correlation was found between the intensity of promoter methylation and MGMT activity. Given a threshold level of 30 fmol/mg of protein, we found a correlation between promoter methylation and no/low MGMT activity in 82.4% of the tumors. This high correlation level was only observed when tumors were excluded showing a hemimethylated promoter (20%). Therefore, classification of hemimethylated tumors remains questionable. Further, we show that 39.1% of pretreatment GB and 5.3% of recurrences were promoter methylated, which is in line with the observed increase of MGMT activity in recurrences. Although individual exceptions were found, the data show an overall correlation between promoter methylation and lack/low MGMT activity in GB and astrocytomas. We also show that promoter methylation assay is superior over immunohistochemistry in determining the MGMT status defined by a given MGMT activity level.

Chemoradiotherapy of newly diagnosed glioblastoma with intensified temozolomide

PURPOSE To evaluate the toxicity and efficacy of chemoradiotherapy with temozolomide (TMZ) administered in an intensified 1-week on/1-week off schedule plus indomethacin in patients with newly diagnosed glioblastoma. PATIENTS AND METHODS A total of 41 adult patients (median Karnofsky performance status, 90%; median age, 56 years) were treated with preirradiation TMZ at 150 mg/m(2) (1 week on/1 week off), involved-field radiotherapy combined with concomitant low-dose TMZ (50 mg/m(2)), maintenance TMZ starting at 150 mg/m(2) using a 1-week on/1-week off schedule, plus maintenance indomethacin (25 mg twice daily). RESULTS The median follow-up interval was 21.7 months. Grade 4 hematologic toxicity was observed in 15 patients (36.6%). Treatment-related nonhematologic Grade 4-5 toxicity was reported for 2 patients (4.9%). The median progression-free survival was 7.6 months (95% confidence interval, 6.2-10.4). The 1-year survival rate was 73.2% (95% confidence interval, 56.8-84.2%). The presence of O(6)-methylguanine-DNA methyltransferase (MGMT) gene promoter methylation in the tumor tissue was associated with significantly superior progression-free survival. CONCLUSION The dose-dense regimen of TMZ administered in a 1-week on/1-week off schedule resulted in acceptable nonhematologic toxicity. Compared with data from the European Organization for Research and Treatment of Cancer/National Cancer Institute of Canada trial 26981-22981/CE.3, patients with an unmethylated MGMT gene promoter appeared not to benefit from intensifying the TMZ schedule regarding the median progression-free survival and overall survival. In contrast, data are promising for patients with a methylated MGMT promoter.

NOA‐05 phase 2 trial of procarbazine and lomustine therapy in gliomatosis cerebri

The NOA‐05 multicenter trial was performed to analyze the efficacy of primary chemotherapy with procarbazine and lomustine (PC) in patients with gliomatosis cerebri (GC) and to define clinical, imaging, and molecular factors influencing outcome.

Nimustine (ACNU) Plus Teniposide (VM26) in Recurrent Glioblastoma

Background: In a previous trial (NOA-01), the combination of nimustine and teniposide showed efficacy in previously untreated glioblastoma (GBM). After establishing temozolomide as standard first-line therapy in GBM patients, the nimustine (ACNU)/teniposide (VM-26) combination has been employed as salvage chemotherapy for recurrent GBM. However, data on the toxicity and efficacy of this regimen in recurrent GBM are lacking. Patients and Methods: In two neurooncological centers, all patients with recurrent GBM treated with nimustine (90 mg/m2, day 1/42) and teniposide (45–70 mg/m2, days 1–3/42) were analyzed retrospectively for progression-free survival (PFS), overall survival (OS) and toxicity. Results: Thirty-five patients (median age 51 years, range 25–71 years) were identified. Six months after chemotherapy initiation, PFS was 29% and the median OS 6 months; 23% of patients were alive ≥1 year after initiation of nimustine-teniposide chemotherapy. Grade 4 hematotoxicity was observed in 12 of 35 patients (34%) and in 14 of 83 evaluable chemotherapy courses (17%). Conclusions: The benefit of the nimustine-teniposide combination is moderate in patients with recurrent GBM. The data support the efficacy of the nimustine-teniposide chemotherapy, but the rate of high-grade hematotoxicity is increased.

Procarbazine and CCNU as Initial Treatment in Gliomatosis Cerebri

Background: Gliomatosis cerebri (GC) is a diffuse infiltrating glial tumor with involvement of at least 3 cerebral lobes. There are only few data on the efficacy of initial chemotherapy in patients with GC. Patients and Methods: In 3 neurooncological centers, patients with newly diagnosed GC who had received procarbazine (60 mg/m2, days 8–21/56) and CCNU (110 mg/m2, day 1/56) chemotherapy (PC) as initial treatment were analyzed for progression-free survival, overall survival and toxicity. Results: Twelve patients (median age 46 years, range 27–72) were analyzed. The median progression-free survival and the median overall survival were 16 and 37 months. Grade 3 or 4 hematotoxicity was observed in 3 of 12 patients (25%). Conclusions: These data support the efficacy of PC chemotherapy in newly diagnosed GC. Initial PC chemotherapy should be considered as a treatment option and evaluated in larger clinical trials.

Erratum to: Gliomatosis cerebri: no evidence for a separate brain tumor entity

Erratum to: Acta Neuropathol DOI 10.1007/s00401‑015‑1495‑z. The original version of this article contained errors in the alignment of several entries in Tables 4 and 5. The corrected Tables 4 and 5 are given below. The original article has been updated accordingly.