Clinical Investigation
Chemoradiotherapy of Newly Diagnosed Glioblastoma With Intensified Temozolomide

Presented orally at the Eighth Meeting of the European Association of Neuro-Oncology, September 12–14, 2008, Barcelona, Spain.
https://doi.org/10.1016/j.ijrobp.2009.05.031Get rights and content

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/m2 (1 week on/1 week off), involved-field radiotherapy combined with concomitant low-dose TMZ (50 mg/m2), maintenance TMZ starting at 150 mg/m2 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 O6-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.

Introduction

The current standard of care in the treatment of newly diagnosed glioblastoma is combined chemoradiotherapy with concomitant and adjuvant temozolomide (TMZ) according to the Phase III trial jointly conducted by the European Organization for Research and Treatment of Cancer (EORTC) and the National Cancer Institute of Canada (NCIC) (1). That trial also demonstrated that hypermethylation of the promoter region of the DNA repair gene O6-methylguanine-DNA methyltransferase (MGMT), which partially mediates chemoresistance against alkylating agents such as TMZ or the nitrosoureas (2) correlates with improved survival in patients treated with combined radiotherapy (RT) and TMZ (3). TMZ dosing schedules allowing a more prolonged exposure might result in greater cumulative doses 4, 5, 6 than the standard 5-day regimen (7) and might deplete MGMT in the tumor, thus sensitizing the tumor cells to the toxic effects of TMZ. However, depletion of MGMT by prolonged exposure to TMZ affects not only tumor cells but also normal cells, particularly hematopoietic precursor cells, potentially enhancing hematologic toxicity (5). Other dose-dense TMZ regimens did not show an unusual incidence of toxicities and also demonstrated promising efficacy data at recurrence (6).

Preclinical and clinical studies have suggested antitumoral effects of cyclooxygenase (COX)-2 inhibitors 8, 9. COX-2 inhibition might result in a tumor cell-specific sensitization toward RT (10) and a reduction of tumor neovascularization (11). The expression of COX-2 has been correlated with shorter survival times in patients with glioma (12). Although selective inhibition of COX-2 is regarded as superior to nonselective COX inhibition (e.g., mediated by nonsteroidal anti-inflammatory drugs) in tumor therapy because of the lack of adverse effects on gastrointestinal and platelet function, two available COX-2-selective inhibitors, rofecoxib and celecoxib, were in discussion for lethal cardiovascular complications before the present trial was initiated.

The University of Tübingen Medical Center (UKT)-05 Phase II trial exploited the antiangiogenic and radiosensitizing effects of the nonsteroidal anti-inflammatory drug indomethacin administered as a continuous maintenance therapy and the cytotoxic effects of an intensified concomitant and adjuvant (1 week on/1 week off) TMZ regimen in addition to RT in the first-line treatment of glioblastoma.

Section snippets

Patients

This prospective Phase II trial accrued between February 1, 2005 and October 31, 2006. The ethics committee at the University of Tübingen (Tübingen, Germany) approved the trial (253/2004). The UKT-05 trial enrolled patients at the three German University Medical Centers of Tübingen (n = 27), Mainz (n = 13), and Bonn (n = 1). All patients gave written informed consent. The main inclusion criteria were a histologic diagnosis of supratentorial glioblastoma, age >18 but ≤65 years, Karnofsky

Patient characteristics

Of the 49 patients with newly diagnosed glioblastoma screened, 7 patients were enrolled into a competing Phase I-IIa trial of cilengitide, TMZ, and RT (18) and 1 patient was excluded from the trial assessment retrospectively because he died of Legionellae pneumonia before the trial therapy was started. With the remaining 41 patients (Table 2), 1 additional patient than originally planned was accrued because at the end of the accrual period, 2 eligible patients agreed at the same time.

Treatment

At the

Discussion

First-line therapy with intensified TMZ combined with maintained daily indomethacin and involved-field RT plus concomitant daily low-dose TMZ was shown to be feasible and effective in patients with glioblastoma. In line with previous studies of other approaches 3, 18, 19, MGMT gene promoter methylation was highly predictive for survival in glioblastoma patients receiving alkylating chemotherapy. The PFS-6 of 70.7% in the UKT-05 trial compares well with the results of the combined RT/TMZ

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  • Cited by (0)

    Supported by the University of Tübingen Medical Center, Tübingen, Germany.

    Conflict of interest: U. Herrlinger, M. Weller, and W. Wick have been consultants to, and have received honoraria from, Schering-Plough.

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