Is Long-Term Survival in Glioblastoma Possible? Updated Results of the EORTC/NCIC Phase III Randomized Trial on Radiotherapy (RT) and Concomitant and Adjuvant Temozolomide (TMZ) versus RT Alone

Reviewer: Eric Shinohara MD, MSCI
Abramson Cancer Center of the University of Pennsylvania
Last Modified: October 30, 2007

Presenter: Rene-Olivier Mirimanoff , MD
Presenter's Affiliation: University Hospital Lausanne, Lausanne, Switzerland
Type of Session: Plenary

  • Glioblastoma Multiforme (GBM) is a devastating malignancy with poor survival even with full surgical resection and radiation.
  • Previously Stupp et al. (NEJM 2005) reported improvement in 2 year survival in patients with GBM treated with concurrent radiation with temozolimide followed by adjuvant temozolamide compared with patients treated with radiation alone after surgery.
  • The present abstract presents updated results from the Stupp trial to determine if the improvement in survival persists over a longer follow up period.
Materials and Methods
  • The present study is an update of the previously published Phase III trial by the EORTC and NCIC examining the use of concurrent followed by adjuvant temozolimide with radiation versus radiation alone in the treatment of glioblastoma.
  • The update encompassed data up until October 1, 2007.
  • 573 patients were randomized and median follow up was 16 months.
  • O6-methylguanine- methyltransferase enzyme (MGMT) methylation status was determined using PCR.
  • Patients were classified using recursive partitioning analysis (RPA). Patients were classified as follows:
    • Class III: <50 years old, performance status 0.
    • Class IV: all others
    • Class V: >50 years old, mini-mental status of <27, biopsy only
  • Patients with newly diagnosed GBM from 18-70 years old were eligible for this study.
  • Only patients with a performance status of 0 or 1 were eligible for this study.
  • Patients were randomized to receive either concurrent followed by adjuvant treatment with temozolamide or radiation alone. Temozolamide was given at a dose of 75 mg/m2 daily, seven days a week for six weeks during radiation. This was followed by six cycles of temozolamide 150-200 mg/m2 daily, for five days, every 28 days after completion of radiation.
  • All patients were treated with 2 Gy fractions to 60 Gy. A GTV-CTV margin of 2-3 cm was used.
  • The primary endpoint of this study was overall survival (OS). The secondary endpoints of this study were progression free survival, quality of life, and toxicity profile.
  • Age, sex, performance status, RPA, surgery type, and MGMT methylation status were well balanced between the two arms.
  • Median dose of radiation for the two arms was 60 Gy.
  • 88% of patients received the entire temozolamide dose.
  • Overall survival for all patients ( radiation alone versus temozolamide with radiation):
    • 2 year OS: 11% versus 27%
    • 3 year OS: 4% versus 16%
    • 4 year OS: 3% versus 12%
    • p<0.0001
  • RPA class III patients only:
    • 2 year OS: 21% versus 41%
    • 3 year OS: 10% versus 32%
    • 4 year OS: 7% versus 28%
    • p=0.012
    • This was the best prognostic indicator
  • RPA class IV patients only:
    • 2 year OS: 11% versus 29%
    • 3 year OS: 4% versus 15%
    • 4 year OS: 3% versus 11%
    • p=0.0001
  • RPA class V only:
    • 2 year OS: 6% versus 18%
    • 3 year OS: 2% versus 10%
    • 4 year OS: 1% versus 6%
    • p=0.014
    • There was no significant difference in 2004 analysis
  • Methylated MGMT promoter:
    • 2 year OS: 24% versus 49%
    • 3 year OS: 8% versus 28%
    • 4 year OS: 5% versus 22%
    • p=0.04
  • Non-methylated MGMT promoter:
    • 2 year OS: 2% versus 15%
    • 3 year OS: 0 versus 11%
    • 4 year OS: 0 versus 11%
    • p=0.035
Author's Conclusions
  • The survival advantage seen in the previous paper by Stupp et al is maintained in this update. However, it is unclear if these patients are cured or if temozolamide is delaying disease progression.
  • There are a significant number of survivors, even after four years.
  • RPA class III and methylated MGMT were associated with the most benefit for OS.
  • Overall prognosis still remains poor. However, temozolamide with radiation in the standard of care and all future trials should be done with temozolamide as a component of the study.
  • Future directions:
    • Currently RTOG 0525 is investigating the use of dose intensive temozolamide with radiation in newly diagnosed GBM.
    • There is interest in investigating the use of biological agents and other concurrent therapies with temozolamide. There are currently trials examining the use of cilengitide with temozolamide and radiation followed by maintenance with both agents in newly diagnosed GBM.
Clinical/Scientific Implications
  • This study demonstrates that the benefit seen with concurrent and maintenance temozolamide compared with radiation alone is maintained over 4 years.
  • This study demonstrated favorable prognostic factors which can help stratify groups of patients that will benefit the most from temozolamide. However, there is still a significant benefit seen in patients without methylation of MGMT and the authors recommend temozolamide in these patients.
  • Anecdotally the authors report more out of field recurrences in the temozolamide group. Prior studies of extensive surgery, even hemispherectomy, still had recurrences. Whole brain radiation has not been shown to produce better outcomes compared with partial brain radiation. It is therefore imperative to find better systemic agents to treat microscopic disease in the brain.
  • The authors recommended considering hypofractionation for patients older than 70.

Partially funded by an unrestricted educational grant from Bristol-Myers Squibb.


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