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Concomitant and adjuvant temozolomide (TMZ) and radiotherapy (RT) for newly diagnosed glioblastoma multiforme (GBM).  Conclusive results of a radomized phase III trial by the EORTC Brain & RT Groups and NCIC Clinical Trials Group.

Reviewer: Charles Wood, MD
Abramson Cancer Center of the University of Pennsylvania
Ultima Vez Modificado: 7 de junio del 2004

Presenter: R. Stupp
Presenter's Affiliation: University Hospital (CHUV), Lausanne, Switzerland
Type of Session: Plenary

Background

• Glioblastoma multiforme is the most malignant and most common primary brain tumor, with a dismal median overall survival of less than one year.
• Radiation treatment has long been the standard of care in treating GBM.
• Previous randomized trials involving single and multiagent chemotherapy regimens have failed to demonstrate a survival advantage.
• Temozolomide, a DNA methylating agent, has shown single agent activity in recurrent gliomas.
• Temozolomide and radiation delivered concurrently have demonstrated synergy in vitro.
• A recent phase II trial showed promising efficacy for concurrent Temozolomide and radiation treatment.
• This phase III study was undertaken to evaluate the concurrent regimen as it applies to overall survival.

Materials and Methods

• This was a multicenter prospective randomized trial involving 85 institutions in 14 countries.
• 573 patients were enrolled between 12/00 and 3/03; stratified at each institution according to age, gender, performance status, and extent of surgery; and randomized to one of two treatment arms.  
• Arm 1 (286 pts.) consisted of external beam radiation treatment to 60 Gy in 2 Gy fractions.
• Arm 2 (287 pts.) consisted of external beam radiation treatment to 60 Gy in 2 Gy fractions along with concurrent Temozolomide (75 mg/m²) taken daily during radiotherapy (6 weeks).  Six cycles of adjuvant Temozolomide (150-200 mg/m²) were then given on days 1 through 5 of each 28 day cycle.
• All patients had histological evidence of glioblastoma multiforme, no prior history of chemotherapy or radiation, were 18 to 70 years of age, and began treatment within 6 weeks of surgery.
• The trial was designed to detect a 33% increase in median overall survival (from 12 to 16 months).
• Primary endpoint was overall survival.
• Secondary endpoints included progression-free survival, quality of life, safety profile, and economic analysis.
• Results were analyzed on an intention-to-treat basis.

Results

• Median follow-up was 2 years.
• Median age was 56 years in the combined treatment group and 57 years in the radiation alone group.
• Median radiation dose was 60 Gy.
• Median time from surgery to radiation was 5 weeks.
• Radiation was delivered as prescribed in 93% of patients.
• Concurrent therapy was administered without interruption in 76% of patients, with temporary interruption in 11% of patients, and prematurely discontinued in 12% of patients.  76% of patients underwent adjuvent temozolomide treatment, and 36% completed all 6 cycles.
• There was a significant increase in the combined therapy group with regard to median overall survival (14.6 mos. combined Tx vs. 12.1 mos. RT alone, p<0.0001), progression-free survival (6.9 mos. combined Tx vs. 5 mos. RT alone, p<0.0001), and overall survival at 2 years (26% combined Tx vs. 8% RT alone, p<0.0001).
• There were no significant differences between the two groups with respect to age, performance status, or extent of tumor resection.
• Grade 3/4 hematologic toxicity was demonstrated in 7% of patients during concurrent treatment and in 16% of patients during adjuvant temozolomide therapy.

Author's Conclusions

• This is the first study evaluating chemotherapy to demonstrate a clinically meaningful survival benefit in glioblastoma multiforme patients.
• Concurrent temozolomide and radiation treatment followed by adjuvant temozolomide therapy should be considered the new standard of care in patients with glioblastoma multiforme. 
• A benefit was observed in all subsets of patients.
• The safety and tolerability of concurrent therapy followed by adjuvant treatment was confirmed.
• The study possessed an impressive accrual rate allowing for rapid results.
• Continued research is necessary to provide new avenues of treatment and improve upon existing regimens in an effort to prolong patient survival.

Clinical/Scientific Implications

This phase III study effectively changes the standard of care in glioblastoma multiforme to include concurrent and adjuvant temozolomide chemotherapy with radiation treatment.  The regimen was well-tolerated and provided significant but modest survival benefit.  It should be noted that the median age of patients was relatively low, inherently excluding older patients and their poorer prognostic profile.  The author made the statement that all subsets of patients analyzed were observed to benefit from chemotherapy, but there has, as of yet, been no attempt to perform a multivariate analysis that would potentially identify significant prognostic factors.  Glioblastoma multiforme is an extremely heterogeneous disease, and defining patient sub-populations with respect to type of therapy employed will be necessary once additional treatment options arise. 

Many issues remain with respect to this combined regimen including the reporting of quality of life data associated with this trial, the determination of the optimal dosing schedule, and the confirmation that all subsets of patients benefit from this treatment.  Furthermore, utilizing additional chemotherapeutic agents in combination with temozolomide now becomes an attractive option owing to the drug's favorable side effect profile. 

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