Combined modality treatment of glioblastoma multiforme: the role of temozolomide

Despite of improvements in the biological and molecular characterization of glioblastoma multiforme and studies of factors associated with tumor growth and progression, this type of malignant astroglial brain tumor is still difficult to treat. The present article reviews established and emerging prognostic and predictive factors and their potential influence on future therapeutic efforts. Recent developments in standard treatment options (surgery, radiotherapy and chemotherapy) are summarized. The integration of the oral cytotoxic agent temozolomide into current treatment protocols of postoperative combination therapy with radiation and drugs is discussed, especially in the context of the recently published randomized trial of the EORTC/NCIC, which showed that radiotherapy plus concomitant and adjuvant temozolomide significantly improved progression-free and overall survival over radiotherapy alone. The study also provided hypotheses about the subgroups, which are most likely to benefit from this reasonably well tolerated regimen. In a subset of patients, investigation of MGMT promoter methylation in tumor tissue was performed. Survival was shorter in patients with unmethylated promoter in both study groups. Patients with methylated promoter treated with radiotherapy had a median survival of 15 months, those treated with radiation plus temozolomide of 22 months (p=0.007). In the unmethylated group, the difference in median survival was only 1 month (p=0.06). Especially for these patients, alternative treatments need to be developed. The optimum schedule of temozolomide administration and the influence of combinations with additional antineoplastic agents remains to be studied. Early results of clinical trials addressing these issues are presented.