MGMT methylation predicts glioblastoma response to temozolomide plus RT

9 March 2009

The benefits of adjuvant temozolomide with radiation therapy for glioblastoma persist through 5 years of follow-up, although long-term survival rates remain low. Methylation status of the methyl-guanine methyl transferase gene (MGMT) is an independent predictor of response to the combination treatment.

In The Lancet Oncology, published online on March 9, investigators report the final results of the European/Canadian EORTC-NCIC trial, which involved 573 patients ages 18 to 70 with newly diagnosed glioblastoma, WHO grade IV. Patients were randomized to radiation therapy (n = 286) or radiation plus temozolomide (n = 287). Radiotherapy comprised 60 Gy given in 30-day fractions of 2 Gy. Temozolomide was administered at 75 mg/m² daily for up to 49 days, followed by up to six cycles of temozolomide, 150-200 mg/m² for 5 days every 28 days.

The original 2-year analysis showed survival of 27.2% in the combined therapy group versus 10.9% in the radiation alone group. At 5 years, mortality was 89% with temozolomide and 97% with radiation alone. All prognostic subgroups benefited from combined therapy, but the largest gain occurred in those with the most favorable characteristics, whose survival at 5 years was 28%. The hazard ratio for death in the temozolomide group relative to the radiotherapy group was 0.63 (p < 0.001).

"Nevertheless," lead author Dr. Roger Stupp at the University of Lausanne, Switzerland, and fellow researchers report, "most patients successfully treated with combined therapy eventually had tumor recurrence and died."

Among 226 patients for whom the methylation status of the MGMT promoter was determined, this factor turned out to be the strongest predictor of survival (HR 0.49, p = 0.001). Median survival was nearly doubled in the combined therapy group among those with methylated MGMT (23.4 months vs 12.6 months).

At this point, cure of glioblastoma is still "not possible," the researchers state. "Rational choice of drugs, mechanism-based translational research, and systematic assessment of new targets and drugs are needed to improve outcome for patients with glioblastoma."

Source Lancet Oncology