Radiotherapy (RT) and concomitant and adjuvant temozolomide (TMZ) versus radiotherapy alone for newly diagnosed glioblastoma (GBM): Overall results and recursive partitioning analysis (RPA) of a phase III randomized trial of the EORTC brain tumor and radiotherapy groups and the NCIC clinical trial group

Abstract

The standard initial treatment for patients with GBM after biopsy or surgical resection is post-operative radiotherapy. Chemotherapy was shown to have only a minimal impact on outcome. In a previous phase II trial, we have suggested that adding TMZ to RT might improve survival (Stupp et al. JCO 20:1375–1382, 2002). In EORTC 26981/22981 NCIC CE3 we compared the efficacy of concomitant and adjuvant TMZ and RT to RT alone. Patients with newly diagnosed and histologically proven GBM (WHO grade IV), PS (WHO) 0–2, age 18–70 were eligible. The randomization was between standard RT (60 Gy in 30 daily fractions of 2 Gy, with a GTV-CTV margin of 2–3 cm), versus the same RT with concomitant TMZ (75 mg/m2 daily 7d/week for 35–42 d), followed by up to 6 cycles of adjuvant TMZ (150–200 mg/m2, daily × 5 d, q 28 d). Patients were stratified for institution, age, PS and extent of surgery. Primary endpoint was overall survival (OS) and secondary endpoints were progression free survival (PFS), quality of life and full toxicity profile. Pathology was centrally reviewed and quality control for RT was assessed by individual case reviews. Between July 2000 and March 2002, a total of 573 patients were randomized by 85 institutions. Sixteen percent of patients had a biopsy only, and 84 % had either partial (44 %) or complete (40 %) surgical tumor removal. Median age was 56 years (19–70.5), 63 % were male. PS was 0, 1 and 2 in 39 %, 48 % and 13 % of patients respectively. There was no difference in the prognostic factors between the two treatment arms. RT was delivered as prescribed in 93 % of patients, concomitant TMZ was administered without interruption in 76 % and temporarily interrupted in 11 %. Adjuvant TMZ was given to 76 % of patients and 36 % completed all 6 cycles. With a median follow-up of 2 years, 436 patients have died, 241 (84 %) in the control (RT only) arm and 195 (68 %) in the experimental (RT/TMZ) arm. Median survival was 12 months (95% c.i. 11.2–13.2) in the RT arm and 15 months (95% c.i. 13.6–16.8) in the RT/TMZ arm (p < .0001), and 2 year survivals were 8 % (95% c.i. 4–12 %) and 26 % (95% c.i. 20–32 %), respectively (p < .0001). The difference between the two treatment arms remained statistically significant in RPA classes III-V. Additional results and detailed analysis of prognostic classes will be presented. Concomitant and adjuvant TMZ/RT significantly improves overall survival compared to RT alone in newly diagnosed glioblastoma, regardless of the prognostic class