Ultra-hypofractionated versus conventional chemoradiation for newly diagnosed glioblastoma: Survival and toxicity results of a multicenter randomized trial

PURPOSE: In glioblastoma, standard first-line chemoradiation since the 2005 EORTC/NCIC trial is 30x2Gy with concurrent and adjuvant temozolomide. A phase II study suggested ultra-hypofractionation (6x6Gy) may offer comparable survival, with reduced treatment time and costs, potentially improving health-related quality of life (HRQoL). This phase III randomized trial (Netherlands Trial Registry, NL72953.041.20) evaluated non-inferiority of ultra-hypofractionated temozolomide chemoradiation in glioblastoma patients. PATIENTS AND METHODS: Adults with newly diagnosed glioblastoma and a Karnofsky performance status ≥70 were randomized (1:1) to ultra-hypofractionated (6x6Gy in 2 weeks) or standard (30x2Gy in 6 weeks) radiotherapy, both with concurrent and 6 cycles of adjuvant temozolomide. The primary endpoint was 2-year overall survival (OS); the non-inferiority margin was a hazard ratio of 1.2. Secondary outcomes included progression-free survival (PFS) and toxicity. RESULTS: Enrollment stopped early, due to slow accrual (n=135/474 planned, 67 experimental, 68 standard). Median OS was shorter in the experimental arm: 13.0 months (95% CI 10.3-15.7) versus 21.0 months (95% CI not estimable). In a time-dependent analysis, survival was similar in the first 6 months (HR 0.99, 95% CI 0.39-2.50), but mortality was higher thereafter (HR 2.54, 95% CI 1.57-4.09, p < 0.001). Radiation necrosis or pseudoprogression was more frequent after ultra-hypofractionation (47.8% vs 16.2%; HR 5.20, 95% CI 2.56-10.58), with increased dexamethasone use at 6-12 months. No grade 4-5 toxicities were observed. CONCLUSION: Non-inferiority of the 6x6 Gy chemoradiation regimen could not be demonstrated. This ultra-hypofractionated regimen was associated with inferior survival and increased radiation necrosis, and therefore should not replace standard chemoradiation.