KEY POINTS
- The multicentre phase III GOLD trial randomized 135 adults with newly diagnosed glioblastoma and Karnofsky performance status ≥70 across eight Dutch radiotherapy centres. Recruitment was stopped early because of slow accrual, well below the planned 474 patients.
- Patients received either ultra-hypofractionated radiotherapy over two weeks - 6 × 6 Gy to GTV + 5 mm with 6 × 4 Gy to the surrounding GTV + 15 mm volume - or standard 30 × 2 Gy over six weeks. Both groups received concurrent temozolomide followed by up to six adjuvant cycles.
- Median overall survival was 13.0 months with the six-fraction regimen versus 21.0 months with standard treatment (p<0.001). One-year survival was 52.2% versus 70.6%.
- Survival curves were initially similar but separated after six months. Beyond six months, the risk of death was more than doubled with ultra-hypofractionation (HR 2.54, 95% CI 1.57–4.09; p<0.001). Non-inferiority therefore could not be demonstrated.
- Median progression-free survival was 9 versus 10 months. Again, the major difference emerged after six months, when the risk of progression or death was higher with the experimental regimen (HR 2.08, 95% CI 1.28–3.38; p=0.003).
- Radiation necrosis or pseudoprogression was reported in 47.8% versus 16.2% of patients, corresponding to an approximately fivefold higher risk with ultra-hypofractionation (HR 5.20, 95% CI 2.56–10.58; p<0.001). Bevacizumab use was also higher (34% vs 8%), and dexamethasone use increased substantially at 6–12 months.
- The dose geometry may help explain the result. The 6 × 6 Gy high-dose region corresponds to approximately 72 Gy EQD2 for late-responding brain tissue, potentially contributing to necrosis, while the surrounding 6 × 4 Gy region corresponds to only about 36 Gy EQD2, potentially underdosing microscopic disease. Concurrent temozolomide exposure was also much lower in the experimental arm (900 vs 3000 mg/m²).
CLINICAL TAKEAWAY
Compressing first-line glioblastoma chemoradiation from six weeks into six fractions was not simply unsuccessful - it was associated with substantially worse survival and considerably more treatment-related brain injury. Despite premature trial closure, the consistency across survival, progression and toxicity endpoints provides strong randomized evidence against using this 6 × 6 Gy strategy as a substitute for standard chemoradiation.