The power of three: hypofractionation, protons, and molecular imaging in glioblastoma radiotherapy

The second technique adopted by Vora and colleagues is proton beam radiotherapy,1 which is being increasingly used for brain tumours with the goal of normal brain tissue sparing and reducing toxicity.5 A phase 2 randomised trial comparing proton bean therapy with photon radiotherapy in 30 fractions, concurrently with chemotherapy, for patients with glioblastoma did not meet its primary endpoint of improved cognitive preservation with proton therapy but did report modest benefits in overall grade 2 or worse adverse events, patient-reported grade 1–2 fatigue, and grade 3 or worse lymphopenia.6,7 The degree to which these modest benefits justify the increased cost of proton therapy or the travel burden for patients living a long distance from proton-equipped centres remains unclear. [...]we reported promising feasibility and adverse event results from a three-site trial of dose-escalated chemoradiotherapy for glioblastoma guided by spectroscopic MRI—a whole-brain MRI technique offering resolution similar to PET without exogenous contrast, and performed on 3T clinical MRI scanners.10 Interestingly, the median spectroscopic MRI-defined dose escalation volume was 18 cm3, compared to an 18F-DOPA PET-defined median volume of only 8 cm3 in Vora and colleagues' study.1 The importance of volume differences between these techniques remains unknown. Combining all three advances into this single-arm trial,1 Vora and colleagues observed an impressive median overall survival of 13·1 months, which is a notable improvement compared with historical controls such as the 9·3 month overall survival that has been reported previously2 for older patients receiving 40 Gy of photon therapy in 15 fractions with concurrent temozolomide.2 Of the three techniques—extreme hypofractionation, proton radiotherapy, and 18F-DOPA PET guidance—whether one technique is the primary driver of the promising results, or if a combination of two or all three contributes to the observed benefits is unclear.