Advances in translational research provide a rationale for clinical re-evaluation of high-dose radiotherapy for glioblastoma.

Despite maximal surgical resection, postoperative radiotherapy and chemotherapy, the median survival of patients with glioblastoma (GBM) is only approximately 10-15 months. Older data in the literature support a radiation dose-survival relationship, and the predominant pattern of relapse is local, and yet, randomised dose-escalation trials have failed to improve survival, and the current standard of care remains 60 Gy in 30 fractions as well as chemotherapy. In light of considerable advances in molecular and radiobiological characterisation of GBM, it is possible to hypothesize that certain subsets might be more responsive to the effects of radiotherapy, and trials enriched with such patients might in fact provide a basis for testing a possible survival advantage with higher doses of radiotherapy. Arguments supporting this hypothesis will be discussed. Building on the improved knowledge about highly radioresistant types of GBM, tumours in whom higher doses of radiation at best might marginally improve cell kill and tumour growth delay, versus less radioresistant types where proportionally larger gains including improved survival can be achieved, is crucial for the design of future trials testing this concept. Markers predicting which GBM are likely to respond favourably to radiation treatment need to be validated prospectively. Moreover, the success of high-dose radiotherapy critically depends on optimal imaging for target volume delineation after maximum safe surgical debulking. Treatment should also include the well established radiosensitizing drug temozolomide. Additional drugs targeting other pathways and microenvironmental features such as invasion, oxygenation and blood supply, might be included in the rational design of future clinical trials, provided initial studies support their use.