Neurocognition-sparing radiotherapy of brain and base of skull tumours: modelling toxicity and probing dose-dependent alterations in the brain using advanced imaging techniques.

Radiotherapy (RT) plays a crucial role in the treatment of many primary brain and skull base tumours, including meningioma and low-grade glioma. Due to the nature of the tumours, and the increasing effectiveness of the treatment, long-term survival can be achieved in an increasing number of patients, making side effects an important issue in the follow-up and social reintegration of these patients. Post-RT neurocognitive decline is one of the most elusive long-term toxicities related to radiotherapy of the brain affecting memory, executive function, attention and processing speed. Since up to 53% of the patients can have significant neurocognitive decline after radiotherapy this poses an important social, psychological and clinical burden on survivors of primary brain and skull base tumours. This process however is poorly understood. However generally radiation damage is considered irreversible and progressive in nature, highlighting the importance of prevention. Highly conformal radiotherapy techniques such as intensity modulated radiotherapy (IMRT) and intensity modulated proton therapy (IMPT) allow us to selectively spare certain regions in the brain, while maintaining an adequate dose to the tumour. This potentially decreases long-term toxicity. However we currently lack sufficient knowledge on which brain structures are essential in the pathogenesis of neurocognitive decline in order to exploit the maximum potential of different techniques such as proton therapy. We this knowledge we could more objectively identify the patients which might truly benefit from proton therapy. Mathematical models of normal tissue complication probability (NTCP) allow us to accurately predict radiation induced toxicities associated with a specific treatment plan in the individual patient, and can play a crucial role in selecting the optimal RT plan and modality for this patient. As both clinical and dosimetrical data can be used to construct such a model it is far more reliable than traditional dose-volume parameters. However, while many retrospective analyses have demonstrated a relation between radiation dose to a certain volume and the incidence of complications we currently lack valid NTCP models with a high sensitivity and specificity for neurocognitive decline after RT. Furthermore advanced imaging techniques and analyses which have been developed recently enable us to probe the deeper architecture of the brain. The information obtained from structural and functional imaging techniques will enable us to better understand the underlying mechanisms of RT-induced neural damage and its association with specific neurocognitive decline. With this project we aim to set up a multicentric study, prospectively gathering standardized clinical, radiological, dosimetrical and neurocognitive information in patients treated with IMRT and IMPT for adult brain and skull base tumours. These data will allow us to build solid NTCP models for neurocognitive decline after RT, enabling us to optimize RT in all patients with a brain or skull base tumor upon completion of the project. This will provide us with a much needed, evidence-based tool to select the optimal treatment modality for each individual patient. It is innovative as the correlation of structural and functional imaging changes with dosimetric data and clinical outcome will further increase our insight into the pathogenesis of neurocognitive decline after radiotherapy, and potentially allow us to capture patients at an increased risk for neurocognitive decline.