PRESTO: A phase III randomised controlled trial of dose-escalated proton beam therapy versus standard of care intensity-modulated radiotherapy for functioning pituitary tumours

Research question: In adults with functioning pituitary adenomas (FA) causing acromegaly and Cushing’s disease, does dose escalated radiotherapy using proton beam therapy (PBT) lead to better disease control? Background: Adults with acromegaly and Cushing’s disease have rare non-cancerous pituitary tumours which produce excess growth hormone and cortisol respectively. These elevated hormones cause significant medical morbidities and impact quality of life. Once diagnosed, FA are managed surgically, and radiotherapy is used in patients who fail to achieve hormone normalisation despite medical treatment. Hormone levels decline slowly following standard photon radiotherapy (RT) with normalisation achieved in half of patients two years after RT. The lower radiation dose deposited in healthy tissues by PBT enables dose escalation to the FA target while offsetting the additional radiotherapy toxicities associated with higher dose. Randomised trials to demonstrate the benefits of increased radiation dose with PBT are required in FA. Aims and objectives: i) To assess the efficacy of dose-escalated radiotherapy using PBT in comparison to standard dose RT in achieving biochemical control in patients with acromegaly or Cushing’s disease. ii) To evaluate early and late toxicities of treatment in the two treatment groups. iii) To undertake a health economic evaluation of PBT vs RT for this indication based on wider health service utilisation. Methods: PRESTO is a multicentre phase III randomised controlled trial. The primary endpoint is time to normalised of hormone levels following randomised treatment. Secondary endpoints include radiological control of disease, reduction in dose or requirement for medical therapies for hormone excess, quality of life, neurocognitive changes, pituitary deficiency rates, ophthalmological outcomes, and health and social care resource use to enable health economic evaluation. 82 participants will be recruited from centres around the UK and randomised 1:1 between RT and PBT. Treatment is delivered at the local RT centre or PBT centre with all follow up undertaken at the local centre in both arms. Endocrine tests of disease activity will be performed at baseline and then every six months for two years. Clinical assessment, quality of life questionnaires, imaging, blood tests, visual assessments and neurocognitive testing will be performed at baseline and throughout follow up. Interim analysis will take place after 48 patients (24 in each arm) have been randomised, which is anticipated at 2.5 years. The final analysis will take place two years after recruitment of the final participant. Timelines for delivery: 9 months for set up; 48 months for recruitment; 24 months to complete follow-up; 3 months for analysis/ write up. Anticipated impact and dissemination: The PRESTO trial will generate an evidence base for the benefit of dose-escalated PBT in FA. If PBT is superior, participants within the trial will benefit through access to a treatment that will better control their disease, potentially with an improved side effect profile. From a health economic perspective, this may lead to reduced requirements on other medical services, and from a societal perspective may enable increased productivity. PRESTO will provide high-quality evidence that will guide health service funding decisions and may improve patient outcomes.