Title: APPROACH: Analysis of Proton vs. Photon Radiotherapy in Oligodendroglioma and Assessment of Cognitive Health
Funder: Medical Research Council

Abstract: We want to find out if proton or photon radiotherapy (RT) is the best treatment for patients with oligodendroglioma to reduce long-term side effects._x000D_ _x000D_ To do this we will compare the long-term side effects of proton and photon RT for patients with oligodendroglioma. The study is called the APPROACH study. APPROACH stands for Analysis of Proton vs. Photon Radiotherapy in Oligodendroglioma & Assessment of Cognitive Health._x000D_ _x000D_ Oligodendroglioma is an uncommon brain tumour with an excellent outlook. Standard treatment involves surgery to remove as much tumour as possible, RT and then chemotherapy. RT helps stop the tumour from re-growing. Standard RT for adult patients in the UK uses photon RT. Photon RT is given as lots of small treatments on weekdays over about six weeks. This is the best way to control the tumour whilst minimising side effects in normal brain tissue. Unfortunately, photon RT for oligodendroglioma can cause long-term side effects. These can develop years after RT and can include memory problems and difficulties in processing information. These can have a negative impact on quality of life. Proton RT is an advanced type of RT, also given on weekdays over about six weeks. It requires expensive technology but can reduce the dose of RT delivered to the normal brain, including parts of the brain used for memory and information processing. We do not know, however, if these lower doses result in fewer long-term side-effects. We do not expect any difference in controlling the growth of the tumour as the same dose of RT is given to the tumour whether photon or proton RT is used._x000D_ _x000D_ Participants in our study will be randomly assigned (by computer) to receive proton RT or photon RT, with an equal chance of either. We will gather information on long-term brain function, quality of life, other side effects and tumour control. Because RT is given over several weeks it can disrupt to day-to-day life for patients and carers, especially as this condition often involves people of working age who are not allowed to drive due to their diagnosis. Patients receiving photon RT will have this at their local RT centre. Proton RT is only available in Manchester and London, so patients having proton RT will need to stay in Manchester or London for the treatment period (accommodation is provided). As part of the study we will look at whether travelling to a distant RT centre is acceptable to patients._x000D_ _x000D_ To assess long-term side effects, we will monitor patients for five years after RT. This will involve:_x000D_ - Carrying out short practical tasks and memory assessments to measure brain function_x000D_ - Completing questionnaires about quality of life and work_x000D_ - Having Magnetic Resonance Imaging (MRI) scans to monitor the tumour_x000D_ - Having blood tests to track hormone levels- these can also be affected by RT_x000D_ _x000D_ We will also ask carers to complete questionnaires, to assess carer experiences._x000D_ _x000D_ We will include 246 patients with oligodendroglioma from across the UK. _x000D_ _x000D_ Patient and Public Involvement (PPI) has played a key role in the study: patients and carers supported the research question and follow-up plan and advised on study design. At least three PPI representatives will sit on the Trial Management Group to ensure the patient voice is represented. The PPI group will have an active role throughout and will contribute to the final scientific report and in the dissemination of the findings, that will be shared with trial participants and the wider public.

Lay abstract: Research question: In adults with oligodendroglioma (ODG), does Proton Beam Therapy (PBT) offer neurocognitive benefits compared to photon radiotherapy (RT)?_x000D_ Background: Adults with ODG brain tumours have median survival in excess of 10 years. RT, traditionally delivered using photon radiation, is an important component of treatment. Despite controlling tumour, photon RT can damage healthy brain resulting in long-term irreversible side effects. These include neurocognitive decline (NCD): even small deficits in neurocognitive function (NCF) have an adverse impact on quality of life (QOL) and noticeable impact on daily living, which is especially relevant for ODG patients, given their young age and prolonged survival. NCD may be apparent as soon as two years post-RT and becomes more obvious over time. PBT is an advanced type of RT that delivers less dose to healthy brain, without compromising tumour control. The lower healthy tissue doses from PBT offer the potential for reduced long term toxicity, including reduced NCD. PBT is expensive, new to the UK and available in only two NHS centres. Randomised trials to demonstrate the patient benefits of PBT over photon RT are required in most adult cancers, including ODG._x000D_ Aims and objectives_x000D_ To determine:_x000D_ i) feasibility of recruitment to a randomised trial of PBT vs. photon RT,_x000D_ ii) whether there are early (2 years post-RT) signals of neurocognitive benefit with PBT compared to photon RT,_x000D_ iii) whether there is a long-term (5 years post-RT) neurocognitive benefit of PBT compared to photon RT._x000D_ Methods:_x000D_ A multi-centre randomised controlled trial with multi-staged assessment. The primary endpoint is NCF at 5 years, assessed using a standard neurocognitive test battery. Secondary endpoints include QOL, additional tests of NCF, endocrinopathy, safety & toxicity, response rates, progression free and overall survival, carer distress and work & productivity. Patients will be recruited from 18 centres and randomised 1:1 between photon RT and PBT, delivered over 6 weeks at the local centre (photon RT) or PBT centre. Neurocognitive tests will be performed at baseline and annually for 5 years. Clinical assessment, QOL and productivity questionnaires, imaging, blood tests and carer questionnaires will be performed throughout follow-up. Interim analyses will assess recruitment feasibility, early (2-year) efficacy, and exclude futility. The final analysis will be at 5 years. 246 patients (123 per arm) are required to detect a moderate effect size in NCF at 2 and 5 years between PBT and photon RT._x000D_ Timelines: 12 months for set up, 42 months to recruit, 60 months to complete follow-up and 6 months for analysis/ write up._x000D_ Mechanism: The aim is to improve understanding of RT dose-NCD relationships in specific brain regions using longitudinal modelling and lesion symptom mapping. This will inform RT planning, prioritising specific regions that can be spared from damage using PBT. This will identify those most likely to benefit from PBT and reduce NCD._x000D_ Impact and dissemination: A UK study offers a unique opportunity to generate an evidence-base for the benefit of PBT over photon RT. If PBT is superior, individuals in the trial will benefit through access to a treatment that causes less NCD and preserves QOL. From a societal perspective this will enable maintained productivity. This trial will provide high-quality evidence regarding PBT in ODG to guide funding decisions and improve long-term patient outcomes

Research activity codes: 5.5 RADIOTHERAPY AND OTHER NON-INVASIVE THERAPIES;6.5 RADIOTHERAPY AND OTHER NON-INVASIVE THERAPIES
Health categories: CANCER AND NEOPLASMS