The neurocognitive benefits of proton beam therapy for patients with oligodendroglioma

INTERVENTION: The APPROACH trial is a Phase III, multicentre trial. Patients will be recruited from 18‐25 centres and randomised 1:1 between photon radiotherapy (RT) and proton beam therapy (PBT), delivered over approximately 6 weeks. Photon RT will be delivered at the local RT centre while PBT will be delivered at one of the two NHS PBT centres in the UK (The Christie or UCLH). Neurocognitive tests will be performed at baseline, one‐month post‐end of RT and annually for 5 years. Follow‐up will also include clinical assessment, blood tests and brain imaging, as per standard follow‐up protocols. Patient quality of life (QoL) and productivity questionnaires and caregiver questionnaires will also be performed throughout follow‐up. Interim analyses will assess the feasibility of recruitment, and early efficacy at 2 years (i.e., signals of improved neurocognitive function (NCF) with PBT), and assess futility. The primary endpoint will be at 5 years. 246 patients (123 per arm) are required to detect a moderate effect size difference in NCF at 2 and 5 years between PBT and photon RT. The required sample size is 246 patients, recruited over 3.5 years. NCF is measured using Clinical Trial Battery Composite (CTB COMP) scoring, calculated from the mean of standardized z‐scores for the Hopkins Verbal Learning Test‐Revised (HVLT‐R), Trail Making Test (TMT)‐A/B, and Controlled Oral Word Association (COWA). The sample size for NCF at 5 years is based on a two‐sample t‐test. A Cohen’s d of 0.5 is considered a moderate effect size; assuming a common standard deviation (SD) of 1 this effect size equates to a mean z‐score of 0.5, and is deemed clinically relevant in this setting given that patients are typically young and of working age, so even small CONDITION: Brain cancer, oligodendroglioma ; Cancer PRIMARY OUTCOME: Neurocognitive function (NCF) at 5 years measured using the standard neurocognitive test battery ‐ EORTC core clinical trial battery composite (CTB COMP) during baseline and at 1, 3, 6, 12, 24, 36, 48 and 60 months post end of RT, as per standard follow‐up schedules SECONDARY OUTCOME: ; 1. Additional tests of neurocognitive function measured using the CNS Vital Signs test battery (Verbal Memory (VBM), Visual Memory (VIM), Finger Tapping (FTT), Symbol Digit Coding (SDC), Stroop Test (ST), Shifting Attention (SAT), Continuous Performance (CPT), Perception of Emotion (POET), On‐Verbal Reasoning (NVRT), and the 4‐part Continuous Performance (FPCPT)) at baseline, and 1, 12, 24, 36, 48 and 60 months post‐RT; 2. Health‐Related Quality of Life (HRQoL) measured using the EORTC Quality of life questionnaire core 30 (QLQ‐C30), QLQ‐BN20, the EuroQol EQ‐5D‐5L, and Multidimensional Fatigue Inventory (MFI) questionnaire and the Hospital Anxiety and Depression Scale (HADS) at baseline, during the final week of RT and at 1, 3, 6, 12, 24, 36, 48, 60 months post‐RT; 3. Endocrinopathy measured using dynamic/static testing in blood for GH/IGF‐1, FSH/LH/testosterone (males) and SHBG (males)/oestradiol (females), cortisol, T4/T3/TSH, and prolactin at baseline and at 6, 12, 24, 36, 48 and 60 months post‐RT, as per standard of care; 4. Treatment compliance measured using patient records with data on the treatment participants receive collected weekly during radiotherapy; 5. Work and economic impact measured using the WPAI general health (WPAI: GH) questionnaire completed by the participant and their primary caregivers at baseline, during the final week of RT and at 1, 3, 6, 12, 24, 36, 48 and 60 months post‐RT; 6. Caregiver distress measured using the 30‐item Caregiver Needs Screen completed by the participant’s primary caregiver at baseline, during the final week of RT and at 1, 3, 6, 12, 24, 36, 48, and 60 months post‐RT; 7. Early (acute) and late toxicity: acute toxicity period, defined from the start of RT to the 3 months post end of RT follow‐up assessment, measured by clinician assessment each week of treatment during clinic and during the 1 and 3 month follow‐up assessments; late toxicity period, defined as after 3 months until the final follow‐up visit at 60 months, measured by clinician assessment during each of the follow‐up visits and will be recorded at 6, 12, 24, 36, 48 and 60 months post start of radiotherapy treatment. Toxicities will also be recorded at each chemotherapy assessment.; 8. Radiological tumour response meaured using MRI scans, performed at baseline, 3, 6, 12, 24, 36, 48 and 60 months post‐RT, as per standard of care. Response will be evaluated based on the RANO criteria. Additional off‐schedule MRI scans may be used in the case of suspected progression.; 9. Progression‐free survival (PFS), defined as the time from randomisation to the date of the first documented evidence of progression or death from any cause measured using response data evaluated by RANO at 3, 6, 12, 24, 36, 48 and 60 months post‐RT. Additional unscheduled MRI scans may be used in the case of suspected progression.; 10. Overall survival (OS), defined as the time from randomisation to the date of death from any cause collected at standard follow‐up visits; INCLUSION CRITERIA: 1. Histologically proven diagnosis of oligodendroglioma (ODG) with 1p19q co‐deletion and isocitrate dehydrogenase (IDH) mutation 2. Randomisation must be performed within 28 days of the magnetic resonance imaging (MRI) that leads to the decision that radiotherapy (RT) is required at that point in time. Outside of 28 days, an updated MRI is required to serve as a contemporaneous baseline scan to assess response to further treatment. 3. Karnofsky Performance Status (KPS) =70%. 4. Adequate wound healing and recovery if recent surgery. 5. Suitable to complete baseline neurocognitive testing (No access to translated tests, can only be administered in English). 6. Patients of childbearing potential should be asked to confirm that they are not pregnant to confirm trial eligibility. Formal Pregnancy testing should be performed if there is any doubt as to pregnancy status or if felt appropriate, including in circumstances such as ir