The survival benefits of re-irradiation and chemotherapy for patients with relapsed glioblastoma

INTERVENTION: BRIOChe is a randomised phase II, multi‐centre open‐label study. The objectives of the trial are to assess 9‐month overall survival rates in patients receiving re‐irradiation or chemotherapy for recurrent GBM in conjunction with patients’ health‐related quality of life perception before, during (if randomised to chemotherapy) and after treatment. A total of 70 patients will be recruited from approximately 16 UK sites. Patients who are eligible for the trial will be consented for trial participation and will be randomised (1:1) to enter either the chemotherapy arm or the re‐irradiation arm. Sample size Thirty‐three patients are required in the re‐irradiation arm, 35 allowing for 5% drop out. For 1:1 randomisation against chemotherapy, 70 patients are required in total. This study is powered to demonstrate that the treatment strategy of re‐irradiation demonstrates sufficient efficacy to warrant further large scale evaluation, including in combination with novel agents, based on 9 month OS with 80% power and 5% significance (one‐sided) Trial design details A Sargent’s three‐outcome, phase II, single‐stage, single‐arm design will be used to determine whether re‐irradiation demonstrates sufficient efficacy to warrant further larger‐scale evaluation. The trial is designed to test the null hypothesis H0 that the proportion of participants alive at 9 months is <25% where re‐irradiation would not be deemed worthy of further investigation against an alternative hypothesis H1 of >45% where re‐irradiation would be deemed worthy of further investigation. If the proportion of participants alive at 9 months is =25% and =45%, this would be an inconclusive region where neither the null or CONDITION: Brain cancer, recurrent glioblastoma ; Cancer ; Malignant neoplasm of brain PRIMARY OUTCOME: Overall survival rates, (i.e. the number and proportion of patients alive) in the re‐irradiation arm at 9 months post‐start of treatment. Overall survival is defined from randomisation to the date of death from any cause and survival data will be collected at all standard follow‐up visits. Overall survival rates in the chemotherapy arm will also be assessed for calibration purposes only and not for direct statistical comparison. SECONDARY OUTCOME: ; 1. Health‐related quality of life (HRQoL) measured using the European Organization for Research and Treatment of Cancer (EORTC) quality of life questionnaires core 30 (QLQ‐C30) and brain cancer module (BN20) completed independently by patients at clinic visits at baseline and at 6‐weekly intervals post‐start of treatment, up to 48 weeks post‐start of treatment.; 2. HRQoL evaluated through one‐off semi‐structured qualitative interviews in a patient/carer subset (n 15 or until data saturation). This will include HRQoL before/during treatment, experience of treatment and what matters most to patients/carers.; 3. Dexamethasone use defined as the dose and frequency of dexamethasone received. Data on dexamethasone use, including dose, any change in dose including the date of change, will be collected at baseline and then on a 6‐weekly basis post‐start of treatment.; 4. Anti‐epileptic drug use defined as the type, dose and frequency of anti‐epileptics received. Data on anti‐epileptic drug use including the name of anti‐epileptic drug(s), dose, any change in dose including the date of change will be collected at baseline and then on a 6‐weekly basis post‐start of treatment.; 5. Radiological response to treatment assessed via MR imaging in accordance with RANO criteria at 12 weeks post‐start of treatment and then at 12‐weekly intervals up to 48 weeks post‐start of treatment or until disease progression; 6. Acute and late toxicities assessed at 6‐weekly intervals post‐start of treatment up to 48 weeks or until progression, whichever is sooner. They will be evaluated according to the current NCI‐CTCAE criteria and include all Adverse Events (AEs). Acute toxicities will be defined as those occurring up to 12 weeks post‐end of treatment. Late toxicities will be defined as those occurring after 12 weeks post‐end of treatment. The period of collection of acute toxicity data will differ between arms due to different treatment lengths, but the overall period of data collection for toxicities will be the same for both treatment arms.; 7. Progression‐free survival (PFS) defined as the time from randomisation to the first documented evidence of disease progression or death (from any cause). PFS includes radiological progression assessed with RANO criteria and non‐RANO evaluable progression where RANO assessment is not possible, (e.g. clinical progression in a patient who is too unwell for further imaging).; INCLUSION CRITERIA: 1. Histologically proven diagnosis of GBM with consistent molecular pathology, based on original pathology (repeat biopsy at recurrence is NOT required). 2. First recurrence of GBM, with contrast‐enhancing disease, following primary treatment (or following surgery alone for first recurrence of GBM; i.e. no previous systemic therapy or re‐irradiation for recurrence permitted). 3. The MRI scan that reveals recurrence must be reviewed by the local multi‐disciplinary meeting, including agreement of a Consultant Neuro‐Radiologist that imaging changes are in keeping with recurrence and not pseudoprogression. 4. Randomisation must be performed within 21 days of the MRI that confirms recurrence. Outside of 21 days, an updated MRI is required to confirm eligibility and serve as a contemporaneous baseline scan to assess response to further treatment. Please see s