Brain Re-Irradiation Or Chemotherapy: a Phase II randomised trial of re-irradiation and chemotherapy in patients with recurrent glioblastoma
Brain cancer, recurrent glioblastoma
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 alternative hypothesis would be rejected and the decision regarding further investigation would be based on other factors. Based on the 3 outcome design, the cut-off values and conclusions for the statistical test are defined as follows. Green: If ≥13/33 patients were alive re-irradiation would d
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 section 4.1 Inclusion Criteria for further details for achieving this. 5. ≥6 months since completion of primary radiotherapy (where the interval since radiotherapy completion is 5 months and 2 weeks or greater, this may be rounded up to 6 months and the patient included in the trial). 6. Prior history of standard dose, conventionally fractionated CNS radiotherapy (i.e. 54-60Gy in 28-33 fractions). 7. As a minimum patients will have completed at least two weeks of temozolomide, concurrent with their original radiotherapy. 8. Up to and including three enhancing lesions: 8.1. In cases of a single recurrent enhancing lesion: 8.1.1. Predicted re-irradiation GTV<75cm3 (based on diagnostic MR imaging and on maximum diameters of enhancing disease in all 3 planes, calculated from 4/3π x ½ x diameter 8.1.1. 1 x ½ x diameter 2 x ½ x diameter 3: see Appendix D – Calculation of volume and explanation for volume limitations for study eligibility for explanation) and 8.1.2. Maximum diameter of enhancing disease must be ≤6 cm. In cases where there is circumferential enhancement around a cavity, such that the cavity and enhancing disea
1. Pregnant (positive pregnancy test) or lactating 2. Critical normal brain structures treated above usual tolerance during initial radiotherapy (i.e. based on 30 fractions initial treatment, >55 Gy delivered to 1% or 0.1 cm³ of optic nerve or chiasm or >55 Gy delivered to >1 cm³ of brainstem or >57 Gy delivered to >0.1 cm³ of brainstem or >50 Gy to 1% or 0.1 cm³ of globes) 3. Recurrence with leptomeningeal disease or only leptomeningeal disease 4. Recurrence defined by non-enhancing disease only 5. More than three enhancing lesions present on MRI or multi-focal recurrence 6. IDH1/2 mutant tumours on original pathology (to avoid unbalance between arms) 7. GBM with known features of PXA, BRAF mutations or 1p19q co-deletion (on original pathology or updated pathology if available) 8. Prior invasive malignancy (except non-melanomatous skin cancer), unless disease-free for a minimum of 1 year 9. Severe active co-morbidity making patient unsuitable for chemotherapy or re-irradiation (e.g. uncontrolled diabetes, uncontrolled hypertension) 10. Prior allergic reaction to nitrosoureas 11. Coeliac disease 12. Any recognised genetic syndrome causing sensitivity to radiotherapy 13. Patient unwilling/unable to attend for follow up in the radiotherapy centre 14. Contraindication to MRI or gadolinium 15. Previous radiotherapy dose distribution unavailable 16. Previous systemic therapy or re-irradiation for recurrent GBM