Title: Radiation versus Observation following surgical resection of Atypical Meningioma: a randomised controlled trial (The ROAM trial).
Funder: Department of Health and Social Care

Abstract: Design: two-arm, multi-centre, randomised controlled trial. This will be a pragmatic trial randomising patients who have undergone gross total resection (GTR) of atypical meningioma to early radiotherapy or active monitoring Main trial: randomisation to early radiotherapy or active monitoring in a ratio of 1:1 Embedded qualitative study: will identify and implement bespoke strategies to enhance recruitment ensuring successful trial delivery After randomisation, patients in both arms will undergo a baseline MRI 4-6 weeks after surgery. Neurocognitive function (NCF) will be tested 6-8 weeks and 2 years after surgery. Adjuvant radiotherapy will commence 8-12 weeks after surgery. Setting: 10 neurosurgery and oncology units in UK & Ireland Target population: patients who have undergone gross total resection of atypical meningioma Inclusion criteria: • Histology confirmed newly diagnosed solitary atypical meningioma (2007 WHO criteria) • Age >/= 16 years • All locations except optic nerve sheath • Complete (Simpson grade I-III) resection assessed by surgeon • WHO performance status 0-2 • Exclusion criteria: • Neurofibromatosis type II • Optic nerve sheath tumour • Multiple meningiomas • Previous radiation to the brain or meninges interfering with the protocol treatment plan • Second malignancies (except history of cervix carcinoma in-situ or skin basal cell carcinoma) • Pregnant or lactating women Health technologies being assessed: a) Surgical resection + active monitoring with MRI and clinic follow-up (comparator) b) Surgical resection + early adjuvant fractionated radiotherapy (intervention) Measurement of costs and outcomes: There are no established Core Outcomes for brain tumour patients (COMET website searched). • Primary outcome: -Time to MRI evidence of local tumour recurrence (disease free survival) • Secondary outcomes: - Time to second line treatment (surgery, radiotherapy, radiosurgery) - Time to death (overall survival) - Toxicity assessed by CTCAE (Common Terminology Criteria for Adverse Events) - Quality of life - Neurocognitive function - Health economic analysis (incremental cost per QALY gained) Health economic analysis: There are no existing economic studies of treatment options in atypical meningioma and to assess the balance of the potential benefits of reduced recurrence rates against the costs, we will conduct a cost utility analysis, from the perspective of the NHS. Resource use will be based on entries made in designated sections of patients' case report forms; complemented with Hospital Episode Statistics data sourced from the NHS Information Centre for patients recruited in England, and data from hospital Patient Administration Systems. Unit costs will be obtained from NHS reference costs and other relevant NHS resources. The number of QALY gained will be estimated by administering the EQ-5D-5L and applying a UK tariff for generating utilities. An economic (Markov) model will be specified with appropriate health states to project lifetime costs and consequences. Costs and QALYs occurring after the first year will be discounted at 3.5% per annum. Incremental cost-effectiveness ratios will be compared with threshold values, and the joint uncertainty in costs and benefits considered (in the trial-based analysis) through the application of bootstrapping and (in the model) using probabilistic sensitivity analysis to generate cost effectiveness acceptability curves. Sample size: 5-year tumour recurrence rates are reported as between 39 and 58%. A 0.05 level two-sided log-rank test for equality of survival curves with 80% power would require 86 patients in each arm (total number of events required = 46) to detect an absolute reduction from 40% in the control group arm to 20%. This sample size calculation, provided in the outline application, has been agreed with the EORTC and the UK arm of the trial for which we are requesting funding would aim to deliver 108 participants with a total of 29 events providing 60% power. The remaining participants would be recruited across Europe within the EORTC funded collaboration. A strong magnitude of effect is required to impact clinical practice and establish a treatment policy across the NHS. This is due in part to the expense of radiotherapy, but also the burden to patients – due to the side effects of radiotherapy (hair loss, skin irritation, cognitive decline, secondary malignancy) and its delivery requiring patients to attend hospital daily (Monday-Friday) for 6 weeks. Patient retention will be high as patients with atypical meningioma are routinely followed up long term and data will be collected at routine clinic visits however an adjustment to allow for a 10% loss to follow up has been made requiring a total number of 190 patients need to be recruited with 118 being recruited in the UK. Project timetables and recruitment rate: Using host institution and The Royal Hallamshire Hospital audit data, it is estimated that ~150 patients per year undergo tumour resection in the UK. In the literature, GTR rates are reported as 58-68%. Based on host institution audit data, the GTR rate was reported as 85%. Using a mean GTR of 70%, it is anticipated that 105 patients a year will be eligible for the trial. Applying a conservative estimate of consent of 50%, this would provide 52 patients per year across the UK. Allowing a 44-month recruitment period, each of the 10 sites would need to recruit approximately 5 cases per year, which is achievable based on the numbers reported in the feasibility questionnaire. We anticipate an initial 9-month start-up period, recruitment over 44 months, 5-year follow-up period and a further 6 months for data cleaning, analysis and report writing (total 119 months). Translational research: The trial will enable the creation of a biobank for atypical meningioma. The applicants have an established brain tumour biobank (Walton Research Tissue Bank). Ethical approval will be sought for tumour tissue and serum banking from patients in participating sites. Separate funding will be sought for research studies: 1. MRI: Volumetric measurements will be used to determine tumour recurrence. The effects of radiotherapy on normal brain adjacent to the resection cavity will be studied 2. Tumour biology: to investigate whether genetic, epigenetic or biochemical factors explain individual variation in tumour recurrence and response to radiotherapy

Lay abstract: Context: Meningiomas are brain tumours arising from the linings of the brain. Most of these tumours are benign (meaning non-cancerous) and can be treated with surgery alone. Very rarely these tumours are malignant (cancerous) and need treatment with both surgery and radiotherapy. There is a third group, called atypical meningiomas that fall between the benign and malignant group. About 150 patients with atypical meningiomas have surgery every year in the UK. These tumours are more likely to re- grow and we don’t know the best way to treat them. We don’t know whether surgery alone is enough, or whether surgery and radiotherapy is needed. We know that radiotherapy affects patients and can cause hair loss, skin irritation, mental decline and risk of other tumours. We also know that when tumours re-grow further surgery, radiotherapy or radiosurgery (focused radiotherapy) may be needed. What the trial does: We want to approach patients who have had surgery to remove an atypical meningioma to see what the best follow up treatment should be so that the risk of the tumour re-growing are reduced. Our aims are to: 1. Determine whether early radiotherapy reduces tumour recurrence 2. Determine the overall cost and health benefits of early radiotherapy 3. Explore patient and doctor views on the treatment options 4. Identify barriers to trial recruitment and to also optimise recruitment Suitable patients will: 1. Have been reviewed by a specialist multi disciplinary team 2. Be 16 years of age or older 3. Meet the inclusion / exclusion criteria. More information: Main trial: Patients will be randomised. This means that they will be split into two groups and assigned at random to one or the other group: • Group 1 – early radiotherapy • Group 2 – active monitoring (without radiotherapy) Embedded qualitative study: this will test how feasible and acceptable the trial is, and will aim to expand recruitment into the trial by understanding the discussions the doctor and patient have about participating in this trial. These discussions will be recorded (audio only) and there will also be follow up interviews with some patients and doctors. This information will be analysed to give us the data that we need. This information will be used to refine the recruitment process, including doctor training in recruitment. All patients will be monitored closely, with MRI scans 4-6 weeks after surgery and then will follow current practice, with scans 6 and 12 months after surgery, then yearly. Their neurocognitive function will also be assessed 6-8 weeks and 2 years after surgery. Quality of life questionnaires will done at every follow up visit. Those patients in group 1 will also need to attend the hospital daily for 6 weeks for their radiotherapy. Outcomes: The outcomes from this trial will include: • Measurement of how long the tumour stays controlled • Measurement of the overall survival of patients • How long before further treatment is needed • Measurement of the patient’s quality of life. This team is well placed to carry out this research and has experience and expertise in brain tumours, clinical trials and health economics.

Research activity codes: 6.5 RADIOTHERAPY AND OTHER NON-INVASIVE THERAPIES;7.3 MANAGEMENT AND DECISION MAKING
Health categories: CANCER AND NEOPLASMS