Seizure prophylaxis in glioma surgery: a synopsis from the SPRING RCT.

Background: In patients with a glioma, 50-80% will have seizures during their lifetime and half of these will be drug resistant. Seizure risk is increased perioperatively (around the time of surgery) at tumour progression and shortly before death. In seizure-naive patients with glioma undergoing surgery, existing guidelines do not recommend routine use of prophylactic antiseizure medication. Despite this, an antiseizure medication, levetiracetam, is frequently prescribed perioperatively in many neurosurgical units. Objectives: To determine whether in seizure-naive, newly diagnosed cerebral glioma patients undergoing surgery, prophylactic levetiracetam, pre-operatively and for at least 1 year post operatively, produces a meaningful (> 50%) reduction in the risk of developing seizures when compared with standard care (no prophylaxis) and is cost-effective. Design and methods: We undertook a two-arm, multicentre phase III randomised trial in 14 neurosurgery units across England and Scotland, with an embedded health economic evaluation, comparing 12 months of prophylactic antiseizure medication (levetiracetam) versus no antiseizure medication (comparator) in patients with suspected cerebral glioma undergoing surgery. The target samples size was 804 participants. Outcome measures: The primary outcome was the occurrence of a seizure within 12 months of randomisation. The secondary outcomes were time to first seizure, time to first tonic-clonic seizure, time to death (overall survival) and time to tumour recurrence (progression-free survival). The impact of prophylactic levetiracetam on mood, personality, fatigue and memory, severity of first seizure if it occurred and quality of life were assessed. The planned health economic outcomes were costs to the National Health Service and Personal Social Services and incremental cost per quality-adjusted life-year at 12 months and modelled over estimated survival. Analyses were carried out using the intention-to-treat principle. Results: Between 9 October 2019 and 30 August 2022, 94 patients were recruited, from 24 to 79 years of age and randomised to prophylactic levetiracetam ( Limitations: The trial was underpowered and closed early due to slow recruitment impacted by the COVID-19 pandemic. Approximately one quarter of patients died within 12 months and did not reach the primary outcome of 1-year risk of seizure. Conclusions: Given the trial was underpowered, there was no evidence of a difference in the 12-month seizure risk between the randomised groups and limited evidence regarding potential cost-effectiveness. The role of prophylactic antiseizure medication in glioma surgery remains undefined. Future work: SPRING provides the highest quality data available for a future, individual patient data meta-analysis. A definite trial is still needed to answer this clinical question. Funding: This synopsis presents independent research funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme as award number 16/31/136.