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

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.

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.

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.

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.

Between 9 October 2019 and 30 August 2022, 94 patients were recruited, from 24 to 79 years of age and randomised to prophylactic levetiracetam (n = 49) or no prophylaxis (n = 45). Due to slow accrual, the trial closed early. Thirteen patients in the prophylactic levetiracetam arm and 9 in the no prophylaxis group died within 1 year of randomisation and did not have a seizure. Of the patients who survived for at least 1 year, 17 (47%) of 36 prophylactic levetiracetam patients had a seizure when compared with 15 (41%) of 36 no prophylaxis patients (odds ratio 1.25, 95% confidence interval 0.49 to 3.21, p = 0.64). Median time to first seizure was 5.0 months in the prophylactic levetiracetam group and 2.5 months in the no prophylaxis group. In the prophylactic levetiracetam group, 20 (41%) of 49 patients died within 12 months (median overall survival 6.8 months; range 0.2-11.9), and in the no prophylaxis group, 14 (31%) of 45 patients died within 12 months (median 4.6 months; range 0.1-12.0). At the 3-month and 6-month data collection points, the mean healthcare costs were lower in the prophylactic levetiracetam group (£1175 and £1278) compared with the no prophylaxis group (£2703 and £2767). At the 9-and 12-month data collection points, the mean healthcare costs were higher in the prophylactic levetiracetam group (£1916 and £1238) as compared with the no prophylaxis group (£1597 and £686). Health-related quality of life as measured by the EuroQol-5 Dimensions, five-level version was similar in the two intervention arms across all time points.

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.

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.

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.

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.