In the evolving landscape of neuro-oncology, managing seizures in patients with primary brain tumors remains a critical clinical challenge. Seizures significantly affect both the quality of life and healthcare resources for these patients. Among antiseizure medications (ASMs), levetiracetam has emerged as the most frequently prescribed agent due to its favorable side effect profile and efficacy. Nevertheless, there exists considerable uncertainty regarding the optimal duration of its administration post-surgery. Traditionally, levetiracetam is prescribed for a standard course of two to three years following tumor resection to mitigate seizure recurrence. Yet, this practice is not grounded in robust scientific evidence, especially considering the relatively low incidence of seizures after successful antitumoral treatments.
Addressing this crucial knowledge gap, a groundbreaking phase 3 randomized controlled trial, termed the LIBRA study, has been designed to rigorously compare the safety and efficacy of short-term versus long-term levetiracetam administration in patients with primary brain tumors. This investigator-initiated trial aims to establish whether a shorter regimen of levetiracetam can achieve non-inferior seizure control compared to the conventional extended treatment protocol, potentially revolutionizing post-surgical care paradigms in neuro-oncology.
The trial focuses on adult patients diagnosed with newly identified primary brain tumors located in the supratentorial compartment, explicitly excluding those with brain metastases. Eligible participants are those who have experienced seizures prior to surgery and have been stabilized on levetiracetam monotherapy for six months postoperatively. Within one year of surgery, these patients are randomized equally into two cohorts: one continuing with the long-term levetiracetam treatment for an additional two years, and the experimental group undergoing a tapered discontinuation of the drug. This meticulous stratification ensures a comprehensive assessment across tumor location, seizure classification, histopathological variables, tumor grade, and adjuvant therapeutic regimens.
The primary endpoint of the LIBRA trial is the rate of seizure-free survival (SFS) over a two-year period, a clinically relevant marker that directly correlates with patient well-being and neurocognitive preservation. Secondary endpoints encompass a spectrum of important outcomes such as seizure burden impact, health-related quality of life metrics, progression-free survival (PFS), and overall survival (OS), reflecting the multidimensional scope of therapeutic benefit and risk.
Statistical calculations underpinning the trial design anticipate an 80% two-year SFS in the control group, estimating that enrollment of 431 patients will provide sufficient power—80% with a significance threshold of 0.05—to assert non-inferiority of the shorter levetiracetam regimen within an 8% margin. Factoring in a substantial attrition rate approximating 40%, attributable to mortality and loss to follow-up, the final sample size is projected at 604 participants, underscoring the methodological rigor and the scale necessary to generate definitive conclusions.
From a mechanistic perspective, levetiracetam is known to modulate synaptic neurotransmitter release via binding to synaptic vesicle protein 2A (SV2A), which contributes to its anticonvulsant properties. However, prolonged exposure to ASMs can introduce risks such as neurotoxicity, cognitive impairment, and metabolic side effects, which may weigh heavily on patients already burdened with neurological deficits and systemic cancer therapies. Therefore, delineating an evidence-based optimal treatment duration is imperative to balance seizure prophylaxis against potential iatrogenic harm.
Beyond individual patient benefits, the implications of the LIBRA trial extend into healthcare system resource optimization. Shortening ASM duration, contingent on non-inferiority, could substantially reduce drug utilization costs, decrease monitoring requirements, and free up clinical resources otherwise allocated to side effect management and medication adherence counseling. This aspect aligns with broader goals of sustainable oncology care delivery and patient-centered medicine.
The significance of the LIBRA trial also lies in its potential to establish level 1 evidence—a gold standard in clinical research. Should the shorter regimen prove comparably efficacious, it could prompt revisions in clinical guidelines globally, standardizing treatment while personalizing care based on robust data rather than empirical tradition. This shift promises to alleviate the long-term treatment burden on patients and caregivers alike.
Ethical oversight for the LIBRA trial has been secured through the Institutional Ethics Committee of Tata Memorial Centre in Mumbai, ensuring that the study adheres to stringent ethical standards safeguarding patient welfare. The study has been duly registered on primary clinical trial registries, namely CTRI and ClinicalTrials.gov, fostering transparency and enabling global collaboration within the scientific community.
As the neuro-oncology field awaits the outcomes of the LIBRA trial, the study epitomizes the growing trend of challenging entrenched medical dogmas through methodologically sound investigations that prioritize patient quality of life alongside survival metrics. By focussing rigorously on ASMs within the intricate milieu of brain tumor management, this research paves the way for safer, more effective, and economically viable strategies.
In the future, the results of this trial may also stimulate further investigations into personalized seizure management strategies, leveraging biomarkers, advanced imaging, and genomic profiling to tailor ASM duration and selection. The LIBRA trial thus not only addresses a pressing clinical question but also catalyzes a paradigm shift toward precision neuro-oncology.
Given the substantial burden of seizures on neurological function, mood, cognition, and social interactions, the ability to safely reduce ASM duration without compromising seizure control will represent a landmark advance. Patients often endure side effects such as fatigue, irritability, and dizziness due to ASMs, compounding cancer-related morbidity. Therefore, validating a shorter course of levetiracetam could dramatically improve patient-reported outcomes.
The careful inclusion criteria excluding brain metastases and focusing on supratentorial tumors underscore the heterogeneity within brain tumor-associated epilepsy and reinforce the need for nuanced treatment stratification. This approach will enhance the external validity of the findings and enable targeted application in clinical practice.
Moreover, the extensive follow-up encompassing seizure recurrence, tumor progression, and survival integrates neurological and oncological endpoints, reflecting the complexity of care in this patient population. This comprehensive evaluation ensures that ASM duration decisions do not inadvertently jeopardize oncological outcomes.
As the medical community eagerly anticipates the LIBRA trial findings, the study stands as a compelling example of how clinical equipoise and robust trial design can drive transformative change in neuro-oncology care paradigms, emphasizing evidence-based optimization over convention.
Subject of Research: Optimal duration of levetiracetam therapy for seizure management in patients with primary brain tumors.
Article Title: Study protocol of short versus long-term levetiracetam in brain tumors (LIBRA): a phase 3 randomized controlled trial.
Article References: Dasgupta, A., Mani, S., Chatterjee, A. et al. Study protocol of short versus long-term levetiracetam in brain tumors (LIBRA): a phase 3 randomized controlled trial. BMC Cancer 25, 911 (2025). https://doi.org/10.1186/s12885-025-14305-7
Image Credits: Scienmag.com
DOI: https://doi.org/10.1186/s12885-025-14305-7
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