Association between Levetiracetam Use and Survival in Patients with Glioblastoma: A Nationwide Population-Based Study

Yeonhu Lee; Eunyoung Lee; Tae Hoon Roh; Se-Hyuk Kim

doi:10.4143/crt.2024.355

Articles

Page Path: HOME > Cancer Res Treat > Volume 57(2); 2025 > Article

Original Article CNS cancer Association between Levetiracetam Use and Survival in Patients with Glioblastoma: A Nationwide Population-Based Study: Yeonhu Lee¹, Eunyoung Lee², Tae Hoon Roh^1,, Se-Hyuk Kim¹; Cancer Research and Treatment : Official Journal of Korean Cancer Association 2025;57(2):369-377.
DOI: https://doi.org/10.4143/crt.2024.355
Published online: September 6, 2024

¹Department of Neurosurgery, Ajou University School of Medicine, Suwon, Korea

²Department of Neurology, McGovern Medical School at UTHealth, Houston, TX, USA

Correspondence: Tae Hoon Roh, Department of Neurosurgery, Ajou University School of Medicine, 164 Worldcup-ro, Yeongtong-gu, Suwon 16499, Korea
Tel: 82-31-219-5230 E-mail: throh@ajou.ac.kr

• Received: April 9, 2024 • Accepted: September 5, 2024

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

1,210 Views
99 Download

prev next

Full Article

Download PDF

Abstract

Purpose
This study aimed to investigate whether levetiracetam (LEV), the most used antiepileptic drug, influences survival in patients with glioblastoma (GBM), using a national database.
Materials and Methods
This study used data from the Korea Health Insurance Review and Assessment database. Patients diagnosed with GBM between 2007-2018 treated with standard therapy were included. The study population was divided into long-term (≥ 60 days) and short-term (< 30 days) LEV groups. A separate long-term valproic acid (VPA) group (≥ 60 days) was identified for comparison. Demographics, disease characteristics, and treatment parameters were collected. Kaplan-Meier method and Cox regression were used to compare survival outcomes between the groups.
Results
Overall, 2,971 patients were included, with 1,319 and 1,652 in the short-term and long-term LEV groups, respectively. The median overall survival (OS) for the entire population was 19.15 months post-surgery. Kaplan-Meier analysis revealed a significantly longer median OS in the long-term LEV group versus the short-term LEV group. After adjusting for confounders, Cox proportional hazard analysis revealed an association of long-term LEV use with improved survival, which was also observed in a subgroup analysis of patients without preoperative seizure history. The long-term LEV group demonstrated longer median OS, compared with the long-term VPA group.
Conclusion
Our nationwide population-based study found an association between long-term LEV use and improved survival in patients with GBM, regardless of preoperative seizure history. Prospective studies are needed to validate these findings and investigate the potential impact of LEV on the survival outcomes of patients with GBM.
Key words: Glioblastoma, Levetiracetam, Survival

Introduction

Glioblastoma (GBM) is the most common malignant primary brain tumor in adults, with a poor survival rate. Maximal safe resection followed by standard combined chemoradiation with temozolomide (TMZ) has been recommended as the first-line treatment. However, the overall survival (OS) rate is less than 2 years, leading to the investigation of novel or adjunctive agents [1-3].

Seizures are known to occur in 30%-60% of patients with GBM, prompting hospital visits where antiepileptic drugs (AEDs) are commonly prescribed. Over the last decade, levetiracetam (LEV) has emerged as the preferred AED for patients with GBM due to its favorable safety profile and effectiveness. There is increasing evidence supporting the role of LEV in GBM development and progression [4-17]. Studies have indicated that LEV may boost the effectiveness of TMZ, enhancing its therapeutic action against GBM. Given these insights, the examination of LEV’s impact on the survival outcomes of patients with GBM is of paramount importance.

The Health Insurance Review and Assessment Service (HIRA) database is a nationally acknowledged resource that contains the medical data of approximately all South Koreans. It collects data from healthcare professionals and insurance claims and ensures reliability through unique patient IDs, enabling vast and long-term data tracking. The database uses a distinct coding system that enables the precise identification of medical treatments and ensures accurate comparisons and analysis. We conducted a large-scale nationwide population-based analysis using the HIRA database of South Korea. Our study included patients with GBM in the HIRA database to determine how the duration of LEV use affects the survival outcomes of patients with GBM.

Materials and Methods

1. Data collection

We analyzed data from the Korean HIRA database to evaluate the effect of LEV on the clinical outcomes of patients with GBM. The data of individuals diagnosed with the International Classification of Diseases (ICD)-10 code C71.x who underwent cranial surgery and tumor removal (codes: S4634, S4635, S4636, and S4637) were obtained. These patients received TMZ chemotherapy and radiation therapy within 6 weeks post-surgery, between January 2007 and November 2021. We excluded patients diagnosed under the age of 18 years, those with more than a 90-day gap between their initial diagnosis and surgical procedure, those who died within 90 days of surgery, and those diagnosed with an additional malignancy. The study included patients diagnosed between 2007 and 2018, with follow-up data collected until November 2021. Patients diagnosed after 2018 were excluded to ensure a sufficient follow-up period for reliable survival analysis, considering that the median survival time after GBM diagnosis is typically between 12 and 24 months. Patients were subsequently divided into two categories based on the total duration of their LEV prescription: the short-term LEV group (LEV use < 30 days) and the long-term LEV group (LEV use ≥ 60 days). Patients prescribed LEV for 30-60 days were excluded from the final study population to clarify the impact of duration of LEV.

2. Assessed variables

We evaluated a comprehensive set of variables, including the duration of follow-up, sex, year of initial diagnosis, age at diagnosis, the interval between surgery and initiation of concurrent chemoradiation (CCRT), and time from diagnosis to surgery. Additionally, we evaluated the LEV administration before surgery, use of any AED before or after surgery, and presence of a seizure history before surgery, as indicated by ICD-10 codes G40 and R56. Other variables, such as the total number of days of AED prescription during the post-surgical follow-up, duration of hospitalization within the first 90 days post-surgery, initial dosage of LEV post-surgery, and number of adjuvant TMZ cycles received, were also considered.

3. Endpoints

The primary objective of our study was to assess the difference in OS between the long- and short-term LEV groups. Additionally, we explored whether LEV is associated with different survival outcomes, compared with other AEDs. We selected valproic acid (VPA) as a representative comparator among other AEDs.

4. Statistical analysis

Descriptive methods were utilized to provide an overview of patient characteristics and treatment approaches. Continuous variables were represented as means with standard deviations and categorized as counts and percentages. Differences between groups were determined using the independent t-test or Mann-Whitney U test for continuous variables, based on data distribution. We employed the chi-squared test or Fisher’s exact test, as appropriate, to analyze categorical data. We plotted Kaplan-Meier survival curves using the log-rank test to distinguish the OS rates between the groups. Both univariable and multivariable Cox proportional hazard models estimated hazard ratios with 95% confidence intervals (CIs) and considered potential confounders. All tests were performed in a two-sided manner, and statistical significance was set at p < 0.05.

Results

1. Population characteristics

We conducted a comprehensive nationwide population-based analysis of data from the HIRA database. First, 8,176 patients diagnosed with GBM (ICD-10 code: C71.x) between January 2007 and November 2021 were included. Among those patients, 5,311 underwent surgery and received CCRT within 6 weeks after surgery, conforming to the standard treatment protocols. After applying the exclusion criteria, 3,286 patients remained. Finally, 2,971 patients were included, after excluding those who received LEV for 30-60 days. Among this cohort, 1,319 were in the short-term LEV group (< 30 days), and 1,652 were in the long-term LEV group (≥ 60 days) (Fig. 1).

Table 1 presents the patient characteristics. The median follow-up time was 1.54 years (range, 0.98 to 2.93 years) for all patients. Men constituted 56.65% of the total population, with no significant difference in their proportion between the short-term (57.8%) and long-term (55.8%) LEV groups (p=0.270). The short-term LEV group had more patients diagnosed between 2007 and 2010 (47.1%), whereas the long-term LEV group had more patients diagnosed between 2015 and 2018 (59.2%, p < 0.001). The mean age was 56.25±12.70 years, with no significant difference between groups (p=0.530). The median time from surgery to CCRT was 25 days (interquartile range [IQR], 0 to 31) in both groups (p=0.598), whereas the median time from diagnosis to surgery was 2 days (IQR, 0 to 7) and 3 days (IQR, 0 to 10) in the short- and long-term LEV groups, respectively (p < 0.001).

LEV was administered before surgery in 8.49% of the short-term LEV group and 29.0% of the long-term LEV group (p < 0.001). A history of seizures before surgery was present in 21.5% and 32.3% of the patients in the short- and long-term LEV groups, respectively (p < 0.001). The median number of AED prescription days for follow-up after surgery differed significantly between groups for LEV, VPA, and other AEDs (all p < 0.001). The median length of hospital stay was similar between the groups. The first LEV dose after surgery varied significantly between the groups (p < 0.001). The mean number of adjuvant TMZ cycles was 4.77±1.69, with a slightly higher number in the long-term LEV group than in the short-term LEV group (p=0.010).

2. Survival analysis

Kaplan-Meier estimates showed a longer median survival in the long-term LEV group (19.06 months; 95% CI, 18.27 to 20.14) than in the short-term LEV group (17.64 months; 95% CI, 16.69 to 18.79; log-rank p=0.0046) (Table 2, Fig. 2A).

In the Cox proportional hazard models, univariable analysis indicated no significant difference in mortality risk between the long- and short-term LEV groups (unadjusted hazard ratio [HR], 0.81; 95% CI, 0.75 to 0.87; p < 0.001). After multivariable adjustment, the long-term LEV group was associated with a lower mortality risk, compared with the short-term LEV group (adjusted HR, 0.89; 95% CI, 0.82 to 0.96; p=0.002).

Other factors associated with mortality risk in the multivariable analysis were age and sex. A history of seizures before surgery was not significantly associated with mortality risk in the multivariable model. Length of stay and the time from diagnosis to surgery were not significantly associated with survival outcomes.

3. Subgroup analysis of patients without seizure history before surgery

Table 3 presents a subgroup analysis of OS in patients without a history of seizures before surgery. The short-term LEV group had a median survival of 17.61 months (95% CI, 16.59 to 18.79), whereas the long-term LEV group had a median survival of 19.71 months (95% CI, 18.46 to 21.03); the difference in survival between the two groups was significant (log-rank test, p=0.009) (Fig. 2B).

Cox proportional hazards analysis showed that a longer LEV prescription (≥ 60 days) was associated with a 13% reduction in the risk of mortality (adjusted HR, 0.87; 95% CI, 0.80 to 0.96; p=0.003). Higher age (adjusted HR, 1.02; 95% CI, 1.017 to 1.024; p < 0.001) and male sex (adjusted HR, 1.35; 95% CI, 1.23 to 1.48; p < 0.001) were associated with an increased risk of mortality. The longer length of hospital stay was also associated with a slightly increased risk of mortality (adjusted HR, 1.006; 95% CI, 1.004 to 1.007; p < 0.001). The time from diagnosis to surgery did not significantly influence the survival outcomes (adjusted HR, 0.999; 95% CI, 0.994 to 1.004; p=0.738).

4. Comparative influence of LEV and VPA on OS outcomes

Among the patients in the VPA group, the median survival was 16.53 months (95% CI, 15.31 to 18.53); patients in the long-term LEV group had a longer median survival of 19.06 months (95% CI, 18.27 to 20.14). The difference in survival between the two groups was significant (log-rank test, p=0.002) (Fig. 2C). In the Cox proportional hazard analyses, the univariable analysis indicated that the long-term LEV group had a reduced risk of mortality, compared with the VPA group (unadjusted HR, 0.83; 95% CI, 0.74 to 0.94; p=0.002). After multivariable adjustment, the long-term LEV group maintained a lower risk of mortality, compared with the VPA group (adjusted HR, 0.84; 95% CI, 0.74 to 0.95; p=0.004).

Other factors associated with increased mortality risk in the multivariable analysis included higher age (adjusted HR, 1.02; 95% CI, 1.017 to 1.025; p < 0.001) and male sex (adjusted HR, 1.26; 95% CI, 1.14 to 1.38; p < 0.001). The longer length of hospital stay was also associated with a slightly increased risk of mortality (adjusted HR, 1.005; 95% CI, 1.004 to 1.007; p < 0.001). A history of seizures before surgery and the time from diagnosis to surgery were not significantly associated with the survival outcomes in the multivariable analysis (Table 4).

Discussion

Our nationwide population-based study revealed that prolonged LEV administration (≥ 60 days) was associated with longer survival in patients with GBM receiving standard treatment. The long-term LEV group had a significantly longer median survival, compared with the short-term LEV group (19.06 vs. 17.64 months). Cox analysis showed that higher age and male sex were associated with a higher mortality risk, consistent with existing literature [18,19]. Long-term LEV usage remained a significant factor when these factors were adjusted for. The association between prolonged LEV use and longer survival was also observed in patients without a history of seizures and it was more pronounced in patients treated with LEV versus those treated with VPA. This suggests that the association between LEV and survival may not be solely attributable to its antiepileptic properties.

Several studies have investigated the survival benefits of LEV in patients with GBM. In 2015, a retrospective analysis of 103 patients with GBM revealed that 58 (56%) patients had been administered LEV for at least 3 months during their TMZ chemotherapy regimen [11]. Their cohort demonstrated significant increases in progression-free survival (PFS) by 2.7 months and in OS by 9 months. A subsequent 2020 study involved 322 patients with GBM diagnosed between 2004 and 2016, with all tumors surgically resected and pathologically confirmed as isocitrate dehydrogenase (IDH)-wild type [15]. The observed differences were 0.9 months in PFS and 3.6 months in OS. The prognostic factors identified included age, extent of resection, O6-methylguianine-DNA methyltransferase (MGMT) promoter methylation status, and Karnofsky performance status (KPS) score. The most recent study in 2022 analyzed a cohort of 460 patients with IDH-wild type GBM and evaluated the effect of LEV during standard chemoradiation [17]. Patients were categorized based on the duration of LEV treatment (full, partial, or none). A case-matched analysis of 54 patients per group indicated a significant survival advantage. Other prognostic factors, such as MGMT promoter methylation and extent of tumor resection, were also significant factors associated with survival.

However, not all studies reported positive outcomes. A comprehensive study including 1,263 patients with GBM aimed to determine the OS benefits of newer AEDs, including LEV, VPA, carbamazepine, oxcarbazepine, lamotrigine, and phenytoin [7]; no significant benefit was identified for any of the AEDs. Only 195 patients received LEV therapy, despite the large sample size. The study design was not planned to assess the effects of LEV on OS and lacked detailed data on LEV dosage and duration, inherently limiting the analysis of LEV efficacy in GBM treatment. In 2016, a study reported that neither VPA nor LEV provided survival benefits in patients newly diagnosed with GBM [18]. However, these studies have not sufficiently investigated the dose-dependent effects of LEV. In a survey of the members of the American Association of Neurological Surgeons and Congress of Neurological Surgeons in November 2015, only 13% of surgeons reported that the prescription of prophylactic postoperative AED was for longer than 6 weeks [19]. Therefore, it seems likely that patients included in previous studies may have been administered LEV for a short duration. Previous studies may have shown a survival benefit from LEV if many patients had been administered LEV for an extended duration.

Our study employed a large sample size to investigate this topic. We used the HIRA database, which encompasses the vast majority of data on patients with GBM in South Korea; therefore, our study can be considered a comprehensive, nationwide population-based study. Our study had a retrospective design and did not ascertain previously recognized prognostic markers, such as KPS, MGMT promoter methylation, and IDH mutation status; nevertheless, the likelihood of selection bias remains minimal owing to the unselected nature of our study population.

Several mechanisms have been proposed to explain the effect of LEV on the OS of patients with GBM. First, LEV may increase the sensitivity of GBM cells to TMZ. LEV is believed to increase the transcription of histone deacetylase 1, leading to the recruitment of the histone deacetylase 1/mSin3A complex. This affects the p53-binding site of the MGMT promoter, downregulating MGMT transcription and possibly enhancing TMZ’s antitumor activity [12-14,16]. Another theory focuses on chloride dynamics. Increased intracellular chloride concentrations have been linked with accelerated tumor progression. LEV’s effect on intracerebral gamma-aminobutyric acid (GABA) concentration and the GABA receptor is hypothesized to influence chloride equilibrium, subsequently aiding tumor progression control [20]. A third theory focuses on neuronal activity. The synaptic connection between presynaptic pyramidal neurons and postsynaptic glioma cells, which is mediated by glutamate, primarily through α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, may promote glioma progression. LEV has anti-AMPA effects; therefore, its long-term use might inhibit neurogliomal synapses and suppress tumor progression [21-23]. This study could not determine the most likely mechanism or provide insights into a new explanation for the OS-extending effects of LEV; nevertheless, scientific evidence has been accumulated over time, considering previous experimental and clinical research outcomes. This research serves as supplementary proof for such hypotheses.

This study has some limitations. The study could not evaluate essential prognostic markers, such as the KPS score, MGMT promoter methylation, and IDH mutation status. Because of the inability to measure KPS, we used alternative indicators, such as the length of hospital stay. Although IDH mutation status was considered after 2016, histologically confirmed GBM cases were still included in the study. It is reasonable to assume that a similar proportion of IDH-mutant grade 4 gliomas were included before and after 2016, as IDH-mutant gliomas were only excluded from the GBM classification after 2021. As LEV was primarily used after 2010, other factors related to the passage of time may have contributed to the improvement in survival rates. However, given that no other treatment methods besides the standard TMZ therapy have been shown to improve survival, the results of this study suggest that long-term LEV use may be a significant factor contributing to the observed differences in survival duration.

We excluded patients who were prescribed LEV for 30-60 days because patients who received LEV for less than 30 days were considered to have been routinely maintained for a short period after surgery, whereas those who received LEV for more than 60 days were considered to have been administered LEV during the CCRT period. Patients who received LEV for 30-60 days were likely to have discontinued treatment due to side effects and were excluded to eliminate ambiguity. Notably, a significant difference was also observed when patients were divided into two groups based on a 60-day cutoff (data not shown).

As this is a retrospective study, the possibility of selection bias cannot be eliminated. To minimize immortal time bias, we only included patients who survived for at least 90 days after surgery. However, this method is not entirely foolproof, and caution should be exercised when interpreting the results.

Furthermore, we discussed the potential mechanisms underlying the effects of LEV; however, we did not validate these mechanisms, and our comparison predominantly focused on VPA, excluding other AEDs. The nuances of LEV dosage and duration remain underexplored. Further prospective studies are required to gain a comprehensive understanding of this phenomenon.

NOTES

Ethical Statement

This study adhered to the ethical standards for studies involving human participants and was approved by the Ethical Committee of Ajou University Hospital (IRB code: AJOUIRB-EX-2022-314). All methodologies, data gathering, and analytical processes were thoroughly reviewed to safeguard the rights and well-being of the individuals involved in the study. The requirement for obtaining informed consent was waived by the IRB due to the retrospective nature of the study.

Author Contributions

Conceived and designed the analysis: Roh TH, Kim SH.

Collected the data: Lee E, Roh TH.

Contributed data or analysis tools: Lee E, Roh TH.

Performed the analysis: Lee E, Roh TH.

Wrote the paper: Lee Y.

Conflict of Interest

Conflict of interest relevant to this article was not reported.

Funding

This research was supported by a grant from the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (HR22C1734), and a National Research Foundation of Korea (NRF) grant funded by the Korean government (MSIT) (RS-2023-00253964).

Fig. 1.

Flow chart of patient selection. CCRT, concomitant chemoradiotherapy; HIRA, Health Insurance Review & Assessment Service; LEV, levetiracetam; TMZ, temozolomide.

Fig. 2.

Kaplan-Meier curves for the overall survival of the short- and long-term levetiracetam (LEV) groups (A), the short- and long-term LEV groups of patients without a history of seizures (B), the LEV and valproic acid (VPA) groups (C). LEV < 30, patients administered LEV for less than 30 days; LEV ≥ 60, patients administered LEV for 60 days or more; VPA ≥ 60, patients administered VPA for 60 days or more.

Table 1.

Baseline characteristics of selected population

	Total (n=2,971)	LEV (< 30) (n=1,319)	LEV (≥ 60) (n=1,652)	p-value
Follow-up (yr), median (range)	1.54 (0.98-2.93)	1.47 (0.94-2.76)	1.59 (1.03-3.02)	0.009
Male sex	1,683 (56.7)	762 (57.8)	921 (55.8)	0.270
Year of diagnosis
2007-2010	678 (22.8)	621 (47.1)	57 (3.5)	< 0.001
2011-2014	1,015 (34.2)	398 (30.2)	617 (37.4)
2015-2018	1,278 (43.0)	300 (22.7)	978 (59.2)
Age (yr), mean±SD	56.25±12.70	56.08±12.93	56.38±12.52	0.530
Time to CCRT from surgery (day), median (IQR)	25 (0-31)	25 (0-31)	25 (0-31)	0.600
Time to surgery from diagnosis (day), median (IQR)	2 (0-8)	2 (0-7)	3 (0-10)	< 0.001
LEV before surgery	591 (19.9)	112 (8.5)	479 (29.0)	< 0.001
History of seizure before surgery	817 (27.5)	284 (21.5)	533 (32.3)	< 0.001
AED prescription days for follow-up after surgery (day), median (IQR)
LEV	371 (150-695)	116 (26-344)	465 (265-822)	< 0.001
VPA	96 (22-275)	129.5 (40-332)	39 (10-141)
Other	119 (30-341)	145 (39-413)	89 (23-281)
length of stay for a hospitalization (day), median (IQR)
Tertiary hospital only	21.5 (12-60)	22 (13-61)	21 (12-58)	0.178
All hospital	35 (15-71)	37 (16-70)	35 (15-72)	0.715
First LEV dose after surgery (mg/day)
≤ 500	646 (33.1)	141(46.8)	505 (30.6)	< 0.001
500-1,000	1,085 (55.6)	113 (37.5)	972 (58.8)
1,000-1,500	121 (6.2)	30 (10.0)	91 (5.5)
1,500-2,000	85 (4.4)	15 (5.0)	70 (4.2)
> 2,000	16 (0.9)	2 (0.7)	14 (0.9)
No. of adjuvant TMZ cycles, mean±SD	4.77±1.69	4.67±1.71	4.84±1.68	0.010
No. of adjuvant temozolomide cycles
< 3	376 (14.6)	174 (15.6)	202 (13.9)	0.903
3-6	2,128 (82.9)	915 (81.8)	1,213 (83.7)
> 6	64 (2.5)	29 (2.6)	35 (2.4)

Values are presented as number (%) unless otherwise indicated. AED, antiepileptic drug; CCRT, concomitant chemoradiotherapy; IQR, interquartile; LEV, levetiracetam; SD, standard deviation; TMZ, temozolomide; VPA, valproic acid.

Table 2.

Comparison of overall survival between long-term vs. short-term LEV groups

	Kaplan-Meier estimates			Cox proportional hazard models
	Kaplan-Meier estimates			Univariable analysis		Multivariable analysis
	Death, n (%)	Median survival (95% CI, mo)	Log-rank p-value	Unadjusted HR (95% CI)	p-value	Adjusted HR (95% CI)	p-value
LEV (≥ 60)	1,408 (85.2)	19.06 (18.27-20.14)	0.005	0.81 (0.75-0.87)	< 0.001	0.89 (0.82-0.96)	0.002
LEV (< 30)	1,208 (91.6)	17.64 (16.69-18.79)		Ref		Ref
Age	-	-	-	1.02 (1.01-1.02)	< 0.001	1.02 (1.017-1.024)	< 0.001
Male sex	-	-	-	1.17 (0.97-1.40)	0.096	1.35 (1.25-1.46)	< 0.001
Female sex	-	-	-	Ref		Ref
History of seizure before surgery	-	-	-	0.93 (0.77-1.14)	0.488	0.997 (0.908-1.095)	0.956
No history of seizure	-	-	-	Ref		Ref
Length of stay	-	-	-	1.006 (1.005-1.008)	0.140	1.006 (1.004-1.007)	< 0.001
Time to surgery from diagnosis	-	-	-	1.004 (0.998-1.011)	0.203	1.001 (0.997-1.004)	0.738

CI, confidence interval; HR, hazard ratio; LEV, levetiracetam.

Table 3.

Comparison of overall survival in patients without seizure before surgery

	Kaplan-Meier estimates			Cox proportional hazard models
	Kaplan-Meier estimates			Univariable analysis		Multivariable analysis
	Death, n (%)	Median survival (95% CI, mo)	Log-rank p-value	Unadjusted HR (95% CI)	p-value	Adjusted HR (95% CI)	p-value
LEV (≥ 60)	958 (86.5)	19.71 (18.46-21.03)	0.009	0.89 (0.81-0.97)	0.009	0.87 (0.80-0.96)	0.003
LEV (< 30)	951 (91.9)	17.61 (16.59-18.79)		Ref		Ref
Age	-	-	-	1.02 (1.016-1.023)	< 0.001	1.02 (1.017-1.024)	< 0.001
Male sex	-	-	-	1.28 (1.17-1.40)	< 0.001	1.35 (1.23-1.48)	< 0.001
Female sex	-	-	-	Ref		Ref
Length of stay	-	-	-	1.005 (1.004-1.007)	< 0.001	1.006 (1.004-1.007)	< 0.001
Time to surgery from diagnosis	-	-	-	1.001 (0.996-1.007)	0.666	0.999 (0.994-1.004)	0.738

CI, confidence interval; HR, hazard ratio; LEV, levetiracetam.

Table 4.

Comparison of overall survival between LEV versus VPA groups

	Kaplan-Meier estimates			Cox proportional hazard models
	Kaplan-Meier estimates			Univariable analysis		Multivariable analysis
	Death, n (%)	Median survival (95% CI, mo)	Log-rank p-value	Unadjusted HR (95% CI)	p-value	Adjusted HR (95% CI)	p-value
LEV (≥ 60)	1,408 (85.2)	19.06 (18.27-20.14)	0.002	0.83 (0.74-0.94)	0.002	0.84 (0.74-0.95)	0.004
VPA (≥ 60)	335 (93.3)	16.53 (15.31-18.53)		Ref		Ref
Age	-	-	-	1.02 (1.016-1.024)	< 0.001	1.02 (1.017-1.025)	< 0.001
Male sex	-	-	-	1.21 (1.096-1.324)	< 0.001	1.26 (1.14-1.38)	< 0.001
Female sex	-	-	-	Ref		Ref
History of seizure before surgery	-	-	-	1.01 (0.91-1.13)	0.793	1.045 (0.93-1.17)	0.450
No history of seizure	-	-	-	Ref		Ref
Length of stay	-	-	-	1.005 (1.004-1.007)	< 0.001	1.005 (1.004-1.007)	< 0.001
Time to surgery from diagnosis	-	-	-	1.002 (0.998-1.006)	0.263	1.00 (0.996-1.004)	0.880

CI, confidence interval; HR, hazard ratio; LEV, levetiracetam; VPA, valproic acid.

REFERENCES

1. Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B, Taphoorn MJ, et al. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med. 2005;352:987–96. Article PubMed
2. Stupp R, Hegi ME, Mason WP, van den Bent MJ, Taphoorn MJ, Janzer RC, et al. Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phase III study: 5-year analysis of the EORTC-NCIC trial. Lancet Oncol. 2009;10:459–66. PubMed
3. Hegi ME, Diserens AC, Gorlia T, Hamou MF, de Tribolet N, Weller M, et al. MGMT gene silencing and benefit from temozolomide in glioblastoma. N Engl J Med. 2005;352:997–1003. Article PubMed
4. Jaeckle KA, Ballman K, Furth A, Buckner JC. Correlation of enzyme-inducing anticonvulsant use with outcome of patients with glioblastoma. Neurology. 2009;73:1207–13. Article PubMed PMC
5. Pallud J, Capelle L, Huberfeld G. Tumoral epileptogenicity: how does it happen? Epilepsia. 2013;54 Suppl 9:30–4. Article PubMed
6. Pallud J, Audureau E, Blonski M, Sanai N, Bauchet L, Fontaine D, et al. Epileptic seizures in diffuse low-grade gliomas in adults. Brain. 2014;137:449–62. PubMed
7. Knudsen-Baas KM, Engeland A, Gilhus NE, Storstein AM, Owe JF. Does the choice of antiepileptic drug affect survival in glioblastoma patients? J Neurooncol. 2016;129:461–9. Article PubMed PDF
8. Cardona AF, Rojas L, Wills B, Bernal L, Ruiz-Patino A, Arrieta O, et al. Efficacy and safety of Levetiracetam vs. other antiepileptic drugs in Hispanic patients with glioblastoma. J Neurooncol. 2018;136:363–71. Article PubMed PDF
9. Ryu JY, Min KL, Chang MJ. Effect of anti-epileptic drugs on the survival of patients with glioblastoma multiforme: a retrospective, single-center study. PLoS One. 2019;14:e0225599Article PubMed PMC
10. Huberfeld G, Vecht CJ. Seizures and gliomas: towards a single therapeutic approach. Nat Rev Neurol. 2016;12:204–16. Article PubMed PDF
11. Kim YH, Kim T, Joo JD, Han JH, Kim YJ, Kim IA, et al. Survival benefit of levetiracetam in patients treated with concomitant chemoradiotherapy and adjuvant chemotherapy with temozolomide for glioblastoma multiforme. Cancer. 2015;121:2926–32. Article PubMed PDF
12. Bobustuc GC, Baker CH, Limaye A, Jenkins WD, Pearl G, Avgeropoulos NG, et al. Levetiracetam enhances p53-mediated MGMT inhibition and sensitizes glioblastoma cells to temozolomide. Neuro Oncol. 2010;12:917–27. Article PubMed PMC
13. Marutani A, Nakamura M, Nishimura F, Nakazawa T, Matsuda R, Hironaka Y, et al. Tumor-inhibition effect of levetiracetam in combination with temozolomide in glioblastoma cells. Neurochem J. 2017;11:43–9. Article PDF
14. Scicchitano BM, Sorrentino S, Proietti G, Lama G, Dobrowolny G, Catizone A, et al. Levetiracetam enhances the temozolomide effect on glioblastoma stem cell proliferation and apoptosis. Cancer Cell Int. 2018;18:136.Article PubMed PMC PDF
15. Roh TH, Moon JH, Park HH, Kim EH, Hong CK, Kim SH, et al. Association between survival and levetiracetam use in glioblastoma patients treated with temozolomide chemoradiotherapy. Sci Rep. 2020;10:10783.Article PubMed PMC PDF
16. Ni XR, Guo CC, Yu YJ, Yu ZH, Cai HP, Wu WC, et al. Combination of levetiracetam and IFN-alpha increased temozolomide efficacy in MGMT-positive glioma. Cancer Chemother Pharmacol. 2020;86:773–82. Article PubMed PDF
17. Pallud J, Huberfeld G, Dezamis E, Peeters S, Moiraghi A, Gavaret M, et al. Effect of levetiracetam use duration on overall survival of isocitrate dehydrogenase wild-type glioblastoma in adults: an observational study. Neurology. 2022;98:e125–40. PubMed
18. Happold C, Gorlia T, Chinot O, Gilbert MR, Nabors LB, Wick W, et al. Does valproic acid or levetiracetam improve survival in glioblastoma? A pooled analysis of prospective clinical trials in newly diagnosed glioblastoma. J Clin Oncol. 2016;34:731–9. Article PubMed PMC
19. Dewan MC, Thompson RC, Kalkanis SN, Barker FG 2nd, Hadjipanayis CG. Prophylactic antiepileptic drug administration following brain tumor resection: results of a recent AANS/CNS Section on Tumors survey. J Neurosurg. 2017;126:1772–8. Article PubMed
20. Pallud J, Le Van Quyen M, Bielle F, Pellegrino C, Varlet P, Cresto N, et al. Cortical GABAergic excitation contributes to epileptic activities around human glioma. Sci Transl Med. 2014;6:244ra89.Article PubMed PMC
21. Venkatesh HS, Morishita W, Geraghty AC, Silverbush D, Gillespie SM, Arzt M, et al. Electrical and synaptic integration of glioma into neural circuits. Nature. 2019;573:539–45. Article PubMed PMC PDF
22. Venkataramani V, Tanev DI, Strahle C, Studier-Fischer A, Fankhauser L, Kessler T, et al. Glutamatergic synaptic input to glioma cells drives brain tumour progression. Nature. 2019;573:532–8. PubMed
23. Tantillo E, Vannini E, Cerri C, Spalletti C, Colistra A, Mazzanti CM, et al. Differential roles of pyramidal and fast-spiking, GABAergic neurons in the control of glioma cell proliferation. Neurobiol Dis. 2020;141:104942.Article PubMed

Figure & Data

REFERENCES

Citations

Citations to this article as recorded by

PubReader
ePub Link

Cite

CITE: export Copy Download Format; Close

Download Citation

Download a citation file in RIS format that can be imported by all major citation management software, including EndNote, ProCite, RefWorks, and Reference Manager.

Format:

RIS — For EndNote, ProCite, RefWorks, and most other reference management software
BibTeX — For JabRef, BibDesk, and other BibTeX-specific software

Include:

Citation for the content below
Citation and abstract for the content below

Association between Levetiracetam Use and Survival in Patients with Glioblastoma: A Nationwide Population-Based Study

Cancer Res Treat. 2025;57(2):369-377. Published online September 6, 2024

DOI: https://doi.org/10.4143/crt.2024.355

XML Download

Abstract
Introduction
Materials and Methods
Results
Discussion
NOTES
REFERENCES

Association between Levetiracetam Use and Survival in Patients with Glioblastoma: A Nationwide Population-Based Study

Fig. 1. Flow chart of patient selection. CCRT, concomitant chemoradiotherapy; HIRA, Health Insurance Review & Assessment Service; LEV, levetiracetam; TMZ, temozolomide.

Fig. 2. Kaplan-Meier curves for the overall survival of the short- and long-term levetiracetam (LEV) groups (A), the short- and long-term LEV groups of patients without a history of seizures (B), the LEV and valproic acid (VPA) groups (C). LEV < 30, patients administered LEV for less than 30 days; LEV ≥ 60, patients administered LEV for 60 days or more; VPA ≥ 60, patients administered VPA for 60 days or more.

Fig. 1.

Fig. 2.

Association between Levetiracetam Use and Survival in Patients with Glioblastoma: A Nationwide Population-Based Study

	Total (n=2,971)	LEV (< 30) (n=1,319)	LEV (≥ 60) (n=1,652)	p-value
Follow-up (yr), median (range)	1.54 (0.98-2.93)	1.47 (0.94-2.76)	1.59 (1.03-3.02)	0.009
Male sex	1,683 (56.7)	762 (57.8)	921 (55.8)	0.270
Year of diagnosis
2007-2010	678 (22.8)	621 (47.1)	57 (3.5)	< 0.001
2011-2014	1,015 (34.2)	398 (30.2)	617 (37.4)
2015-2018	1,278 (43.0)	300 (22.7)	978 (59.2)
Age (yr), mean±SD	56.25±12.70	56.08±12.93	56.38±12.52	0.530
Time to CCRT from surgery (day), median (IQR)	25 (0-31)	25 (0-31)	25 (0-31)	0.600
Time to surgery from diagnosis (day), median (IQR)	2 (0-8)	2 (0-7)	3 (0-10)	< 0.001
LEV before surgery	591 (19.9)	112 (8.5)	479 (29.0)	< 0.001
History of seizure before surgery	817 (27.5)	284 (21.5)	533 (32.3)	< 0.001
AED prescription days for follow-up after surgery (day), median (IQR)
LEV	371 (150-695)	116 (26-344)	465 (265-822)	< 0.001
VPA	96 (22-275)	129.5 (40-332)	39 (10-141)
Other	119 (30-341)	145 (39-413)	89 (23-281)
length of stay for a hospitalization (day), median (IQR)
Tertiary hospital only	21.5 (12-60)	22 (13-61)	21 (12-58)	0.178
All hospital	35 (15-71)	37 (16-70)	35 (15-72)	0.715
First LEV dose after surgery (mg/day)
≤ 500	646 (33.1)	141(46.8)	505 (30.6)	< 0.001
500-1,000	1,085 (55.6)	113 (37.5)	972 (58.8)
1,000-1,500	121 (6.2)	30 (10.0)	91 (5.5)
1,500-2,000	85 (4.4)	15 (5.0)	70 (4.2)
> 2,000	16 (0.9)	2 (0.7)	14 (0.9)
No. of adjuvant TMZ cycles, mean±SD	4.77±1.69	4.67±1.71	4.84±1.68	0.010
No. of adjuvant temozolomide cycles
< 3	376 (14.6)	174 (15.6)	202 (13.9)	0.903
3-6	2,128 (82.9)	915 (81.8)	1,213 (83.7)
> 6	64 (2.5)	29 (2.6)	35 (2.4)

	Kaplan-Meier estimates			Cox proportional hazard models
	Kaplan-Meier estimates			Univariable analysis		Multivariable analysis
	Death, n (%)	Median survival (95% CI, mo)	Log-rank p-value	Unadjusted HR (95% CI)	p-value	Adjusted HR (95% CI)	p-value
LEV (≥ 60)	1,408 (85.2)	19.06 (18.27-20.14)	0.005	0.81 (0.75-0.87)	< 0.001	0.89 (0.82-0.96)	0.002
LEV (< 30)	1,208 (91.6)	17.64 (16.69-18.79)		Ref		Ref
Age	-	-	-	1.02 (1.01-1.02)	< 0.001	1.02 (1.017-1.024)	< 0.001
Male sex	-	-	-	1.17 (0.97-1.40)	0.096	1.35 (1.25-1.46)	< 0.001
Female sex	-	-	-	Ref		Ref
History of seizure before surgery	-	-	-	0.93 (0.77-1.14)	0.488	0.997 (0.908-1.095)	0.956
No history of seizure	-	-	-	Ref		Ref
Length of stay	-	-	-	1.006 (1.005-1.008)	0.140	1.006 (1.004-1.007)	< 0.001
Time to surgery from diagnosis	-	-	-	1.004 (0.998-1.011)	0.203	1.001 (0.997-1.004)	0.738

	Kaplan-Meier estimates			Cox proportional hazard models
	Kaplan-Meier estimates			Univariable analysis		Multivariable analysis
	Death, n (%)	Median survival (95% CI, mo)	Log-rank p-value	Unadjusted HR (95% CI)	p-value	Adjusted HR (95% CI)	p-value
LEV (≥ 60)	958 (86.5)	19.71 (18.46-21.03)	0.009	0.89 (0.81-0.97)	0.009	0.87 (0.80-0.96)	0.003
LEV (< 30)	951 (91.9)	17.61 (16.59-18.79)		Ref		Ref
Age	-	-	-	1.02 (1.016-1.023)	< 0.001	1.02 (1.017-1.024)	< 0.001
Male sex	-	-	-	1.28 (1.17-1.40)	< 0.001	1.35 (1.23-1.48)	< 0.001
Female sex	-	-	-	Ref		Ref
Length of stay	-	-	-	1.005 (1.004-1.007)	< 0.001	1.006 (1.004-1.007)	< 0.001
Time to surgery from diagnosis	-	-	-	1.001 (0.996-1.007)	0.666	0.999 (0.994-1.004)	0.738

	Kaplan-Meier estimates			Cox proportional hazard models
	Kaplan-Meier estimates			Univariable analysis		Multivariable analysis
	Death, n (%)	Median survival (95% CI, mo)	Log-rank p-value	Unadjusted HR (95% CI)	p-value	Adjusted HR (95% CI)	p-value
LEV (≥ 60)	1,408 (85.2)	19.06 (18.27-20.14)	0.002	0.83 (0.74-0.94)	0.002	0.84 (0.74-0.95)	0.004
VPA (≥ 60)	335 (93.3)	16.53 (15.31-18.53)		Ref		Ref
Age	-	-	-	1.02 (1.016-1.024)	< 0.001	1.02 (1.017-1.025)	< 0.001
Male sex	-	-	-	1.21 (1.096-1.324)	< 0.001	1.26 (1.14-1.38)	< 0.001
Female sex	-	-	-	Ref		Ref
History of seizure before surgery	-	-	-	1.01 (0.91-1.13)	0.793	1.045 (0.93-1.17)	0.450
No history of seizure	-	-	-	Ref		Ref
Length of stay	-	-	-	1.005 (1.004-1.007)	< 0.001	1.005 (1.004-1.007)	< 0.001
Time to surgery from diagnosis	-	-	-	1.002 (0.998-1.006)	0.263	1.00 (0.996-1.004)	0.880

Table 1. Baseline characteristics of selected population

Table 2. Comparison of overall survival between long-term vs. short-term LEV groups

CI, confidence interval; HR, hazard ratio; LEV, levetiracetam.

Table 3. Comparison of overall survival in patients without seizure before surgery

CI, confidence interval; HR, hazard ratio; LEV, levetiracetam.

Table 4. Comparison of overall survival between LEV versus VPA groups

CI, confidence interval; HR, hazard ratio; LEV, levetiracetam; VPA, valproic acid.