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Abstract

Background

Tumor-related epilepsy (TRE) is common in patients with low-grade oligodendrogliomas. TRE is difficult to control despite multiple antiepileptic drugs (AEDs) in up to 30% of patients. Chemotherapy has been used for treatment to avoid potential radiotherapy-related neurotoxicity. This study evaluates the effect of temozolomide on seizure frequency in a homogeneous group with World Health Organization (WHO) grade II oligodendrogliomas.

Methods

A retrospective analysis was conducted of adult patients with WHO grade II oligodendrogliomas and TRE followed at Memorial Sloan Kettering between 2005 and 2015 who were treated with temozolomide alone either as initial treatment or for disease progression. All had seizures 3 months prior to starting temozolomide. Seizure frequency was reviewed every 2 cycles and at the end of temozolomide treatment. Seizure reduction of ≥50% compared to baseline was defined as improvement.

Results

Thirty-nine individuals met inclusion criteria. Median follow-up since starting temozolomide was 6 years (0.8-13 years). Reduction in seizure frequency occurred in 35 patients (89.7%). Improvement was independent of AED regimen adjustments or prior antitumor treatment in 16 (41%); of these, AED dosage was successfully reduced or completely eliminated in 10 (25.6%). Twenty-five patients (64.1%) remained on a stable AED regimen. The majority (n = 32, 82%) had radiographically stable disease, 5 (12.8%) had objective radiographic response, and 2 (5.2%) had disease progression.

Conclusions

Temozolomide may result in reduced seizure frequency, and permit discontinuation of AEDs in patients with WHO II oligodendroglioma. Improvement was observed irrespective of objective tumor response on MRI, emphasizing the importance of incorporating seizure control in assessing response to tumor-directed therapy.

oligodendroglioma, response, seizures, temozolomide

Tumor-related epilepsy (TRE) is common in patients with low-grade glioma (LGG), occurring in up to 90% of patients depending on histopathological type.1 Among LGGs, seizures are more frequent in patients with oligodendrogliomas.2 In many cases, seizures are difficult to control despite multiple antiepileptic drugs (AEDs) and have a negative effect on quality of life in this population of young adults.1,3,4 Therefore, good seizure control is essential in improving clinical outcome. Furthermore, reduction in seizure frequency has been shown to be an independent prognostic factor for survival in patients with LGGs and may be a surrogate marker to assess the benefit of tumor-directed therapy.5,6

Treatment with surgery or radiotherapy reduces seizure frequency in LGGs.2,7–10 The antiseizure efficacy of chemotherapy alone with procarbazine, lomustine, and vincristine (PCV), or temozolomide, has been observed in a few prospective and retrospective studies in a subset of patients with LGGs.11–14 However, these studies included a mixture of patients with oligodendroglial and astrocytic tumors, further complicating their interpretation.

The aim of this study is to expand on the results of the few existing reports in the literature looking at the course of TRE after temozolomide chemotherapy by analyzing seizure response in a homogeneous group of adult patients with World Health Organization (WHO) grade II oligodendrogliomas. We focused on oligodendrogliomas because of their unique chemosensitivity and, therefore, possibly greater potential for TRE to respond to temozolomide.

Methods

Data Collection and Assessment of Seizure Outcome

We performed a retrospective study of adult patients with a histopathological diagnosis of supratentorial WHO grade II oligodendrogliomas who were treated at Memorial Sloan Kettering Cancer Center (MSKCC) between 2005 and 2015. Patients were identified through our institutional database and were included if they met the following criteria: (1) presence of at least 1 seizure while on AED within 3 months prior to starting temozolomide, (2) available data on seizure frequency at each clinic visit and after treatment completion, (3) no other tumor-directed therapy during temozolomide treatment.

Medical records were reviewed to determine patient characteristics, prior treatment, extent of surgical resection, indication for temozolomide chemotherapy, length of follow-up, loss of the heterozygosity of chromosomes 1p and 19q, isocitrate dehydrogenase (IDH) mutation status, and seizure history. Temozolomide treatment cycles, changes in seizure frequency, AED regimen, and radiographic response as interpreted by neuro-radiology and the treating neuro-oncologist were assessed at each follow-up visit by reviewing clinical notes and radiographic reports based on response criteria used at the time. The follow-up visits were scheduled every 8 weeks in most cases unless there was a clinical change prompting an earlier visit. Improvement in seizure control was defined as a reduction in seizure frequency by 50% or greater compared with baseline assessed at each clinic visit and after treatment completion. This retrospective study was approved by the MSKCC Institutional Review Board.

Results

Patient Characteristics and Tumor Management

We identified 39 patients who met our inclusion criteria (Table 1). Median age at tumor diagnosis was 41 years (range 22-62 years). The median length of follow-up was 9 years (range 2-25 years). The most frequent tumor location was the frontal lobe in 25 patients (64.1%) (Table 2). Thirty-four tumors (87.2%) had chromosome 1p and 19q codeletion; the status was unknown for 5 tumors. IDH gene mutation status was available for 19 tumors (48.7%), all of which had mutations.

Table 1
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Patient Characteristics

All Patients (n = 39)
Median Age at Diagnosis, Years (Range)41 (22-62)
Median Length of Follow-Up, Years (Range)9 (2-25)
Gender, n (%)
 Male24 (61.5)
 Female15 (38.5)
Extent of Surgery, n (%)
 Gross total resection18 (46.2)
 Subtotal resection10 (25.6)
 Biopsy11 (28.2)
Prior Tumor-Directed Therapy, n (%)
 Radiotherapya6 (15.3)
 PCV chemotherapya3 (7.6)
 None30 (76.9%)
All Patients (n = 39)
Median Age at Diagnosis, Years (Range)41 (22-62)
Median Length of Follow-Up, Years (Range)9 (2-25)
Gender, n (%)
 Male24 (61.5)
 Female15 (38.5)
Extent of Surgery, n (%)
 Gross total resection18 (46.2)
 Subtotal resection10 (25.6)
 Biopsy11 (28.2)
Prior Tumor-Directed Therapy, n (%)
 Radiotherapya6 (15.3)
 PCV chemotherapya3 (7.6)
 None30 (76.9%)

Abbreviations: PCV, procarbazine, lomustine, and vincristine.

aOne patient received radiotherapy and PCV.

Table 1
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Patient Characteristics

All Patients (n = 39)
Median Age at Diagnosis, Years (Range)41 (22-62)
Median Length of Follow-Up, Years (Range)9 (2-25)
Gender, n (%)
 Male24 (61.5)
 Female15 (38.5)
Extent of Surgery, n (%)
 Gross total resection18 (46.2)
 Subtotal resection10 (25.6)
 Biopsy11 (28.2)
Prior Tumor-Directed Therapy, n (%)
 Radiotherapya6 (15.3)
 PCV chemotherapya3 (7.6)
 None30 (76.9%)
All Patients (n = 39)
Median Age at Diagnosis, Years (Range)41 (22-62)
Median Length of Follow-Up, Years (Range)9 (2-25)
Gender, n (%)
 Male24 (61.5)
 Female15 (38.5)
Extent of Surgery, n (%)
 Gross total resection18 (46.2)
 Subtotal resection10 (25.6)
 Biopsy11 (28.2)
Prior Tumor-Directed Therapy, n (%)
 Radiotherapya6 (15.3)
 PCV chemotherapya3 (7.6)
 None30 (76.9%)

Abbreviations: PCV, procarbazine, lomustine, and vincristine.

aOne patient received radiotherapy and PCV.

Table 2
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Tumor Characteristics

All patients (n = 39)
N (%)
Tumor Type
 Oligodendroglioma39 (100)
1p/19q codeletion
 1p/19q codeleted34 (87.2)
 Unknown5 (12.8)
IDH1/2 mutation status
 IDH1/2 mutant19 (48.7)
 Unknown20 (51.3)
Tumor Location
 Frontal25 (64.1)
 Temporal6 (15.3)
 Parietal4 (10.2)
 Occipital2 (5.2)
 Basal ganglia1 (2.6)
 Diffuse hemispheric1 (2.6)
All patients (n = 39)
N (%)
Tumor Type
 Oligodendroglioma39 (100)
1p/19q codeletion
 1p/19q codeleted34 (87.2)
 Unknown5 (12.8)
IDH1/2 mutation status
 IDH1/2 mutant19 (48.7)
 Unknown20 (51.3)
Tumor Location
 Frontal25 (64.1)
 Temporal6 (15.3)
 Parietal4 (10.2)
 Occipital2 (5.2)
 Basal ganglia1 (2.6)
 Diffuse hemispheric1 (2.6)

Abbreviation: IDH1/2, isocitrate dehydrogenase gene.

Table 2
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Tumor Characteristics

All patients (n = 39)
N (%)
Tumor Type
 Oligodendroglioma39 (100)
1p/19q codeletion
 1p/19q codeleted34 (87.2)
 Unknown5 (12.8)
IDH1/2 mutation status
 IDH1/2 mutant19 (48.7)
 Unknown20 (51.3)
Tumor Location
 Frontal25 (64.1)
 Temporal6 (15.3)
 Parietal4 (10.2)
 Occipital2 (5.2)
 Basal ganglia1 (2.6)
 Diffuse hemispheric1 (2.6)
All patients (n = 39)
N (%)
Tumor Type
 Oligodendroglioma39 (100)
1p/19q codeletion
 1p/19q codeleted34 (87.2)
 Unknown5 (12.8)
IDH1/2 mutation status
 IDH1/2 mutant19 (48.7)
 Unknown20 (51.3)
Tumor Location
 Frontal25 (64.1)
 Temporal6 (15.3)
 Parietal4 (10.2)
 Occipital2 (5.2)
 Basal ganglia1 (2.6)
 Diffuse hemispheric1 (2.6)

Abbreviation: IDH1/2, isocitrate dehydrogenase gene.

All patients underwent surgery: gross total resection in 18 patients (46.2%), biopsy in 11 (28.2%), and subtotal resection in 10 (25.6%). The median time from initial surgery to starting temozolomide was 3 years (range 0-17 years). Thirty patients (76.9%) had not received any tumor-directed therapy prior to temozolomide. Six patients (15.3%) had received prior radiotherapy, and the median time between radiotherapy and the start of temozolomide was 4 years (range 0.25-12 years); 1 of these patients started temozolomide 3 months after radiotherapy because of disease progression. Three patients (7.7%) had received PCV a median of 9 years (range 2-10 years) prior to starting temozolomide. None of the patients in this cohort received steroids during the temozolomide treatment period.

Temozolomide was started in 21 patients (53.8%) because of clinical and radiographic progression; 7 patients (18%) had radiographic progression only, and 11 patients (28.2%) were considered high risk after initial surgery because of extensive persistent tumor. Increase in seizure frequency was the presenting symptom in all patients who had clinical progression. Of the 28 patients who progressed, 5 patients (12.8%) had a second surgery; 3 were subtotal resections and 2 were biopsies; histology remained low-grade oligodendroglioma and all tumors were 1p and 19q codeleted and IDH mutant.

Median follow-up since starting temozolomide was 6 years (range 0.8-13 years). Median number of temozolomide cycles was 12 (range 2-24 cycles). Temozolomide had to be discontinued because of tumor progression in 2 patients (5.2%). Nineteen patients (48.7%) had further disease progression posttemozolomide treatment. Median time to progression from temozolomide was 3 years (0.3-8 years). Increase in seizure frequency was an indicator of disease progression in 16/21 patients (76.2%). Fifteen patients (38.4%) had another resection after disease progression; histology showed malignant transformation in 8 patients (20.5%). The 1p and 19q codeletion and IDH mutation status was available for 13/15 (86.7%) and 5/15 (33.3%) tumors, respectively, all of which were codeleted and mutated. Eleven of 21 patients (52.3%) were rechallenged with temozolomide at disease progression, 8 of whom received concurrent radiotherapy.

Seizure Characteristics

With 1 exception, all patients had simple or complex partial seizures; 1 patient had only generalized seizures (Table 3). Three patients (7.6%) had other neurologic symptoms including language and cognitive difficulties.

Table 3
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Seizure Characteristics

All patients (n = 39)
N (%)
Seizure Type
 Simple partial7 (18)
 Complex partial10 (25.6)
 Simple and complex partial7 (18)
 Partial and generalized14 (35.8)
 Generalized1 (2.6)
Seizure Frequency
 Daily9 (23)
 ≥1 per week12 (30.8)
 <1 per week18 (46.2)
AED Regimen Changes Within 3 Months Prior to Starting Temozolomide
 New AED10 (25.6)
 Dosage increase14 (35.9)
 Multiple changes5 (12.8)
AED Polytherapy21 (54)
All patients (n = 39)
N (%)
Seizure Type
 Simple partial7 (18)
 Complex partial10 (25.6)
 Simple and complex partial7 (18)
 Partial and generalized14 (35.8)
 Generalized1 (2.6)
Seizure Frequency
 Daily9 (23)
 ≥1 per week12 (30.8)
 <1 per week18 (46.2)
AED Regimen Changes Within 3 Months Prior to Starting Temozolomide
 New AED10 (25.6)
 Dosage increase14 (35.9)
 Multiple changes5 (12.8)
AED Polytherapy21 (54)

Abbreviation: AED, antiepileptic drug.

Table 3
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Seizure Characteristics

All patients (n = 39)
N (%)
Seizure Type
 Simple partial7 (18)
 Complex partial10 (25.6)
 Simple and complex partial7 (18)
 Partial and generalized14 (35.8)
 Generalized1 (2.6)
Seizure Frequency
 Daily9 (23)
 ≥1 per week12 (30.8)
 <1 per week18 (46.2)
AED Regimen Changes Within 3 Months Prior to Starting Temozolomide
 New AED10 (25.6)
 Dosage increase14 (35.9)
 Multiple changes5 (12.8)
AED Polytherapy21 (54)
All patients (n = 39)
N (%)
Seizure Type
 Simple partial7 (18)
 Complex partial10 (25.6)
 Simple and complex partial7 (18)
 Partial and generalized14 (35.8)
 Generalized1 (2.6)
Seizure Frequency
 Daily9 (23)
 ≥1 per week12 (30.8)
 <1 per week18 (46.2)
AED Regimen Changes Within 3 Months Prior to Starting Temozolomide
 New AED10 (25.6)
 Dosage increase14 (35.9)
 Multiple changes5 (12.8)
AED Polytherapy21 (54)

Abbreviation: AED, antiepileptic drug.

All patients were on AEDs prior to starting temozolomide; 21 patients (54%) were on multiple AEDs. Most commonly used AEDs either as monotherapy or in combination were levetiracetam (n = 26, 66.6%), phenytoin (n = 9, 23%), lamotrigine (n = 8, 20.5%), carbamazepine (n = 5, 12.8%), oxcarbazepine (n = 5, 12.8%), phenobarbital (n = 4, 10.2%), lacosamide (n = 4, 10.2%), zonisamide (n = 4, 10.2%), clonazepam (n = 3, 7.6%), valproic acid (n = 3, 7.6%), gabapentin (n = 1, 2.6%), clobazam (n = 1, 2.6%), and topiramate (n = 1, 2.6%).

Prior to temozolomide, 9 patients (23%) reported daily seizures and 12 (30.8%) reported more than 1 seizure per week. The AED regimen was changed in 29 patients (74.3%) within 3 months prior to temozolomide treatment. A new AED was added in 10 patients (25.6%), 14 (35.9%) had an increase in AED dosage, and 5 (12.8%) required multiple changes. Fifteen of these patients (38.5%) had no improvement in seizure frequency despite AED adjustments and 14 (35.8%) had improvement.

Seizure Outcome

A reduction in seizure frequency of 50% of baseline or greater was noted in 35 patients (89.7%); 4 patients had no improvement (Table 4). Seventeen patients (43.6%) had improvement as the AED regimen was adjusted during temozolomide treatment. Two patients (5.2%) had improvement after a second surgical resection of the tumor prior to starting temozolomide.

Table 4
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Seizure Outcome

All Patients (n = 39)
No. (%)
No improvement4 (10.2)
Improvement
 Possibly due to AED regimen adjustmenta17 (43.6)
 Due to prior surgery2 (5.2)
 Independent of AED and prior antitumor treatment16 (41)
All Patients (n = 39)
No. (%)
No improvement4 (10.2)
Improvement
 Possibly due to AED regimen adjustmenta17 (43.6)
 Due to prior surgery2 (5.2)
 Independent of AED and prior antitumor treatment16 (41)

Abbreviation: AED, antiepileptic drug.

aImprovement in seizure frequency noted as AED regimen adjustments made during temozolomide treatment.

Table 4
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Seizure Outcome

All Patients (n = 39)
No. (%)
No improvement4 (10.2)
Improvement
 Possibly due to AED regimen adjustmenta17 (43.6)
 Due to prior surgery2 (5.2)
 Independent of AED and prior antitumor treatment16 (41)
All Patients (n = 39)
No. (%)
No improvement4 (10.2)
Improvement
 Possibly due to AED regimen adjustmenta17 (43.6)
 Due to prior surgery2 (5.2)
 Independent of AED and prior antitumor treatment16 (41)

Abbreviation: AED, antiepileptic drug.

aImprovement in seizure frequency noted as AED regimen adjustments made during temozolomide treatment.

An improvement independent of AED regimen changes or prior antitumor treatment was observed in 16 patients (41%); of these the AED dosage was successfully reduced or completely eliminated in 10 patients (25.6%) at the end of temozolomide treatment. Seizure response was noted after a minimum of 4 cycles of temozolomide. Twenty-five patients (64.1%) remained on a stable AED regimen.

Objective radiographic response at time of temozolomide treatment completion was observed in 5 patients (12.8%), all of whom had seizure reduction that was independent of AED regimen modification or prior antitumor treatment (4 patients). The majority of patients (n = 32, 82%) had radiographically stable disease; of these, 30 patients had improvement. Two patients (5.2%) had radiographic tumor progression during temozolomide treatment presenting clinically with increased seizure frequency.

Discussion

Oligodendrogliomas have a higher frequency of seizures than any other glioma subtype. This may be a consequence of their molecular properties.2 Mutant IDH reduces α-ketoglutarate to 2-hydroxyglutarate (2-HG), which is structurally similar to the excitatory neurotransmitter glutamate and may explain the increased seizure frequency in IDH-mutated tumors.15–17 Oligodendroglial tumor diagnosis now requires the presence of both IDH mutation and 1p/19q codeletion according to the 2016 WHO classification and all of our tested tumors were 1p/19q codeleted or IDH mutated. Older specimens had not been subjected to molecular analysis, but we included them here because of their classic oligodendroglial histology.18

Thirty percent of patients with TRE due to LGGs have uncontrolled seizures despite AED polytherapy.2,3 As such, health-related quality of life outcome in this generally young population can be significantly compromised by uncontrolled seizures. In addition, AEDs have a negative impact on patients’ self-reported quality of life and were found to be strongly associated with cognitive impairment.3,19 Reduction in seizure frequency has recently been suggested to be an independent prognostic marker for survival in patients with LGGs.6 These reasons all contribute to the growing recognition that seizure control may be an important clinical metric.5

Tumor-directed therapy has been shown to reduce seizure frequency in LGGs. Maximal surgical resection significantly reduces seizure frequency in up to 80% of patients.2,20 However, LGGs are frequently infiltrative and complete resection is often impossible. Radiotherapy using different modalities including conventional external radiotherapy, interstitial brachytherapy, and stereotactic radiosurgery can also improve seizure control in 25% to 75% of patients.10,21–23 In all of these studies, patients had either astrocytic or oligodendroglial tumors and in some studies the role of AEDs was not considered. Many patients with 1p/19q codeleted oligodendrogliomas receive chemotherapy alone when postoperative treatment is indicated to defer possible radiotherapy-related neurotoxicity for as long as possible. This is in part because oligodendrogliomas are more chemosensitive than other LGGs.11,24–26 The long-term outcome of this approach is not well understood as yet, although recent data support the use of radiotherapy and chemotherapy over radiotherapy alone.26

Emerging data in the literature suggest that chemotherapy alone using PCV or temozolomide may improve seizure control.27 Temozolomide is more frequently used because of its favorable toxicity profile and ease of administration compared to PCV. A recent systematic review of previously published studies evaluating the effect of chemotherapy on seizure frequency showed that most studies found a favorable seizure response to chemotherapy.27

Four previous studies evaluated the effect of temozolomide on seizure frequency defining a seizure reduction of 50% or greater as improvement similar to our study (Table 5). Seizure frequency was assessed as a secondary aim in a prospective study of 43 patients with progressive LGGs who received temozolomide. Only 4 patients had pure oligodendroglioma. Seizure response was noted in 15/31 patients (48%) with previously uncontrolled seizures. The clinical benefit was significantly higher in those with nonenhancing disease.13 A second prospective study evaluated 30 patients with recurrent LGGs; 18 (60%) had oligodendroglioma. Thirteen patients had intractable seizures and 8 (62%) improved although the pathologic subtype and prior resection, if any, of the 8 patients with seizure response was not reported.28

Table 5
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Summary Table of Studies Included in the Discussion Section

Authors Study DesignNo. of PatientsOligodendroglioma
N (%)		Seizure Response
N (%)		Prior Treatment
Type (N)		Median No. of Temozolomide Cycles (Range)Radiographic Response (N)
Pace et al, 200313Prospective434 (9.3)15/31 (48)Resection (32)
RT (30)
PCV (16)		10 (3-22)CR = 4
PR = 16
SD = 17
PD = 6
Tosoni et al, 200828Prospective3018 (60)8/13 (62)Resection (20)12aPR = 9
SD = 17
PD = 4
Koekkoek et al, 201527Retrospective10424 (23.1%)b29/66 (44)Resection (66)
RT (46)		Assessment at 6 monthsPR = 14
MR = 43
SD = 54
PD = 40
Sherman et al, 201114Retrospective3920 (56%)23/39 (59)Resection (24)7 (range N/S)N/S
Authors Study DesignNo. of PatientsOligodendroglioma
N (%)		Seizure Response
N (%)		Prior Treatment
Type (N)		Median No. of Temozolomide Cycles (Range)Radiographic Response (N)
Pace et al, 200313Prospective434 (9.3)15/31 (48)Resection (32)
RT (30)
PCV (16)		10 (3-22)CR = 4
PR = 16
SD = 17
PD = 6
Tosoni et al, 200828Prospective3018 (60)8/13 (62)Resection (20)12aPR = 9
SD = 17
PD = 4
Koekkoek et al, 201527Retrospective10424 (23.1%)b29/66 (44)Resection (66)
RT (46)		Assessment at 6 monthsPR = 14
MR = 43
SD = 54
PD = 40
Sherman et al, 201114Retrospective3920 (56%)23/39 (59)Resection (24)7 (range N/S)N/S

Abbreviations: CR, complete response; MR, minor response; N/S, not specified; PCV, procarbazine, lomustine, and vincristine; PD, progressive disease; PR, partial response; RT, radiotherapy; SD, stable disease.

aAll patients received 12 cycles.

bThere were a total of 14 patients (21%) with oligodendroglioma out of the 66 patients with intractable seizures.

Table 5
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Summary Table of Studies Included in the Discussion Section

Authors Study DesignNo. of PatientsOligodendroglioma
N (%)		Seizure Response
N (%)		Prior Treatment
Type (N)		Median No. of Temozolomide Cycles (Range)Radiographic Response (N)
Pace et al, 200313Prospective434 (9.3)15/31 (48)Resection (32)
RT (30)
PCV (16)		10 (3-22)CR = 4
PR = 16
SD = 17
PD = 6
Tosoni et al, 200828Prospective3018 (60)8/13 (62)Resection (20)12aPR = 9
SD = 17
PD = 4
Koekkoek et al, 201527Retrospective10424 (23.1%)b29/66 (44)Resection (66)
RT (46)		Assessment at 6 monthsPR = 14
MR = 43
SD = 54
PD = 40
Sherman et al, 201114Retrospective3920 (56%)23/39 (59)Resection (24)7 (range N/S)N/S
Authors Study DesignNo. of PatientsOligodendroglioma
N (%)		Seizure Response
N (%)		Prior Treatment
Type (N)		Median No. of Temozolomide Cycles (Range)Radiographic Response (N)
Pace et al, 200313Prospective434 (9.3)15/31 (48)Resection (32)
RT (30)
PCV (16)		10 (3-22)CR = 4
PR = 16
SD = 17
PD = 6
Tosoni et al, 200828Prospective3018 (60)8/13 (62)Resection (20)12aPR = 9
SD = 17
PD = 4
Koekkoek et al, 201527Retrospective10424 (23.1%)b29/66 (44)Resection (66)
RT (46)		Assessment at 6 monthsPR = 14
MR = 43
SD = 54
PD = 40
Sherman et al, 201114Retrospective3920 (56%)23/39 (59)Resection (24)7 (range N/S)N/S

Abbreviations: CR, complete response; MR, minor response; N/S, not specified; PCV, procarbazine, lomustine, and vincristine; PD, progressive disease; PR, partial response; RT, radiotherapy; SD, stable disease.

aAll patients received 12 cycles.

bThere were a total of 14 patients (21%) with oligodendroglioma out of the 66 patients with intractable seizures.

Two additional studies were retrospective in nature. A seizure response was noted in 29/66 patients (44%) after 6 months of temozolomide treatment while on a stable AED dosage regimen. Fourteen of 66 patients (21%) had oligodendroglioma. A confounding factor in this study is that prior surgical resection (37/66 [56%]) and radiotherapy (46/66 [70%]) were given to a high proportion of patients before temozolomide was started.12

Sixty-nine patients with LGGs were followed for seizure response in 39 patients after temozolomide compared to 30 patients who were under observation alone. Twenty patients (56%) in the temozolomide group and only 9 patients (30%) in the control group had pure oligodendroglioma. In the temozolomide cohort, 12 patients (31%) had no further seizures after initial presentation compared to 14 patients in the control group (47%); a response independent of AEDs was observed in 18% and 0%, respectively. However, patients were heavily selected for treatment or observation, compromising a direct comparison.14

This is the first study analyzing the effect of temozolomide on seizure control in a homogeneous group of patients with only confirmed WHO grade II oligodendroglioma, as these patients have a higher incidence of seizures and longer survival rates compared with other LGGs. The results confirm and expand on the existing knowledge that temozolomide produced a notable reduction of seizure frequency in a high proportion of patients 16/39 (41%), independent of AED regimen adjustments or prior antitumor treatment. This improvement was observed after a minimum of 4 cycles.

Furthermore, reduction of AED dosage or complete elimination was successful in 10/39 (25.6%) patients at the end of temozolomide treatment. This is important in reducing drug toxicity and improving cognitive outcome. In our cohort, seizure improvement was observed in patients irrespective of objective tumor response on MRI. This finding was reported in previous studies and further emphasizes the discordance between clinical benefit and radiographic response. It highlights the importance of seizure reduction as an indicator of response to antitumor therapy although we do not know whether seizure reduction alone translates to longer progression-free survival or overall survival.14,21,23,25,29–31

There are several limitations to our study. First, retrospective counting of seizures is not always accurate. Second, there was patient selection bias as we included only those who had detailed follow-up data. Third, temozolomide was not always the initial antineoplastic treatment in this cohort. However, we looked carefully at any improvement that was potentially related to AED regimen changes, prior surgery, or prior antineoplastic therapies. Thus, this study strongly suggests that temozolomide improves seizure control in adult patients with WHO grade II oligodendroglioma. This study further highlights the need to incorporate standardized measures of seizure control in future prospective studies of any therapeutic treatment for LGGs.

Funding

This work was supported by a grant from the National Institutes of Health [P30-CA008748].

Conflict of interest statement. None declared.

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